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Abstracts

Green Tea: 292 Research Abstracts

101. Mol Cell Biochem. 2002 Jul;236(1-2):173-81.

Protective effect of green tea extract against the erythrocytic oxidative stress injury during mycobacterium tuberculosis infection in mice.

Guleria RS, Jain A, Tiwari V, Misra MK.

Department of Microbiology, K. G's. Medical College, Lucknow, UP, India.

The present study has been undertaken to monitor the extent of oxidative stress in mice infected with M tuberculosis and the role of crude green tea extract in repairing the oxidative damage. The mice were divided into three groups of 9 each; normal, infected-untreated and infected-treated. The infected group of animals exhibited significant enhancement of erythrocytic catalase and glutathione peroxidase activities along with elevated levels of erythrocytic total thiols and plasma lipid peroxidation as compared to normal animals. The infected group also exhibited significantly decreased activity of superoxide dismutase and levels of glutathione in erythrocytes. Upon oral administration of green tea extract for seven days the oxidative stress parameters were reverted back to near normal levels as evidenced by a fall in catalase, glutathione peroxidase, total thiol and extent of lipid peroxidation with concomitant increase in the levels of SOD and reduced glutathione in infected animals. The findings thus, portray that there is a high oxidative stress during early stages of tuberculosis and antioxidants such as green tea extract, can play a vital role by reducing stress through adjuvant therapy.

102. Redox Rep. 2002;7(3):171-7.

Protective effects of green tea polyphenols and their major component, (-)-epigallocatechin-3-gallate (EGCG), on 6-hydroxydopamine-induced apoptosis in PC12 cells.

Nie G, Cao Y, Zhao B.

Laboratory of Visual Information Processing, Department of Molecular and Cell Biophysics, Institute of Biophysics, Academia Sinica, 15 Datun Road, Chaoyang District, Beijing 100101, P.R. China.

Green tea polyphenols exert a wide range of biochemical and pharmacological effects, and have been shown to possess antimutagenic and anticarcinogenic properties. Oxidative stress is involved in the pathogenesis of Parkinson's disease. However, although green tea polyphenols may be expected to inhibit the progression of Parkinson's disease on the basis of their known antioxidant activity, this has not previously been established. In the present study, we evaluated the neuroprotective effects of green tea polyphenols in the Parkinson's disease pathological cell model. The results show that the natural antioxidants have significant inhibitory effects against apoptosis induced by oxidative stress. 6-Hydroxydopamine (6-OHDA)-induced apoptosis in catecholaminergic PC12 cells was chosen as the in vitro model of Parkinson's disease in our study. Apoptotic characteristics of PC12 cells were assessed by MTT assay, flow cytometry, fluorescence microscopy and DNA fragmentation. Green tea polyphenols and their major component, EGCG at a concentration of 200 microM, exert significant protective effects against 6-OHDA-induced PC12 cell apoptosis. EGCG is more effective than the mixture of green tea polyphenols. The antioxidant function of green tea polyphenols may account for this neuroprotective effect. The present study supports the notion that green tea polyphenols have the potential to be effective as neuropreventive agents for the treatment of neurodegenerative diseases.

103. Br J Cancer. 2002 Jul 29;87(3):309-13.

A prospective study of stomach cancer death in relation to green tea consumption in Japan.

Hoshiyama Y, Kawaguchi T, Miura Y, Mizoue T, Tokui N, Yatsuya H, Sakata K, Kondo T, Kikuchi S, Toyoshima H, Hayakawa N, Tamakoshi A, Ohno Y, Yoshimura T; Japan Collaborative Cohort Study Group.

Department of Public Health, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan. yhkiss@med.showa-u.ac.jp

To evaluate whether green tea consumption provides protection against stomach cancer death, relative risks were calculated using Cox proportional hazards regression analysis in the Japan Collaborative Study for Evaluation of Cancer Risk, sponsored by the Ministry of Health and Welfare (JACC Study). The study was based on 30 370 men and 42 481 women aged 40-79. After adjustment for age, smoking status, history of peptic ulcer, family history of stomach cancer along with certain dietary items, the risks associated with drinking one or two, three or four, five to nine, and 10 or more cups of green tea per day, relative to those of drinking less than one cup per day, were 1.6 (95% CI: 0.9-2.9), 1.1 (95% CI: 0.6-1.9), 1.0 (95% CI: 0.5-2.0), and 1.0 (95% CI: 0.5-2.0), respectively, in men (P for trend=0.669), and 1.1 (95% CI: 0.5-2.5), 1.0 (95% CI: 0.5-2.5), 0.8 (95% CI: 0.4-1.6), and 0.8 (95% CI: 0.3-2.1), respectively, in women (P for trend=0.488). We found no inverse association between green tea consumption and the risk of stomach cancer death. Copyright 2002 Cancer Research UK

104. Biochem Biophys Res Commun. 2002 Aug 23;296(3):584-8.

Inhibition of beta-catenin/Tcf activity by white tea, green tea, and epigallocatechin-3-gallate (EGCG): minor contribution of H(2)O(2) at physiologically relevant EGCG concentrations.

Dashwood WM, Orner GA, Dashwood RH.

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.

Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in white tea and green tea. Recently, it was reported that the addition of EGCG and other tea polyphenols to cell culture media, minus cells, generated significant levels of H(2)O(2), with the corollary that this might represent an "artifact" in cell culture studies which seek to examine the chemopreventive mechanisms of tea. We show here that in cell growth media with and without serum, and in growth media containing human embryonic kidney 293 (HEK293) cells plus serum, physiologically relevant concentrations of EGCG (< or =25 microM) generated H(2)O(2) with a peak concentration of the order of 10-12 microM. However, addition of 20 microM H(2)O(2) directly to HEK293 cells transiently transfected with wild-type or mutant beta-catenin constructs and TCF-4 had no significant effect on beta-catenin/TCF-4 reporter activity or beta-catenin expression levels. In contrast, 2-25 microM EGCG inhibited beta-catenin/TCF-4 reporter activity in a concentration-dependent fashion and there was a concomitant reduction in beta-catenin protein levels in the cell lysates without changes in TCF-4 expression. The inhibition of reporter activity was recapitulated by white tea and green tea, each tested at a 25 microM EGCG equivalent concentration in the assay, and this was unaffected by the addition of exogenous catalase. The results indicate that physiologically relevant concentrations of tea and EGCG inhibit beta-catenin/TCF-4 reporter activity in HEK293 cells due to reduced expression of beta-catenin and that this is unlikely to be an artifact of H(2)O(2) generation under the assay conditions used here. These data are consistent with the findings from in vivo studies, showing the suppression of intestinal polyps by tea, via an apparent down-regulation of beta-catenin and Wnt target genes.

105. Int J Oncol. 2002 Sep;21(3):487-91.

Inhibition of fibroblast growth factors by green tea.

Sartippour MR, Heber D, Zhang L, Beatty P, Elashoff D, Elashoff R, Go VL, Brooks MN.

Department of Surgery, Division of Oncology, University of California-Los Angeles, Los Angeles, CA 90095, USA.

Investigators have shown that green tea may decrease the risk of cancer. It is widely accepted that the main active component of green tea is EGCG (epigallocatechin-3-gallate). In our previous study, we examined the effect of green tea on breast cancer growth and endothelial cells both in in vitro assays and in animal models. Our data show that both mixed green tea extract (GTE) as well as its individual catechin components are effective in inhibiting breast cancer and endothelial cell proliferation in vitro, and that GTE suppresses breast cancer xenograft size and decreases the tumor blood vessel density in vivo. In the present study, we further demonstrate that 40 microg/ml GTE or EGCG can decrease the levels of the angiogenic factor bFGF (basic fibroblast growth factor) levels in the cells. This phenomenon is observed in both human umbilical vein endothelial cells (HUVECs) and in human breast cancer cells MDA-MB231. This effect is dose dependent. Furthermore, GTE and EGCG decrease the transcript levels of bFGF and aFGF (acidic fibroblast growth factor) in HUVECs and MDA-MB231 cells. Our findings suggest that the inhibition of the angiogenic fibroblast growth factors could account for one of the mechanisms of green tea's actions. Since cancer is angiogenesis dependent, this may partially explain the antineoplastic effects associated with green tea consumption.

106. J Epidemiol. 2002 May;12(3):191-8.

Relationship between coffee and green tea consumption and all-cause mortality in a cohort of a rural Japanese population.

Iwai N, Ohshiro H, Kurozawa Y, Hosoda T, Morita H, Funakawa K, Okamoto M, Nose T.

Department of Public Health, Faculty of Medicine, Tottori University, Yonago, Japan.

We conducted a cohort study to investigate the effects of coffee and green tea consumption on all-cause mortality in a rural Japanese population. Data were obtained from 2,855 men and women aged 40-79 years in 1989, and during the subsequent 9.9 years of follow-up. Using the Cox regression model to adjust for potential confounding factors, we calculated the multivariate hazard ratios of death from all causes separately for men and women. The multivariate hazard ratio of mortality for men who consumed two or more cups of coffee per day, compared with those who consumed less than half a cup per day, was 0.43 (95% confidence interval, 0.30-0.63), and the ratio for those who consumed half to one cup of coffee per day was 0.70 (95% confidence interval, 0.52-0.94). Exclusion of subjects with less than 5 years of follow-up did not substantially change the findings. No other statistically significant associations were identified between consumption of the two beverages and all-cause mortality. For men, multivariate hazard ratios of death from apoplexy showed a significant inverse association with increasing coffee consumption. The effects of habitual coffee consumption and its related factors on health in Japan need to be studied in greater detail.

107. J Nutr. 2002 Aug;132(8):2307-11.

Green tea inhibits vascular endothelial growth factor (VEGF) induction in human breast cancer cells.

Sartippour MR, Shao ZM, Heber D, Beatty P, Zhang L, Liu C, Ellis L, Liu W, Go VL, Brooks MN.

Department of Surgery, Division of Oncology and. Center for Human Nutrition, University of California, Los Angeles 90095, USA.

Investigators have shown that green tea and its main catechin epigallocatechin-3 gallate (EGCG) may decrease the risk of cancer. Our previous study showed that green tea extract (GTE) as well as its individual catechin components inhibited MDA-MB231 breast cancer cell and human umbilical vein endothelial cell (HUVEC) proliferation. Further, GTE suppressed breast cancer xenograft size and decreased the tumor vessel density in vivo. In the current study, we investigated the effect of GTE on the major angiogenic factor vascular endothelial growth factor (VEGF) in an in vitro experiment. GTE or EGCG (40 mg/L) significantly decreased the levels of the VEGF peptide secreted into conditioned media. This occurred in both HUVEC and human breast cancer cells and the effect was dose dependent. Furthermore, GTE and EGCG decreased the RNA levels of VEGF in MDA-MB231 cells. This inhibition occurred at the transcriptional regulation level and was accompanied by a significant decrease in VEGF promoter activity. We also showed that GTE decreased c-fos and c-jun RNA transcripts, suggesting that activator protein (AP)-1-responsive regions present in the human VEGF promoter may be involved in the inhibitory effect of GTE. Furthermore, GTE suppressed the expression of protein kinase C, another VEGF transcription modulator, in breast cancer cells. Inhibition of VEGF transcription appeared to be one of the molecular mechanism(s) involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer treatment and/or prevention.

108. Cytokine. 2002 Jun 7;18(5):266-73.

Green tea polyphenol blocks h(2)o(2)-induced interleukin-8 production from human alveolar epithelial cells.

Matsuoka K, Isowa N, Yoshimura T, Liu M, Wada H.

Department of Thoracic Surgery, Kyoto University, Japan.

Reactive oxygen species (ROS) play crucial roles in ischemia-reperfusion (IR) injury of lung transplants. Reactive oxygen species may stimulate the production of neutrophil chemotactic factors such as interleukin-8 (IL-8), from alveolar epithelial cells, causing recruitment and activation of neutrophils in the reperfused tissue. Green tea polyphenol has potent anti-oxidative activities and anti-inflammatory effects by decreasing cytokine production. In the present study, we found that green tea polyphenol significantly inhibited IL-8 production induced by hydrogen peroxide (H(2)O(2)) in human lung alveolar epithelial cells (A549 line). It has been shown that mitogen activated protein kinases, such as Jun N-terminal kinase (JNK), p38 and p44/42, could mediate IL-8 production from a variety of cell types. We further investigated the effect of green tea polyphenol on these protein kinases, and demonstrated that H(2)O(2)-induced phosphorylation of JNK and p38 but not p44/42 was inhibited by green tea polyphenol in A549 cells. We speculate that green tea polyphenol may inhibit H(2)O(2)-induced IL-8 production from A549 cells through inactivation of JNK and p38.

109. Prostaglandins Leukot Essent Fatty Acids. 2002 May-Jun;66(5-6):519-24.

Green tea extracts can counteract the modification of fatty acid composition induced by doxorubicin in cultured cardiomyocytes.

Hrelia S, Bordoni A, Angeloni C, Leoncini E, Toschi TG, Lercker G, Biagi PL.

Nutrition Research Center, Department of Biochemistry G. Moruzzi University of Bologna, Italy. hrelia@biocfarm.unibo.it

Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid peroxidation but also a decreased biosynthesis of highly unsaturated fatty acids, leading to significant modification in cardiomyocyte fatty acid composition. We have evaluated whether naturally occurring antioxidants could counteract this side-effect. Green tea is an excellent source of catechins; we supplemented cultured rat cardiomyocytes with different green tea extracts to relate their catechin content and composition to their ability in protecting cells against doxorubicin-induced damage. The determination of total lipid fatty acid composition, of conjugated diene production (indicator of lipid peroxidation), and of lactate dehydrogenase release revealed that supplementation with tea extracts could counteract significant modifications in the fatty acyl pattern due to doxorubicin exposure, although to different extents. These differences could be ascribed to the different total catechin content and to qualitative differences among the tea extracts, determined by HPLC analysis.

110. Addict Biol. 2002 Jul;7(3):307-14.

Green tea as a potent antioxidant in alcohol intoxication.

Skrzydlewska E, Ostrowska J, Stankiewicz A, Farbiszewski R.

Department of Analytical Chemistry, Medical Academy of Bialystok, Bialystok, Poland. skrzydle@amb.ac.bialystok.pl

Ethanol oxidation to acetaldehyde and next to acetate is accompanied by free radical generation. Free radicals can affect cell integrity when antioxidant mechanisms are no longer able to cope with the free radical generation observed in ethanol intoxication. Natural antioxidants are particularly useful in such a situation. The present study was designed to investigate the efficacy of green tea as a source of water-soluble antioxidants (catechins) on the liver and blood serum antioxidative potential of rats chronically (28 days) intoxicated with ethanol. Alcohol caused a decrease in liver superoxide dismutase, glutathione peroxidase and catalase activities and an increase in activity of glutathione reductase. Moreover, a decrease in the level of reduced glutathione, ascorbic acid, vitamins A and E and beta-carotene were observed. The activity of serum glutathione peroxidase decreased while glutathione reductase activity increased. The level of serum non-enzymatic antioxidants was also decreased in the liver. Alcohol administration caused an increase in the liver and serum lipid peroxidation products, measured as thiobarbituric acid-reactive substances. However, green tea prevents the changes observed after ethanol intoxication. Green tea also protects membrane phospholipids from enhanced peroxidation. These results indicate a beneficial effect of green tea in alcohol intoxication.

111. J Biol Chem. 2002 Sep 20;277(38):34933-40. Epub 2002 Jul 12.

Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production.

Waltner-Law ME, Wang XL, Law BK, Hall RK, Nawano M, Granner DK.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.

Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70(s6k) activity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent.

112. Urol Clin North Am. 2002 Feb;29(1):49-57, viii.

Green tea and prostate cancer.

Gupta S, Mukhtar H.

Department of Urology, University Hospitals of Cleveland, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

Many laboratory studies and human epidemiological data suggest that most prostate cancer deaths are attributable to lifestyle, including nutritional factors where diet plays a major role in initiation as well as subsequent progression of the disease. Under these circumstances, chemoprevention seems to be a logical and obvious strategy. Because of its long latency and high incidence, prostate cancer is an ideal disease for chemoprevention. The suitable agent(s) for prostate cancer chemoprevention should be the one(s) that has efficacy in the laboratory experiments on one hand, and also possesses proven epidemiological basis on the other hand. In this article, we address the use of green tea for prostate cancer chemoprevention. Experimental as well as the epidemiological basis for this possibility is provided.

113. Nutr Cancer. 2001;41(1-2):119-25.

Green tea catechins and vitamin E inhibit angiogenesis of human microvascular endothelial cells through suppression of IL-8 production.

Tang FY, Meydani M.

Vascular Biology Laboratory, JM USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.

Epidemiological and animal studies have indicated that consumption of green tea and high vitamin E intake are associated with a reduced risk of developing certain forms of cancer. However, the inhibitory mechanism of green tea catechins and vitamin E in angiogenesis, an important process in tumor growth, has not been well established. In the present study, alpha-tocopherol and several major catechins of green tea (catechin, epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate) were tested for their ability to inhibit tube formation in vitro using a model in which human microvascular endothelial cells were exposed to a constant rate of a physiologically low level of H2O2. In this model, the production of interleukin (IL)-8 by human microvascular endothelial cells at a low level of H2O2 was required for angiogenesis, as assessed by tube formation in three-dimensional gel in culture. Vitamin E (d-alpha-tocopherol, 40 microM) in the culture media significantly reduced IL-8 production and angiogenesis. Among the green tea catechins, epigallocatechin (0.5-1 microM) was the most effective in reducing IL-8 production and inhibiting angiogenesis. These results suggest that consumption of green tea catechins or supplemental intake of vitamin E may have preventive effects on tumor development, mediated, at least in part, through inhibition of angiogenesis via suppression of IL-8 production.

114. Food Chem Toxicol. 2002 Jul;40(7):949-57.

Volatile N-nitrosamine inhibition after intake Korean green tea and Maesil (Prunus mume SIEB. et ZACC.) extracts with an amine-rich diet in subjects ingesting nitrate.

Choi SY, Chung MJ, Sung NJ.

Department of Food and Nutrition, Gyeongsang National University, Jinju 660-701, South Korea.

The formation of carcinogenic nitrosamines under simulated gastric conditions was studied during the incubation of amine rich food and nitrate, and its possible inhibition by adding kumquat, sweet orange, strawberry, garlic, kale juices, Maesil (Prunus mume) and green tea extracts. The strawberry, kale juices, Maesil and green tea extracts were equally effective in reducing the formation of N-nitrosodimethylamine (NDMA). The fruits of P. mume SIEB. et ZACC. (Korean name, Maesil) have been used as a traditional drug and health food in Korea. During four weeks of test (designated EW1, EW2, EW3 and EW4; experiment week 1, 2, 3 and 4 diets) volunteers consumed a diet of low nitrate and amine (EW1) and consumed a fish meal rich in amines as nitrosatable precursors in combination with intake of nitrate-containing drinking water without (EW2) or with Maesil and green tea extracts (EW3 and EW4, respectively). The intake of nitrate-containing drinking water (340 mg nitrate/100 ml) resulted in a significant rise in mean salivary nitrate and nitrite concentrations and in mean urinary nitrate levels. Mean urinary nitrate was increased to 455.0+/-66.2, 334.6+/-67.8 and 333.4+/-50.7 mg/18 h after the nitrate intake of EW2, EW3 and EW4, respectively. Significant increases in urinary dimethylamine and trimethylamine levels were observed in consumption of diets (EW2, EW3, and EW4) rich in amine and nitrate. Maesil and green tea extract in EW3 and EW4 enhanced the increase of urinary dimethylamine and trimethylamine levels. Urinary excretion of N-nitrosodimethylamine in consumption of diet rich in nitrate and amine (EW2) increased to 6504.4+/-2638.7 ng/18 h from 257.0+/-112.0 ng/18 h of low nitrate and amine diet (EW1). Korean green tea and Maesil extracts in nitrate and amine rich diet reduced the excretion of N-nitrosodimethylamine to 249.7+/-90.6 and 752.7+/-595.3 ng/18 h, respectively, compared with 6504.4+/-2638.7 ng /18 h after ingestion of TD1 diet.

115. Food Chem Toxicol. 2002 Jul;40(7):925-33.

Inhibition of aromatase activity by green tea extract catechins and their endocrinological effects of oral administration in rats.

Satoh K, Sakamoto Y, Ogata A, Nagai F, Mikuriya H, Numazawa M, Yamada K, Aoki N.

Department of Toxicology, The Tokyo Metropolitan Research Laboratory of Public Health, 24-1 Hyakunincho 3 chome, Shinjuku-ku, Japan. sato@tokyo-eiken.go.jp

We orally administered polyphenone-60 (P-60), green tea extract catechins, in the diet (0, 1.25 and 5%) to male rats for 2, 4 and 8 weeks initiated at 5 weeks old. It was found that a 5% dose to male rats for 2-8 weeks induced goiters and decreased weights of the body, testis and prostate gland. Endocrinologically, elevating plasma thyroid stimulating hormone (TSH), luteinizing hormone (LH) and testosterone levels and decreasing tri-iodothyronine (T(3)) and thyroxine (T(4)) levels were induced by this treatment. We also found that P-60 as a whole and some of its constituents exhibited inhibitory effects on human placental aromatase activity by in vitro assay. The concentration of P-60 that required producing 50% inhibition of the aromatase activity (IC(50) value) was 28 microg/ml. The IC(50) values of (-)-catechin gallate (Cg), (-)-epigallocatechin (EGC), (-)-epigallocatechin gallate (EGCg) and (-)-gallocatechin gallate (GCg) were 5.5 x 10(-6), 1.0 x 10(-4), 6.0 x 10(-5) and 1.5 x 10(-5) M, respectively. (-)- Epicatechin gallate (ECg) at 1.0 x 10(-4) M produced 20% inhibition. (-)-Epicatechin (EC) and (+)-catechin (CT) exhibited no effects on aromatase activity. The endocrinological changes observed in vivo were in conformity with antithyroid effects and aromatase inhibition effects of P-60 and its constituents.

116. J Biol Chem. 2002 Aug 23;277(34):30574-80. Epub 2002 Jun 10.

Involvement of protein kinase C activation and cell survival/ cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action.

Levites Y, Amit T, Youdim MB, Mandel S.

Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Dept. of Pharmacology, Technion-Faculty of Medicine, 31096 Haifa, Israel.

Studies from our laboratory have demonstrated that the major green tea polyphenol, (-)-epigallocatechin 3-gallate (EGCG), exerts potent neuroprotective actions in the mice model of Parkinson's disease. These studies were extended to neuronal cell culture employing the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA). Pretreatment with EGCG (0.1-10 microm) attenuated human neuroblastoma (NB) SH-SY5Y cell death, induced by a 24-h exposure to 6-OHDA (50 microm). Potential cell signaling candidates involved in this neuroprotective effect were further examined. EGCG restored the reduced protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) activities caused by 6-OHDA toxicity. However, the neuroprotective effect of EGCG on cell survival was abolished by pretreatment with PKC inhibitor GF 109203X (1 microm). Because EGCG increased phosphorylated PKC, we suggest that PKC isoenzymes are involved in the neuroprotective action of EGCG against 6-OHDA. In addition, gene expression analysis revealed that EGCG prevented both the 6-OHDA-induced expression of several mRNAs, such as Bax, Bad, and Mdm2, and the decrease in Bcl-2, Bcl-w, and Bcl-x(L). These results suggest that the neuroprotective mechanism of EGCG against oxidative stress-induced cell death includes stimulation of PKC and modulation of cell survival/cell cycle genes.

117. Arch Biochem Biophys. 2002 May 1;401(1):29-37.

Green tea constituent epigallocatechin-3-gallate inhibits angiogenic differentiation of human endothelial cells.

Singh AK, Seth P, Anthony P, Husain MM, Madhavan S, Mukhtar H, Maheshwari RK.

Center for Combat Casualty and Life Sustainment Research, Department of Pathology, Uniformed Services University of Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20852, USA.

Several independent research studies have shown that consumption of green tea reduces the development of cancer in many animal models. Epidemiological observations, though inconclusive, are suggesting that green tea consumption may also reduce the risk of some cancers in humans. These anti-carcinogenic effects of green tea have been attributed to its constituent polyphenols. Angiogenesis is a crucial step in the growth and metastasis of cancers. We have investigated the effect of the major polyphenolic constituent of green tea, epigallocatechin-3-gallate (EGCG), on the tube formation of human umbilical vein endothelial cells (HUVEC) on matrigel. Tube formation was inhibited by treatment both prior to plating and after plating endothelial cells on matrigel. EGCG treatment also was found to reduce the migration of endothelial cells in matrigel plug model. The role of matrix metalloproteinases (MMP) has been shown to play an important role during angiogenesis. Zymography was performed to determine if EGCG had any effect on MMPs. Zymographs of EGCG-treated culture supernatants modulated the gelatinolytic activities of secreted proteinases indicating that EGCG may be exerting its inhibitory effect by regulating proteinases. These findings suggest that EGCG acts as an angiogenesis inhibitor by modulating protease activity during endothelial morphogenesis. (c) 2002 Elsevier Science (USA).

118. Phytomedicine. 2002 Apr;9(3):232-8.

Protective effect of green tea against lipid peroxidation in the rat liver, blood serum and the brain.

Skrzydlewska E, Ostrowska J, Farbiszewski R, Michalak K.

Department of Analytical Chemistry, Medical Academy of Bialystok, Poland. skrzydle@solar.amb.edu.pl

This paper reports data on the effect of green tea on the lipid peroxidation products formation and parameters of antioxidative system of the liver, blood serum and central nervous tissue of healthy young rats drinking green tea for five weeks. The rats were permitted free access to solubilized extract of green tea. Bioactive ingredients of green tea extract caused in the liver an increase in the activity of glutathione peroxidase and glutathione reductase and in the content of reduced glutathione as well as marked decrease in lipid hydroperoxides (LOOH), 4-hydroksynonenal (4-HNE) and malondialdehyde (MDA). The concentration of vitamin A increased by about 40%. Minor changes in the measured parameters were observed in the blood serum. GSH content increased slightly, whereas the index of the total antioxidant status increased significantly. In contrast, the lipid peroxidation products, particularly MDA was significantly diminished. In the central nervous tissue the activity of superoxide dismutase and glutathione peroxidase decreased while the activity od glutathione reductase and catalase increased after drinking green tea. Moreover the level of LOOH, 4-HNE and MDA significantly decreased. The use of green tea extract appeared to be beneficial to rats in reducing lipid peroxidation products. These results support and substantiate traditional consumption of green tea as protection against lipid peroxidation in the liver, blood serum, and central nervous tissue.

119. J Nutr. 2002 Jun;132(6):1282-8.

Green tea extract inhibits the lymphatic absorption of cholesterol and alpha-tocopherol in ovariectomized rats.

Loest HB, Noh SK, Koo SI.

Department of Human Nutrition, Kansas State University, Manhattan, KS 66506, USA.

Evidence indicates that green tea consumption lowers the serum level of cholesterol (CH). This study was conducted to determine whether green tea lowers the intestinal absorption of CH and other lipids in ovariectomized (OX) rats. OX rats with lymph duct cannulae were infused at 3.0 mL/h for 8 h via an intraduodenal catheter with a lipid emulsion containing (14)C-cholesterol ((14)C-CH) and alpha-tocopherol (alphaTP) without (GT0) or with green tea extract standardized to 42.9 mg (GT1) or 120.5 mg (GT2) of total catechins in PBS (pH 6.5). Green tea extracts dose-dependently reduced (P < 0.05) the lymphatic absorption of (14)C-CH. The cumulative absorptions of (14)C-CH in rats infused with GT0, GT1 and GT2 were 36.3 +/- 1.1, 20.7 +/- 4.3 and 4.8 +/- 4.1% dose, respectively. The percentage distribution of esterified CH did not differ between rats infused with GT0 and GT1 (80.2 +/- 2.3% vs. 79.0 +/- 1.7%), but was significantly lower in those given GT2 (69.1 +/- 6.8%). The absorption of alphaTP also was significantly reduced by GT1 (736.5 +/- 204.9 nmol, 20.8 +/- 5.8% dose) and GT2 (281.0 +/- 190.8 nmol, 7.9 +/- 5.4% dose) compared with GT0 (1048.8 +/- 174.9 nmol, 29.6 +/- 4.9% dose). The absorption of fat was significantly increased by GT1 (862.6 +/- 151.1 micromol) but lowered by GT2 (557.9 +/- 252.2 micromol) relative to GT0 (717.7 +/- 39.1 micromol). The findings provide direct evidence that green tea has a profound inhibitory effect on the intestinal absorption of CH and alphaTP in OX rats. Whether the inhibitory effect of green tea extract is attributable to a specific catechin(s) and other components in green tea remains to be determined.

120. Biosci Biotechnol Biochem. 2002 Apr;66(4):711-6.

Effects of dietary powdered green tea and theanine on tumor growth and endogenous hyperlipidemia in hepatoma-bearing rats.

Zhang G, Miura Y, Yagasaki K.

Department of Applied Biological Science, Tokyo Noko University, Fuchu, Japan.

The effects of dietary powdered green tea (PGT) and theanine on in vivo hepatoma growth and cancerous hyperlipidemia were investigated in rats that had been implanted with a rat ascites hepatoma cell line of AH109A cells. The hepatoma-bearing rats were fed with a 20% casein diet (20C), 20C containing 2% PGT, or 20C containing 0.1% theanine for 14 days. Dietary PGT significantly and time-dependently reduced the solid tumor volume and weight as did dietary theanine. The hepatoma-induced endogenous hyperlipidemia, which was characterized by rises in the serum cholesterol (hypercholesterolemia) and triglyceride (hypertriglyceridemia) levels, was significantly suppressed by PGT and theanine supplementation. Bile acid excretion into the feces was significantly higher in the PGT- and theanine-fed rats than in the control rats. This inhibition of hypercholesterolemia may have resulted from tumor growth suppression as well as increased excretion of steroids from the body. These results suggest that PGT had both anti-proliferative activity toward hepatoma cells and hypolipidemic activity in the hepatoma bearing rats. They also suggest that theanine was, at least in part, responsible for the PGT actions.

121. J Agric Food Chem. 2002 Jun 5;50(12):3549-52.

Antioxidative activity of green tea polyphenol in cholesterol-fed rats.

Yokozawa T, Nakagawa T, Kitani K.

Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. yokozawa@ms.toyoma-mpu.ac.jp

This study investigated the effects of green tea polyphenol on the serum antioxidative activity and cholesterol levels of cholesterol-fed rats and compared them with those of probucol, an antioxidant hypocholesterolemic agent. To evaluate the antioxidative activity, the susceptibility to oxidative modification of low-density lipoprotein (LDL) isolated from the serum of cholesterol-fed rats was measured, as was the serum antioxidative activity using the spontaneous autoxidation system of brain homogenate. Administration of green tea polyphenol effectively inhibited LDL oxidation and elevated serum antioxidative activity to the same degree as probucol. However, higher amounts of polyphenol than probucol needed to be administered to reduce the total, free, and LDL cholesterol levels. Furthermore, green tea polyphenol increased the levels of high-density lipoprotein (HDL) cholesterol, leading to dose-dependent improvement of the atherogenic index, an effect that was not seen with probucol. Thus, green tea polyphenol may exert an antiatherosclerotic action by virtue of its antioxidant properties and by increasing HDL cholesterol levels.

122. Biol Chem. 2002 Mar-Apr;383(3-4):663-70.

Green tea extract protects against early alcohol-induced liver injury in rats.

Arteel GE, Uesugi T, Bevan LN, Gabele E, Wheeler MD, McKim SE, Thurman RG.

Department of Pharmacology, University of North Carolina at Chapel Hill, 27599-7365, USA.

Oxidants have been shown to be involved in alcohol-induced liver injury. This study was designed to test the hypothesis that the antioxidant polyphenolic extract of green tea, comprised predominantly of epigallocatechin gallate, protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-14 g kg(-1) day(-1)) and green tea (300 mg kg(-1) day(-1)) continuously for 4 weeks using an intragastric enteral feeding protocol. Mean body weight gains (approximately 4 g/day) were not significantly different between treatment groups, and green tea extract did not the affect average concentration or the cycling of urine ethanol concentrations (0-550 mg dl(-1) day(-1)). After 4 weeks, serum ALT levels were increased significantly about 4-fold over control values (35+/-3 IU/l) by enteral ethanol (114+/-18); inclusion of green tea extract in the diet significantly blunted this increase (65+/-10). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver. While not affecting fat accumulation or inflammation, green tea extract significantly blunted increases in necrosis caused by ethanol. Furthermore, ethanol significantly increased the accumulation of protein adducts of 4-hydroxynonenal, a product of lipid peroxidation and an index of oxidative stress; green tea extract blocked this effect almost completely. TNFalpha protein levels were increased in liver by alcohol; this phenomenon was also blunted by green tea extract. These results indicate that simple dietary antioxidants, such as those found in green tea, prevent early alcohol-induced liver injury, most likely by preventing oxidative stress.

123. Amino Acids. 2002;22(1):1-13.

Cancer therapy and prevention by green tea: role of ornithine decarboxylase.

Bachrach U, Wang YC.

Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. bachur@md2.huji.ac.il

Green tea which is widely consumed in China, Japan and India, contains polyphenolic compounds, which account for 30% of the dry weight of the leaves. Most of the polyphenols are flavanols, of which (-)-epigallocatechin-3-gallate (EGCG) is most abundant. Epidemiological studies revealed that the incidences of stomach and prostate cancers are the lowest in the world among a population that consumes green tea on a regular basis. It has also been reported that the quantity of green tea consumed, plays an important role in reducing cancer risk and in delaying cancer outbreak and recurrence. Various systems were used to confirm anti-cancer activities of green tea and/or EGCG. These included experimental animals in which cancer was induced chemically. Cultured cells transformed chemically or by oncogenes were also used. These studies clearly demonstrated that green tea or EGCG have anticancer and cancer preventive properties. The mechanisms of these activities have also been studied in details. It has been shown that green tea and its active components interfere with signal transduction pathways. Thus the activities of various protein kinases are inhibited, the expression of nuclear proto-oncogenes declines and the activity of ornithine decarboxylase (ODC) is reduced. ODC, which catalyzes the rate-limiting step in the biosynthesis of polyamines is closely linked with cellular proliferation and carcinogenesis. Inhibitors of ODC, like alpha-difluoromethylornithine (DFMO) have long been used for cancer prevention and therapy. It has been suggested that polyamine depletion by green tea could offer one explanation for its anti-cancer activities.

124. Biol Trace Elem Res. 2002 May;86(2):177-91.

Antimutagenic activity of selenium-enriched green tea toward the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline.

Amantana A, Santana-Rios G, Butler JA, Xu M, Whanger PD, Dashwood RH.

Department of Envionmental and Molecular Toxicology, Oregon State University, Corvallis 97331, USA.

Both selenium and green tea have been reported to exhibit antigenotoxic and cancer chemopreventive properties. We compared the antimutagenic activities of regular green tea and selenium-enriched green tea obtained from Hubei Province, China, toward the heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the Salmonella assay. Selenium-enriched green tea obtained by foliar application of selenite exhibited concentration-dependent inhibition of IQ-induced mutagenesis in the presence of rat liver S9 and was significantly more effective than regular green tea tested under the same conditions. Analytical studies revealed no major differences in the polyphenol or caffeine content between regular green tea and selenium-enriched green tea, but the latter tea contained approximately 60-fold higher concentrations of selenium compared with regular green tea. The only soluble form of selenium was identified as selenite. The antimutagenic effects of certain individual tea constituents, such as epicatechin gallate and catechin, were enhanced by the addition of selenite to the Salmonella assay. Sodium selenite, sodium selenate, seleno-DL-cysteine, seleno-L-methionine, and L-Se-methylselenocysteine were not antimutagenic toward IQ when tested alone, but augmented significantly the inhibitory potency of green tea. The results suggested an enhancing ("coantimutagenic") effect of selenium in combination with green tea in vitro, but in vivo studies are needed to assess whether there is a synergistic effect of tea and selenium to protect against heterocyclic amine-induced mutagenesis and carcinogenesis.

125. Gen Dent. 2002 Mar-Apr;50(2):140-6.

Chemoprevention of oral cancer by green tea.

Hsu SD, Singh BB, Lewis JB, Borke JL, Dickinson DP, Drake L, Caughman GB, Schuster GS.

Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, Medical College of Georgia, Augusta, USA.

Green tea has been a popular beverage for many centuries. Only recently, however, has the anti-cancer power of green tea constituents been unveiled. Green tea polyphenols are found to induce apoptosis (programmed cell death) in many types of tumor cells, including oral cancer cells. However, mechanisms that enable normal cells to evade the apoptotic effect still are not understood. In this study, cell growth and invasion assays combined with apoptosis assays were used to examine the effects of green tea extracts, green tea polyphenols, and the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on normal human keratinocytes and oral carcinoma cells. The results showed that green tea and its constituents selectively induce apoptosis only in oral carcinoma cells, while EGCG was able to inhibit the growth and invasion of oral carcinoma cells. These differential responses to green tea and its constituents between normal and malignant cells were correlated with the induction of p57, a cell cycle regulator. These data suggest that the chemopreventive effects of green tea polyphenols may involve a p57 mediated survival pathway in normal epithelial cells, while oral carcinoma cells undergo an apoptotic pathway. Therefore, regular consumption of green tea could be beneficial in the prevention of oral cancer.

126. Wien Med Wochenschr. 2002;152(5-6):153-8.

[Cancer prevention with green tea: reality and wishful thinking]

[Article in German]

Bertram B, Bartsch H.

Abteilung fur Toxikologie und Krebsrisikofaktoren, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Deutschland. b.bertram@dkfz.de

Different processing of the leaves of the tea plant Camellia sinensis yields green or black tea, the subject of numerous investigations on the preventive effects on chronic degenerative diseases. The tea polyphenols, in particular (-)-epigallocatechin gallate (EGCG) were found to account for most of the protective effects. Since the concentration of EGCG is 5 times higher in green than in black tea, it is assumed that green tea possesses a greater preventive potential. Protection against cancer and cardiovascular diseases are the most important biomedical effects. In experimental models the preventive activity of tea is well documented for tumors at many organ sites. In humans, tea was reported to be protective against tumors of the lung, the gastrointestinal tract and the liver. Tea polyphenols, especially EGCG, were shown to exert cancer-protective activity by the following mechanisms: they inhibit the metabolic activation of carcinogens and induce at the same time detoxifying enzymes. They inhibit signaling pathways controlling cell proliferation and tumor growth such as protein kinase C and the release of tumor necrose factor-alpha from cells. Tea polyphenols reactivate processes which are impaired in tumor cells, such as the programmed cell death and the tumorsuppressor gene p53. Finally, tea polyphenols can also block angiogenesis leading to a starvation of the tumor. By inactivation of proteolytic enzymes they inhibit the development of metastases. This short review summarizes relevant recent findings on the protective effects of green tea constituents.

127. Food Chem Toxicol. 2002 Jun;40(6):841-4.

Induction of UDP-glucuronosyltransferase 1 (UDP-GT1) gene complex by green tea in male F344 rats.

Embola CW, Sohn OS, Fiala ES, Weisburger JH.

Department of Pathology, New York Medical College, 10595, Valhalla 10595, USA.

Tea is one of the most frequently consumed beverages in the world, second only to water. Epidemiological studies have associated the consumption of green tea with a lower risk of several types of cancers, including stomach, oral cavity, esophagus, and lung. This paper deals with the mechanism of action of tea as an effective chemopreventive agent for toxic chemicals and especially carcinogens. UDP-glucuronosyltransferase (UDP-GT) activities towards p-nitrophenol were markedly increased (51.8% or 1.5-fold) in rats that consumed tea compared with the control animals on water. Induction of UDP-glucuronosyltransferase activity by tea may involve the UDP-GT1 (UGT1A) gene complex of the UDP-GT multigene family. Therefore, a major mechanism of tea as a chemopreventive agent is induction of the microsomal detoxification enzyme, UDP-glucuronosyltransferase.

128. Nutr Cancer. 2001;40(2):149-56.

Green tea and its catechins inhibit breast cancer xenografts.

Sartippour MR, Heber D, Ma J, Lu Q, Go VL, Nguyen M.

Department of Surgery, University of California, Los Angeles, CA 90095, USA.

Investigators have shown that green tea may decrease the risk of cancer. It is widely accepted that the main active component of green tea is epigallocatechin-3-gallate (EGCG). In this study, we examined the effect of green tea on breast cancer growth and endothelial cells in in vitro assays and in animal models. Furthermore, we compared the potency of the different catechin components of green tea extract (GTE), including EGCG. Our data showed that mixed GTE and its individual catechin components were effective in inhibiting breast cancer and endothelial cell proliferation. In mouse experiments, GTE suppressed xenograft size and decreased the tumor vessel density. Our results demonstrated the value of all catechins and argued for the use of a mixed GTE as a botanical dietary supplement, rather than purified EGCG, in future clinical trials.

129. Mol Cell Biochem. 2002 Jan;229(1-2):85-92.

Green tea catechins decrease apolipoprotein B-100 secretion from HepG2 cells.

Yee WL, Wang Q, Agdinaoay T, Dang K, Chang H, Grandinetti A, Franke AA, Theriault A.

Division of Medical Technology, University of Hawaii, Honolulu 96822, USA.

To understand the hypocholesterolemic activity of green tea, our in vitro studies screened the relative efficacy of two structurally distinct green tea catechins, epicatechin (EC) and epigallocatechin gallate (EGCG), on apolipoprotein B-100 (apoB) and lipid production using a well established human hepatoma cell-line, HepG2, as the model system. This study showed that HepG2 cells pretreated with EC and EGCG for 8 h exerted a dose-dependent inhibitory effect on apoB secretion. Total protein and albumin synthesis and secretion were unaffected indicating the effects on apoB secretion to be specific. Under lipid-rich conditions, apoB secretion was markedly reduced by EGCG and to a lesser extent by EC at 50 microM. Mechanistic study showed that tea catechins inhibited apoB secretion via a proteasome-independent pathway as indicated by a lack of response to N-acetyl-leucyl-leucyl-norleucinal (ALLN), a proteasome inhibitor. The effect on apoB secretion was also found to be independent of lipid biosynthesis. In summary, the data suggest that EGCG in contrast to EC is a potent inhibitor of apoB secretion. The results indicate that the gallate moiety in the catechin molecule may result in a beneficial effect on lipid metabolism in terms of apoB secretion.

130. Phytother Res. 2002 Mar;16 Suppl 1:S91-2.

Vitamin C is one of the lipolytic substances in green tea.

Hasegawa N, Niimi N, Odani F.

Department of Food and Nutrition, Nagoya Bunri College, 2-1 Sasazuka-cho, Nishi-ku, Nagoya 451-0077, Japan. hsgwn@nagoya-bunri.ac.jp

We have studied the influence of vitamin C contained in green tea on the lipolysis of well-differentiated 3T3-L1 cells. When mature adipocytes were exposed to vitamin C the triglyceride concentration was decreased (p < 0.05) and the activity of glycerophosphate dehydrogenase, a marker of adipose conversion, was significantly inhibited (p < 0.01). These data suggest that green tea may have a lipolytic activity due to the mechanism by which the vitamin C contained in it inhibits triglyceride accumulation. Copyright 2002 John Wiley & Sons, Ltd.

131. J Agric Food Chem. 2002 Apr 10;50(8):2418-22.

Protective activity of green tea against free radical- and glucose-mediated protein damage.

Nakagawa T, Yokozawa T, Terasawa K, Shu S, Juneja LR.

Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Toyama 930-0194, Japan.

Protein oxidation and glycation are posttranslational modifications that are implicated in the pathological development of many age-related disease processes. This study investigated the effects of green tea extract, and a green tea tannin mixture and its components, on protein damage induced by 2,2'-azobis(2-amidinopropane) dihydrochloride (a free radical generator) and glucose in in vitro assay systems. We found that green tea extract can effectively protect against protein damage, and showed that its action is mainly due to tannin. In addition, it was shown that the chemical structures of tannin components are also involved in this activity, suggesting that the presence of the gallate group at the 3 position plays the most important role in the protective activity against protein oxidation and glycation, and that there is also a contribution by the hydroxyl group at the 5' position in the B ring and the sterical structure. These findings demonstrate the mechanisms of the usefulness of green tea in protein oxidation- and glycation-associated diseases.

132. Biol Chem. 2002 Jan;383(1):101-5.

Anti-invasive effects of green tea polyphenol epigallocatechin-3-gallate (EGCG), a natural inhibitor of metallo and serine proteases.

Benelli R, Vene R, Bisacchi D, Garbisa S, Albini A.

Centro di Biotecnologie Avanzate,Genova, Italy.

Several reports have attributed to green tea chemopreventive and therapeutic properties. Epidemiological studies have linked the regular use of green tea to a reduced incidence of breast and colon carcinomas. Tea contains several antioxidants, including polyphenols of the catechin (green tea) and theaflavin (black tea) groups. Green tea derivatives have been shown to act in vitro and in vivo as anti-inflammatory, anti-viral and anti-tumor drugs. Despite the extensive body of data only few studies have investigated the molecular mechanisms underlying these effects. In this brief review we focus on the inhibitory activity of catechins derived from green tea toward proteases involved in tumor invasion.

133. Phytomedicine. 2002 Jan;9(1):3-8.

Recent findings of green tea extract AR25 (Exolise) and its activity for the treatment of obesity.

Chantre P, Lairon D.

Laboratoires Arkopharma, Carros, France. r-d@arkopharma.com

The green tea extract AR25 is an 80% ethanolic dry extract standardized at 25% catechins expressed as epigallocatechin gallate (EGCG). In vitro, green tea extract AR25 exerts a direct inhibition of gastric and pancreatic lipases and a stimulation of thermogenesis. In an open study, the effects of extract AR25 were evaluated in moderately obese patients. After 3 months, body weight was decreased by 4.6% and waist circumference by 4.48%. These results suggest the green tea extract AR25 to be a natural product for the treatment of obesity, which exerts its activity by several ways: inhibition of lipases and stimulation of thermogenesis.

134. AIDS. 2002 Apr 12;16(6):939-41.

Polyphenolic antioxidant (-)-epigallocatechin-3-gallate from green tea as a candidate anti-HIV agent.

Fassina G, Buffa A, Benelli R, Varnier OE, Noonan DM, Albini A.

Instituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.

Epigallocatechin-3-gallate (EGCG), one of the components of green tea, has been suggested to have antiviral activity. To determine the effects of EGCG on HIV infection, peripheral blood lymphocytes were incubated with either LAI/IIIB or Bal HIV strains and increasing concentrations of EGCG. EGCG strongly inhibited the replication of both virus strains as determined by reverse transcriptase and p24 assays on the cell supernatants.

135. Am J Clin Nutr. 2002 Apr;75(4):749-53.

Green tea extract decreases muscle necrosis in mdx mice and protects against reactive oxygen species.

Buetler TM, Renard M, Offord EA, Schneider H, Ruegg UT.

Pharmacology Group, School of Pharmacy, University of Lausanne, Switzerland.

BACKGROUND: Duchenne muscular dystrophy is a severe X-linked congenital disorder characterized by lethal muscle wasting caused by the absence of the structural protein dystrophin. OBJECTIVE: Because generation of reactive oxygen species appears to play an important role in the pathogenesis of this disease, we tested whether antioxidant green tea extract could diminish muscle necrosis in the mdx mouse dystrophy model. DESIGN: A diet supplemented with 0.01% or 0.05% green tea extract was fed to dams and neonates for 4 wk beginning on the day of birth. Muscle necrosis and regeneration were determined in stained cryosections of soleus and elongator digitorum longus muscles. Radical scavenging by green tea extract was determined in differentiated cultured C2C12 cells treated with tert-butylhydroperoxide, with the use of 2',7'-dichlorofluorescin diacetate as a radical detector. RESULTS: This feeding regimen significantly and dose-dependently reduced necrosis in the fast-twitch muscle elongator digitorum longus but at the doses tested had no effect on the slow-twitch soleus muscle. Green tea extract concentration-dependently decreased oxidative stress induced by tert-butylhydroperoxide treatment of cultured mouse C2C12 myotubes. The lower effective dose tested in mdx mice corresponds to approximately equal to 1.4 L (7 cups) green tea/d in humans. CONCLUSION: Green tea extract may improve muscle health by reducing or delaying necrosis in mdx mice by an antioxidant mechanism.

136. Anticancer Res. 2001 Nov-Dec;21(6A):3743-8.

Chemopreventive effects of green tea polyphenols correlate with reversible induction of p57 expression.

Hsu S, Lewis JB, Borke JL, Singh B, Dickinson DP, Caughman GB, Athar M, Drake L, Aiken AC, Huynh CT, Das BR, Osaki T, Schuster GS.

Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, Medical College of Georgia, Augusta 30912-1126, USA. shsu@mail.mcg.edu

Green tea polyphenols are known to induce apoptosis in certain types of tumor cells. However, the mechanism(s) that enables normal cells to evade the apoptotic effect is still not understood. In this study, Western blot analysis combined with cycloheximide treatment was used to examine the effects of green tea polyphenols on the expression levels of p57, a cyclin-dependent kinase and apoptosis inhibitor, in normal human keratinocytes and in the oral carcinoma cell lines SCC25 and OSC2. The results showed that the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), induced p57 in normal keratinocytes in a dosage- and time-dependent manner, while the levels of p57 protein in oral carcinoma cells were unaltered. The differential response in p57 induction was consistent with the apoptosis status detected by annexin V assay. The data suggest that the chemopreventive effects of green tea polyphenols may involve p57-mediated cell cycle regulation in normal epithelial cells.

137. Ann Epidemiol. 2002 Apr;12(3):157-65.

Green tea consumption and serum lipids and lipoproteins in a population of healthy workers in Japan.

Tokunaga S, White IR, Frost C, Tanaka K, Kono S, Tokudome S, Akamatsu T, Moriyama T, Zakouji H.

Department of Preventive Medicine, Graduate School of Medical School of Medical Sciences, Kyushu University, Fukuoka, Japan. Toksan@phealth.med.kyushu-u.ac.jp

PURPOSE: To examine the relation between green tea consumption and serum lipids and lipoproteins. METHODS: The subjects were 13,916 workers (8476 men and 5440 women) aged 40-69 years at over 1000 workplaces in Nagano prefecture, central Japan. They underwent health screening offered by a single medical institute between April 1995 and March 1996 and did not have morbid conditions affecting serum cholesterol levels. Serum concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides were measured at the screening. The consumption of green tea and other life-style characteristics were ascertained by a questionnaire. The data were analyzed with multivariate linear model. RESULTS: Daily consumption of green tea was reported by 86.7% of subjects. Green tea consumption was, statistically, significantly associated with lower levels of serum total cholesterol in both men and women while its associations with serum triglycerides and HDL cholesterol were not statistically significant. The inverse association of serum total cholesterol with green tea consumption appeared to level off at the consumption of more than 10 cups/day. Excluding the outlying subjects drinking more than 10 cups/day (0.4%), the regression analysis adjusting for age, body mass index, ethanol intake, smoking habit, coffee intake, and type of work showed that daily consumption of one cup of green tea was associated with a reduction in serum total cholesterol by 0.015 mmol/L (95% confidence interval 0.006 to 0.024, p < 0.001) in men and 0.015 mmol/L (0.004 to 0.025, p < 0.01) in women. After additional adjustment for selected dietary factors, the inverse association remained statistically significant; one cup of green tea per day was associated with a reduction in serum total cholesterol by 0.010 mmol/L (0.001 to 0.019, p = 0.03) in men and 0.012 mmol/L (0.001 to 0.022, p = 0.03) in women. CONCLUSION: Consumption of green tea was associated with lower serum concentration of total cholesterol in Japanese healthy workers age 40-69 years; however, green tea consumption was unrelated to serum HDL-cholesterol and triglycerides.

138. J Nutr. 2002 Mar;132(3):341-6.

Catechins from green tea (Camellia sinensis) inhibit bovine and human cartilage proteoglycan and type II collagen degradation in vitro.

Adcocks C, Collin P, Buttle DJ.

Division of Genomic Medicine, University of Sheffield Medical School, Sheffield S10 2RX, UK.

Polyphenolic compounds from green tea have been shown to reduce inflammation in a murine model of inflammatory arthritis, but no studies have been undertaken to investigate whether these compounds are protective to joint tissues. We therefore investigated the effects of catechins found in green tea on cartilage extracellular matrix components using in vitro model systems. Bovine nasal and metacarpophalangeal cartilage as well as human nondiseased, osteoarthritic and rheumatoid cartilage were cultured with and without reagents known to accelerate cartilage matrix breakdown. Individual catechins were added to the cultures and the amount of released proteoglycan and type II collagen was measured by metachromatic assay and inhibition ELISA, respectively. Possible nonspecific or toxic effects of the catechins were assessed by lactate output and proteoglycan synthesis. Catechins, particularly those containing a gallate ester, were effective at micromolar concentrations at inhibiting proteoglycan and type II collagen breakdown. No toxic effects of the catechins were evident. We conclude that some green tea catechins are chondroprotective and that consumption of green tea may be prophylactic for arthritis and may benefit the arthritis patient by reducing inflammation and slowing cartilage breakdown. Further studies will be required to determine whether these compounds access the joint space in sufficient concentration and in a form capable of providing efficacy in vivo.

139. Biochim Biophys Acta. 2002 Jan 30;1542(1-3):209-20.

Green tea polyphenol (-)-epigallocatechin 3-gallate inhibits MMP-2 secretion and MT1-MMP-driven migration in glioblastoma cells.

Annabi B, Lachambre MP, Bousquet-Gagnon N, Page M, Gingras D, Beliveau R.

Centre de Cancerologie Charles-Bruneau, Hopital Ste-Justine et Universite du Quebec a Montreal, C.P. 8888, Succ. Centre-ville, H3C 3P8, Montreal, QC, Canada.

We have recently shown that green tea polyphenols, and especially (-)-epigallocatechin 3-gallate (EGCg), acted as potent inhibitors of matrix metalloproteinase activities as well as of proMMP-2 activation (M. Demeule, M. Brossard, M. Page, D. Gingras, R. Beliveau, Biochim. Biophys. Acta 1478 (2000)). In the present work, we sought to examine the involvement of MT1-MMP in the EGCg-induced inhibition of proMMP-2 activation. The incubation of U-87 glioblastoma cells in the presence of concanavalin A or cytochalasin D, two potent activators of MT1-MMP, resulted in proMMP-2 activation that was correlated with the cell surface proteolytic processing of MT1-MMP to its inactive 43 kDa form. Addition of EGCg strongly inhibited the MT1-MMP-dependent proMMP-2 activation. The inhibitory effect of EGCg on MT1-MMP was also demonstrated by the down-regulation of MT1-MMP transcript levels and by the inhibition of MT1-MMP-driven cell migration of transfected COS-7 cells. These observations suggest that this catechin may act at both the MT1-MMP gene and protein expression levels. In addition, treatment of cells with non-cytotoxic doses of EGCg significantly reduced the amount of secreted proMMP-2, and led to a concomitant increase in intracellular levels of that protein. This effect was similar to that observed using well-characterized secretion inhibitors such as brefeldin A and manumycin, suggesting that EGCg could also potentially act on intracellular secretory pathways. Taken together, these results indicate that EGCg targets multiple MMP-mediated cellular events in cancer cells and provides a new mechanism for the anticancer properties of that molecule.

140. Biochim Biophys Acta. 2002 Jan 30;1542(1-3):149-59.

Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols.

Jodoin J, Demeule M, Beliveau R.

Laboratoire de Medecine Moleculaire, Centre de Cancerologie Charles Bruneau, Universite du Quebec a Montreal, Canada.

Many beneficial proprieties have been associated with polyphenols from green tea, such as chemopreventive, anticarcinogenic, antiatherogenic and antioxidant actions. In this study, we investigated the effects of green tea polyphenols (GTPs) and their principal catechins on the function of P-glycoprotein (P-gp), which is involved in the multidrug resistance phenotype of cancer cells. GTPs (30 microg/ml) inhibit the photolabeling of P-gp by 75% and increase the accumulation of rhodamine-123 (R-123) 3-fold in the multidrug-resistant cell line CH(R)C5, indicating that GTPs interact with P-gp and inhibit its transport activity. Moreover, the modulation of P-gp transport by GTPs was a reversible process. Among the catechins present in GTPs, EGCG, ECG and CG are responsible for inhibiting P-gp. In addition, EGCG potentiates the cytotoxicity of vinblastine (VBL) in CH(R)C5 cells. The inhibitory effect of EGCG on P-gp was also observed in human Caco-2 cells, which form an intestinal epithelial-like monolayer. Our results indicate that, in addition to their anti-cancer properties, GTPs and more particularly EGCG inhibit the binding and efflux of drugs by P-gp. Thus, GTPs or EGCG might be potential agents for modulating the bioavailability of P-gp substrates at the intestine and the multidrug resistance phenotype associated with expression of this transporter in cancer cells.

141. Int J Exp Pathol. 2001 Dec;82(6):309-16.

Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea.

Jung YD, Ellis LM.

Chonnam University Research Institute of Medical Sciences, Chonnam National University Medical School, Kwangju, Korea.

Epidemiological studies have suggested that consumption of green tea may decrease cancer risk. In addition, abundant pre-clinical data from several laboratories have provided convincing evidence that polyphenols present in green tea afford protection against cancer in both in vivo and in vitro studies. Recently, epigallocatechin gallate (EGCG), a putative chemopreventive agent and a major component of green tea, was reported to inhibit tumour invasion and angiogenesis, processes that are essential for tumour growth and metastasis. Understanding the basic principles by which EGCG inhibits tumour invasion and angiogenesis may lead to the development of new therapeutic strategies, in addition to supporting the role of green tea as a cancer chemopreventive agent.

142. Arch Biochem Biophys. 2002 Jan 15;397(2):424-9.

Effect of drinking green tea on age-associated accumulation of Maillard-type fluorescence and carbonyl groups in rat aortic and skin collagen.

Song DU, Jung YD, Chay KO, Chung MA, Lee KH, Yang SY, Shin BA, Ahn BW.

Chonnam National University Research Institute of Medical Sciences, Hakdong 5, Donggu, Kwangju 501-746, Korea.

Tea catechins and other flavonoids have been shown to potentially protect against chronic cardiovascular diseases such as coronary heart disease and atherosclerosis. In this study, 6-month-old female Sprague-Dawley rats were fed green tea extract (50 mg/100 ml in drinking water) up to the age of 22 months, and the age-associated changes in Maillard-type fluorescence and carbonyl groups in the aortic and skin collagen were compared with those occurring in the water-fed control animals. Collagen-linked Maillard-type fluorescence was found to increase in both the aortic and skin tissues as animals aged. The age-associated increase in the fluorescence in the aortic collagen was remarkably inhibited by the green tea extract treatment, while that occurring in the skin collagen was not significantly inhibited by the treatment. The collagen carbonyl content also increased in both the aortic and skin tissues as animals aged. In contrast with the case of Maillard-type fluorescence, however, the age-associated increase in the carbonyl content was not inhibited by the green tea extract treatment either in the aortic or skin collagen. These results suggest that the inhibition of AGE formation in collagen is an important mechanism for the protective effects of tea catechins against cardiovascular diseases. (c)2002 Elsevier Science.

143. J Nutr Biochem. 2002 Feb;13(2):103-111.

Green tea protection of hypoxia/reoxygenation injury in cultured cardiac cells.

Bordoni A, Hrelia S, Angeloni C, Giordano E, Guarnieri C, Caldarera CM, Biagi PL.

Centro Ricerche sulla Nutrizione, Dipartimento di Biochimica "G.Moruzzi", Universita' di Bologna, via Irnerio-48, 40126, Bologna, Italy

Antioxidant-rich diets exert a protective effect in diseases involving oxidative damage. Among dietary components, green tea is an excellent source of antioxidants. In this study, cultured neonatal rat cardiomyocytes were used to clarify the protective effect of a green tea extract on cell damage and lipid peroxidation induced by different periods of hypoxia followed by reoxigenation. Cultures of neonatal rat cardiomyocytes were exposed to 2--8 hr hypoxia, eventually followed by reoxygenation, in the absence or presence of alpha-tocopherol or green tea. LDH release and the production of conjugated diene lipids were measured, and appeared linearly related to the duration of hypoxia. During hypoxia, both LDH release and conjugated diene production were reduced by alpha-tocopherol and, in a dose dependent manner, by green tea, the 50 &mgr;g/ml being the most effective dose. Reoxygenation caused no further increase in LDH leakage, while it caused a significant increase in conjugate dienes, which absolute value was lower in antioxidant supplemented cells. Anyway, the ratio between conjugated diene production after hypoxia and after reoxygenation was similar in all groups, indicating that the severity of free radical-induced reoxygenation injury is proportional to the severity of previous hypoxic injury. Since hypoxic damage is reduced by alpha-tocopherol and green tea, our data suggest that any nutritional intervention to attenuate reoxygenation injury must be directed toward the attenuation of the hypoxic injury. Therefore, recommendations about a high dietary intake of antioxidants may be useful not only in the prevention, but also in the reduction of cardiac injury following ischemia.

144. J Nutr Biochem. 2002 Feb;13(2):96-102.

Green tea flavonoids inhibit the LDL oxidation in osteogenic disordered rats fed a marginal ascorbic acid in diet.

Kasaoka S, Hase K, Morita T, Kiriyama S.

Department of Health and Nutrition, Bunkyo University Women's College, 1100 Namegaya, Chigasaki, 253-8550, Kanagawa, Japan

Osteogenic Disorder Shionogi (ODS) rats can not synthesize ascorbic acid (AA). We have examined the capacity of green tea flavonoids (GTF) to modify low-density lipoprotein (LDL) oxidation in ODS rats with dietary AA restriction. In the first experiment, ODS rats were fed diets containing 300 (AA300 diet) or 0 (AA0 diet) mg AA/kg diets for 20 d. In comparison with the AA300 diet, the AA0 diet significantly decreased the concentrations of plasma AA and alpha-tocopherol in LDL and significantly shortened the lag time of LDL oxidation in vitro. In the second experiment, ODS rats were fed one of the following three diets: the AA300 diet, the diet containing 25 mg AA (AA25, marginal AA)/kg diet (AA25 diet), or the diet containing 25 mg AA + 8 g GTF/kg diet (AA25 + GTF diet) for 20 d. Plasma AA concentration were significantly lower in rats fed AA25 compared with AA300 but not in those fed AA25 + GTF. LDL oxidation lag time was significantly longer in rats fed AA25 + GTF compared with the other two groups. Lag time for LDL oxidation was significantly and positively correlated with LDL alpha-tocopherol (r = 0.6885, P = 0.0191). These results suggest that dietary flavonoids suppress the LDL oxidation through the sparing effect on LDL alpha-tocopherol and/or plasma AA when AA intake is marginal in the ODS rats.

145. Cancer Res. 2002 Feb 1;62(3):652-5.

Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells.

Pianetti S, Guo S, Kavanagh KT, Sonenshein GE.

Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118-2394, USA.

Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer is associated with poor prognosis. With evidence accumulating for a chemopreventive role of green tea polyphenols, the effects of epigallocatechin-3 gallate (EGCG) on Her-2/neu-overexpressing breast cancer cells were examined. EGCG inhibited mouse mammary tumor virus (MMTV)-Her-2/neu NF639 cell growth in culture and soft agar. EGCG reduced signaling via the phosphatidylinositol 3- kinase, Akt kinase to NF-kappaB pathway because of inhibition of basal Her-2/neu receptor tyrosine phosphorylation. EGCG similarly inhibited basal receptor phosphorylation in SMF and Ba/F3 2 + 4 cells, which suggests the potential beneficial use of EGCG in adjuvant therapy of tumors with Her-2/neu overexpression.

146. World J Gastroenterol. 1998 Feb;4(1):29.

Effect of garlic and garlic-green tea mixture on serum lipids in MNNG-induced experimental gastric carcinoma and precancerous lesion.

Su Q, Luo ZY, Teng H, Yun WD, Li YQ, He XE.

Institute of Oncology,Hengyang Medical College,Hengyang 421001,Hunan Province,China.

INTRODUCTION:To study effect of garlic and garlic-green tea mixture on serum contents of Tch,LDL and HDL in MNNG induced gastric carcinoma (GC) and precancerous lesion (PL) in Wistar rats.METHODS:Serum contents of Tch,LDL and HDL in normal control group (n=10,NG),MNNG group (n=30,MG),prevention group (n=30,PG),treatment group I (n=20,TG I) and treatment group II(n=20,TG II) were detected by PGE 6000/COD.RESULTS:Serum Tch and LDL of rats of MG (6.86+/-1.39 3.72+/-1.10) and its GC(6.95+/-1.37 3.77+/-1.08) and PL(6.42+/-1.04 3.56+/-0.74) were lower than that of NG (8.74+/-1.89 5.89+/-1.61) PG(7.73+/-3.18 4.96+/-2.89) and its GC(8.36+/-3.41 5.93+/-3.31) and PL(7.45+/-3.16 4.55+/-2.71),TGI(8.86+/-1.75 5.38+/-1.76) and its GC (9.10+/-2.27 5.55+/-2.51) and PL (8.61+/-1.17 5.22+/-0.55) and TG II (8.16+/-0.76 5.32+/-0.72) and its GC(8.52+/-0.67 5.96+/-0.48) and PL (8.02+/-0.79 5.09+/-0.65),respectively (P <0.01-0.05).Serum HDL of MG rats (2.76+/-0.48) and its GC(2.79+/-0.48) were remarkably higher than that of MG (2.20+/-0.85) and GC of PG (2.24+/-0.38) (P <0.05).CONCLUSION:Experimental gastric carcinoma and precancerous lesion were associated with hypocholesterolaemia,LDL and HDL.Garlic and garlic-green tea mixture can inhibit and reverse MNNG-induced gastric carcinoma and precancerous lesion in Wistar rats.

147. Arch Biochem Biophys. 2002 Feb 1;398(1):125-31.

Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate.

Ahmad N, Adhami VM, Gupta S, Cheng P, Mukhtar H.

Department of Dermatology, Case Western Reserve University, The Research Institute of University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA.

Because of the demonstrated role of green tea polyphenol epigallocatechin-3-gallate (EGCG) in cancer chemoprevention, there is considerable emphasis in understanding its mechanism of action. In this study, we assessed the involvement of the retinoblastoma (pRb)-E2F/DP pathway as an important contributor in the antiproliferative effects of EGCG. As shown by immunoblot analysis, EGCG treatment of A431 cells resulted in a dose- as well as time-dependent decrease in the total pRb with a relative increase in the hypophosphorylated form of pRb. EGCG also resulted in serine-780 phosphorylation of pRb in these cells. Further, EGCG was found to downregulate the protein expression of other members of the pRb family, viz. p130 and p107, in a dose- as well as time-dependent manner. This response was accompanied by downregulation in the protein expression of the E2F (1 through 5) family of transcription factors and their heterodimeric partners DP1 and DP2. Taken together, our study suggests that EGCG causes a downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of "free" E2F. This series of events leads to stoppage of cell cycle progression at the G1-->S phase transition thereby causing G0/G1 arrest and subsequent apoptotic cell death. This, to our knowledge, is the first study showing the involvement of the pRb-E2F/DP pathway in antiproliferative and apoptotic effects of EGCG.

148. Life Sci. 2001 Dec 21;70(5):603-14.

The green tea polyphenol (-)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons.

Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, Park J, Park CW, Suh SI.

Department of Psychiatry, Keimyung University School of Medicine, Taegu, Korea.

Previous evidence has indicated that the neuronal toxicity of amyloid beta (betaA) protein is mediated through oxygen free radicals and can be attenuated by antioxidants and free radical scavengers. Recent studies have shown that green tea polyphenols reduced free radical-induced lipid peroxidation. The purpose of this study was to investigate whether (-)-epigallocatechin gallate (EGCG) would prevent or reduce the death of cultured hippocampal neuronal cells exposed to betaA because EGCG has a potent antioxidant property as a green tea polyphenol. Following exposure of the hippocampal neuronal cells to betaA for 48 hours, a marked hippocampal neuronal injuries and increases in malondialdehyde (MDA) level and caspase activity were observed. Co-treatment of cells with EGCG to betaA exposure elevated the cell survival and decreased the levels of MDA and caspase activity. Proapoptotic (p53 and Bax), Bcl-XL and cyclooxygenase (COX) proteins have been implicated in betaA-induced neuronal death. However, in this study the protective effects of EGCG seem to be independent of the regulation of p53, Bax, Bcl-XL and COX proteins. Taken together, the results suggest that EGCG has protective effects against betaA-induced neuronal apoptosis through scavenging reactive oxygen species, which may be beneficial for the prevention of Alzheimer's disease.

149. Cancer Res. 2002 Jan 15;62(2):381-5.

Green tea catechins inhibit vascular endothelial growth factor receptor phosphorylation.

Lamy S, Gingras D, Beliveau R.

Laboratoire de Medecine Moleculaire, Centre de Cancerologie Charles-Bruneau, Hopital Ste-Justine et Universite du Quebec a Montreal, Montreal, Quebec H3C 3P8, Canada.

Vascular endothelial growth factor (VEGF) receptors (VEGFR) play a major role in tumor angiogenesis and, thus, represent attractive targets for the development of novel anticancer therapeutics. In this work, we report that green tea catechins are novel inhibitors of VEGFR-2 activity. Physiological concentrations (0.01-1 microM) of epigallocatechin-3 gallate, catechin-3 gallate, and, to a lesser extent, epicatechin-3 gallate induce a rapid and potent inhibition of VEGF-dependent tyrosine phosphorylation of VEGFR-2. The inhibition of VEGFR-2 by epigallocatechin-3 gallate was similar to that induced by Semaxanib (SU5416), a specific VEGFR-2 inhibitor. The inhibition of VEGFR-2 activity by the catechins displayed positive correlation with the suppression of in vitro angiogenesis. These observations suggest that the anticancer properties of green tea extracts may be related to their inhibition of VEGF-dependent angiogenesis.

150. J Photochem Photobiol B. 2001 Dec 31;65(2-3):109-14.

Green tea polyphenols: DNA photodamage and photoimmunology.

Katiyar SK, Bergamo BM, Vyalil PK, Elmets CA.

Department of Dermatology, School of Medicine, University of Alabama at Birmingham, 1670 University Blvd., VH501, Box 202, Birmingham, AL 35294, USA. skatiyar@uab.edu

Green tea is a popular beverage consumed worldwide. The epicatechin derivatives, which are commonly called 'polyphenols', are the active ingredients in green tea and possess antioxidant, anti-inflammatory and anti-carcinogenic properties. Studies conducted by our group on human skin have demonstrated that green tea polyphenols (GTP) prevent ultraviolet (UV)-B-induced cyclobutane pyrimidine dimers (CPD), which are considered to be mediators of UVB-induced immune suppression and skin cancer induction. GTP treated human skin prevented penetration of UV radiation, which was demonstrated by the absence of immunostaining for CPD in the reticular dermis. The topical application of GTP or its most potent chemopreventive constituent (-)-epigallocatechin-3-gallate (EGCG) prior to exposure to UVB protects against UVB-induced local as well as systemic immune suppression in laboratory animals. Additionally, studies have shown that EGCG treatment of mouse skin inhibits UVB-induced infiltration of CD11b+ cells. CD11b is a cell surface marker for activated macrophages and neutrophils, which are associated with induction of UVB-induced suppression of contact hypersensitivity responses. EGCG treatment also results in reduction of the UVB-induced immunoregulatory cytokine interleukin (IL)-10 in skin as well as in draining lymph nodes, and an elevated amount of IL-12 in draining lymph nodes. These in vivo observations suggest that GTPs are photoprotective, and can be used as pharmacological agents for the prevention of solar UVB light-induced skin disorders associated with immune suppression and DNA damage.

151. Arch Toxicol. 2001 Dec;75(10):591-6.

Goitrogenic effects of green tea extract catechins by dietary administration in rats.

Sakamoto Y, Mikuriya H, Tayama K, Takahashi H, Nagasawa A, Yano N, Yuzawa K, Ogata A, Aoki N.

Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan. sakamoto@tokyo-eiken.go.jp

The effects of green tea extract catechins on the rat thyroid were examined in a 13-week feeding study and subsequent 2-,4- and 8-week studies. Commercially available polyphenon-60 (P-60) which contains green tea extract catechins at 66.2% was used as a source of catechins. A basic diet containing different concentrations of P-60 was used for experiments. In the 13-week study, 10 rats of each sex were administered diets containing P-60 at 0 (control), 0.625, 1.25, 2.5 and 5.0%. Goiters were observed in the 13-week test. The mean thyroid weight of rats fed a diet containing 5.0% of P-60 (5.0% group) significantly increased to 444% of the control in males and to 304% of the control in females. Histological examinations of the thyroid of the 5.0% group revealed marked hypertrophy and/or hyperplasia of the follicles, some with depletion of colloid and some with rich colloid, and formation of a fibrous capsule. Slight hypertrophy of follicular cells was observed in male rats fed a diet containing 1.25% of P-60 (1.25% group) and female rats fed a diet containing 2.5% of P-60 (2.5% group). Degree and incidence of thyroid lesions were higher in males than in females in the 1.25, 2.5 and 5.0% groups. In the 2-8-week studies, five rats of each sex were given diets containing 0 (control) and 5.0% of P-60. In the 5.0% group, the mean thyroid weight in males significantly increased to 161% of the control as early as 2 weeks and increased to 357% of the control at 8 weeks. Histologically, these goiters were also associated with follicular cell hypertrophy/hyperplasia as in the 13-week study. The degree and incidence of thyroid lesions were higher in males than in females. These results indicate that dietary administration of the green tea extract catechins at high doses induced goiters in rats, and this may be due to antithyroid effects of catechins. In the 13-week study, the no-observed effect level (NOEL) of green tea extract catechins for F344 rats based on histological changes of the thyroid was considered to be 0.625% in males and 1.25% in females in the diet, respectively.

152. Ann N Y Acad Sci. 2001 Apr;928:274-80.

A new function of green tea: prevention of lifestyle-related diseases.

Sueoka N, Suganuma M, Sueoka E, Okabe S, Matsuyama S, Imai K, Nakachi K, Fujiki H.

Saitama Cancer Center Research Institute, Japan.

In the normal human life span, there occur lifestyle-related diseases that may be preventable with nontoxic agents. This paper deals with the preventive activity of green tea in some lifestyle-related diseases. Green tea is one of the most practical cancer preventives, as we have shown in various in vitro and in vivo experiments, along with epidemiological studies. Among various biological effects of green tea, we have focused on its inhibitory effect on TNF-alpha gene expression mediated through inhibition of NF-kappaB and AP-1 activation. Based on our recent results with TNF-alpha-deficient mice, TNF-alpha is an endogenous tumor promoter. TNF-alpha is also known to be a central mediator in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. We therefore hypothesized that green tea might be a preventive agent for chronic inflammatory diseases. To test this hypothesis, TNF-alpha transgenic mice, which overexpress TNF-alpha only in the lungs, were examined. The TNF-alpha transgenic mouse is an animal model of human idiopathic pulmonary fibrosis which also frequently develops lung cancer. Expressions of TNF-alpha and IL-6 were inhibited in the lungs of these mice after treatment with green tea in drinking water for 4 months. In addition, judging from the results of a prospective cohort study in Saitama Prefecture, Japan, green tea helps to prevent cardiovascular disease. In this study, a decreased relative risk of death from cardiovascular disease was found for people consuming over 10 cups of green tea a day, and green tea also had life-prolonging effects on cumulative survival. These data suggest that green tea has preventive effects on both chronic inflammatory diseases and lifestyle-related diseases (including cardiovascular disease and cancer), resulting in prolongation of life span.

153. Rocz Akad Med Bialymst. 2001;46:240-50.

The influence of green tea on the activity of proteases and their inhibitors in plasma of rats after ethanol treatment.

Skrzydlewska E, Roszkowska A, Makiela M, Skrzydlewski Z.

Department of Analytical Chemistry, Medical Academy of Bialystok, Bialystok, Poland.

Ethanol oxidation in the liver is accompanied by formation of acetaldehyde and free radicals. These compounds can react with biologically active proteins, including proteolytic enzymes and their inhibitors. The aim of this paper was to determine the influence of green tea on the activity of cathepsin G and elastase and their inhibitors such as alpha-1-antitrypsin and alpha-2-macroglobulin, total antioxidant status and lipid peroxidation in plasma of young rats chronically intoxication with ethanol. The activity of cathepsin G and elastase was increased, while the activity of their inhibitors was reduced after ethanol treatment. AT the same time, the total antioxidant status was significantly decreased while lipid peroxidation measured as malondialdehyde and 4-hydroxynonenal was significantly increased. Giving green tea to rats did not change the proteases and their inhibitors activity, but significantly increased total antioxidant status and decreased lipid peroxidation. Drinking green tea with ethanol partially prevents the changes observed after ethanol intoxication.

154. Hong Kong Med J. 2001 Dec;7(4):369-74.

The medicinal action of androgens and green tea epigallocatechin gallate.

Liao S.

Tang Center for Herbal Medicine Research, Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois, USA.

Unorthodox (non-traditional or alternative) medicinal practices have been expanding very rapidly in western countries. Modern physicians, scientists, and non-traditional medicine practitioners now must join forces to promote evidence-based medicine to benefit patients. Green tea extracts are among the most widely used ancient medicinal agents, while androgens are probably the oldest drugs used in a purified form in traditional Chinese medicine. It is now clear that a specific green tea catechin, (-)epigallocatechin-3-gallate, can modulate the production and biological actions of androgens and other hormones. Modulation of androgenic activity and administration of (-)epigallocatechin-3-gallate may be useful for the treatment of various hormone-related abnormalities, such as benign prostatic hyperplasia, baldness, and acne, as well as androgen-dependent and -independent prostate cancers. (-)Epigallocatechin-3-gallate has also been shown to modulate appetite and control obesity in animals.

155. Nutr Cancer. 2001;39(2):239-43.

Effects of green tea on colonic aberrant crypt foci and proliferative indexes in rats.

Jia X, Han C.

Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine, Beijing 100050, People's Republic of China.

The present study was designed to investigate the effect of green tea on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) formation in Wistar rats. Forty-five male weanling Wistar rats were randomly divided into three groups. Rats in Group 1 were injected with DMH (20 mg/kg s.c.) once a week for 10 weeks. Animals in Group 2 received 2% green tea water extract as the sole source of drinking fluid in addition to the same treatment used for Group 1. Group 3 was the negative control group. Animals were killed at the end of Week 16 after the first DMH treatment. ACF were formed in animals in their DMH-treated groups at the end of Week 16. Group 2 had fewer ACF than Group 1. Compared with the positive control group, proliferating cell nuclear antigen labeling index, silver-stained nucleolar organizer regions, and ras-p21 expression were significantly reduced in Group 2. It was concluded that green tea drinking inhibited ACF formation in rats, and such effects may be related to the suppression of cell proliferation in the intestinal crypts.

156. Eur J Pharmacol. 2002 Jan 2;434(1-2):1-7.

Green tea polyphenols inhibit human vascular smooth muscle cell proliferation stimulated by native low-density lipoprotein.

Locher R, Emmanuele L, Suter PM, Vetter W, Barton M.

Department of Internal Medicine, Medical Policlinic and Clinical Atherosclerosis Research Laboratory, University Hospital Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland.

This study investigated whether human vascular smooth muscle cell proliferation induced by native low-density lipoprotein (LDL) is affected by green tea catechins. Furthermore, the effects of native LDL on extracellular signal-regulated kinase (ERK) 1/2 activity were determined. Cell proliferation stimulated by native LDL was concentration-dependently inhibited by epigallocatechin, epigallocatechin-3-gallate, green tea polyphenon, and the nonspecific antioxidant N-acetylcysteine (P<0.05). Combined treatment of green tea polyphenon and N-acetylcysteine markedly potentiated the effect of each drug on vascular smooth muscle cell proliferation. ERK1/2 activity was only partly inhibited by green tea catechins alone or in combination with N-acetylcysteine (P<0.05). These data suggest that green tea constituents inhibit proliferation of human vascular smooth muscle cells exposed to high levels of native LDL. Green tea constituents and antioxidants may exert vascular protection by inhibiting human vascular smooth muscle cell growth associated with hypercholesterolemia.

157. J Biomed Sci. 1994 Jun;1(3):163-166.

Inhibitory Effects of Polyphenolic Catechins from Chinese Green Tea on HIV Reverse Transcriptase Activity.

Chang CW, Hsu FL, Lin JY.

Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.

Three polyphenolic catechins, epigallocatechin (1), epicatechin-3-O-gallate (2) and epigallocatechin-3-O-gallate (3), were isolated from Chinese green tea, Ti-Kaun-Yin (Camellia sinensis) and demonstrated as a new class of human immunodeficiency virus-reverse transcriptase (HIV-RT) inhibitor. The concentrations required for 50% inhibition for the compounds (1), (2) and (3) were 7.80, 0.32 and 0.68 &mgr;M, respectively. The polyphenolic catechins with a galloyl group at the 3 position were potent inhibitors of HIV-RT. Kinetic analysis indicated that the polyphenolic catechins were competitive inhibitors with respect to the template-primer (rA)(n)(dT)(12-18) and noncompetitive inhibitors to dTTP. Copyright 1994 S. Karger AG, Basel

158. J Agric Food Chem. 2001 Nov;49(11):5639-45.

Green tea upregulates the low-density lipoprotein receptor through the sterol-regulated element binding Protein in HepG2 liver cells.

Bursill C, Roach PD, Bottema CD, Pal S.

CSIRO Health Sciences and Nutrition, Adelaide, SA 5000, Australia.

Green tea from Camellia sinensis lowers plasma cholesterol in animal models of hypercholesterolemia. The aim of this study was to determine the effects of green tea on the expression of the hepatic low-density lipoprotein (LDL) receptor, a cell surface protein involved in the control of plasma cholesterol. Incubating human HepG2 liver cells in culture with green tea increased both LDL receptor binding activity and protein. An ethyl acetate extract of green tea, containing 70% (w/w) catechins, also increased the LDL receptor binding activity, protein, and mRNA, indicating that (1) the effect was at the level of gene transcription and that (2) the catechins were the active constituents. The mechanism by which green tea up-regulated the LDL receptor was then investigated. Green tea decreased the cell cholesterol concentration (-30%) and increased the conversion of the sterol-regulated element binding protein (SREBP-1) from the inactive precursor form to the active transcription-factor form. Consistent with this, the mRNA of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, was also increased by green tea. In conclusion, green tea up-regulated the LDL receptor in HepG2 cells. The effect was most likely mediated through SREBP-1 in response to a decrease in the intracellular cholesterol concentration. The LDL receptor may therefore play a role in the hypocholesterolemic effect of green tea in vivo.

159. J Agric Food Chem. 2001 Nov;49(11):5340-7.

Factors affecting the caffeine and polyphenol contents of black and green tea infusions.

Astill C, Birch MR, Dacombe C, Humphrey PG, Martin PT.

Unilever Research Colworth, Colworth House, Sharnbrook, Bedford MK44 1LQ, United Kingdom. conrad.astill@unilever.com

The effects of product and preparation variables on the in-cup chemical composition of tea extracts is of interest because the appearance and taste characteristics and the possible health effects of a tea liquor arise from the chemical components extracted from the leaf during tea preparation. A comprehensive study was therefore undertaken to determine the contributions of product and preparation variables on the total soluble solids, caffeine, and polyphenol contents of tea extracts. The results of this study show that the variety, growing environment, manufacturing conditions, and grade (particle size) of the tea leaves each influence the tea leaf and final infusion compositions. In addition, the composition of the tea infusion was shown to be influenced by whether the tea was contained in a teabag and, if so, the size and material of construction of the bag. Finally, the preparation method, including the amounts of tea and water used, infusion time, and amount of agitation, was shown to be a major determinant of the component concentrations of tea beverages as consumed. An illustration of the variation introduced by these product and preparation factors is provided by comparing solids, caffeine, and polyphenol contents of green and black tea infusions when commercial products are prepared according to the instructions given on their packaging.

160. J Cardiovasc Pharmacol. 2001 Dec;38(6):875-84.

Antiplatelet activity of green tea catechins is mediated by inhibition of cytoplasmic calcium increase.

Kang WS, Chung KH, Chung JH, Lee JY, Park JB, Zhang YH, Yoo HS, Yun YP.

College of Pharmacy, Chungbuk National University, 48 Gaesin-Dong, Heungduk-Gu, Cheongju, 361-763, Korea.

We have previously reported that green tea catechins (GTC) display a potent antithrombotic activity, which might be due to antiplatelet rather than anticoagulation effects. In the current study, we investigated the antiplatelet mechanism of GTC. We tested the effects of GTC on the aggregation of human platelets and on the binding of fluorescein isothiocyanate-conjugated fibrinogen to human platelet glycoprotein (GP) IIb/IIIa. GTC inhibited the collagen-, thrombin-, adenosine diphosphate (ADP)-, and calcium ionophore A23187-induced aggregation of washed human platelets, with 50% inhibitory concentration values of 0.64, 0.52, 0.63, and 0.45 mg/ml, respectively. GTC significantly inhibited fibrinogen binding to human platelet surface GPIIb/IIIa complex but failed to inhibit binding to purified GPIIb/IIIa complex. These results indicate that the antiplatelet activity of GTC may be due to inhibition of an intracellular pathway preceding GPIIb/IIIa complex exposure. We also investigated the effects of GTC on intracellular calcium levels, which are critical in determining the activation status of platelets and on induction of platelet aggregation by thapsigargin, which is a selective inhibitor of the Ca(2+)-ATPase pump. Pretreatment of human platelets with GTC significantly inhibited the rise in intracellular Ca(2+) concentration induced by thrombin treatment, and GTC significantly inhibited the thapsigargin-induced platelet aggregation. We also examined the effect of GTC on the second messenger, inositol 1,4,5-triphosphate (IP(3)). GTC significantly inhibited the phosphoinositide breakdown induced by thrombin. Taken together, these observations suggest that the antiplatelet activity of GTC is be mediated by inhibition of cytoplasmic calcium increase, which leads to the inhibition of fibrinogen-GPIIb/IIIa binding via the activation of Ca(2+)-ATPase and inhibition of IP(3) formation.

161, Biochem Pharmacol. 2001 Nov 1;62(9):1175-83.

Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues.

Hong J, Smith TJ, Ho CT, August DA, Yang CS.

Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.

The effects of green and black tea polyphenols on cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid metabolism in normal human colon mucosa and colon cancers were investigated. At a concentration of 30 microg/mL, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) from green tea and theaflavins from black tea inhibited LOX-dependent activity by 30-75%. The formation of 5-, 12-, and 15-LOX metabolites was inhibited to a similar extent. Tea polyphenols also inhibited COX-dependent arachidonic acid metabolism in microsomes from normal colon mucosa, with ECG showing the strongest inhibition. The formation of thromboxane (TBX) and 12-hydroxyheptadecatrienoic acid (HHT) was decreased to a greater extent than other metabolites. The inhibitory effects of tea polyphenols on COX activity, however, were less pronounced in tumor microsomes than in normal colon mucosal microsomes. Theaflavins strongly inhibited the formation of TBX and HHT, but increased the production of prostaglandin E(2) (PGE(2)) in tumor microsomes. The enhancing effect of theaflavins on PGE(2) production was related to the COX-2 level in the microsomes. Although theaflavin inhibited ovine COX-2, its activity in the formation of PGE(2) was stimulated by theaflavin when ovine COX-2 was mixed with microsomes, suggesting that theaflavin affects the interaction of COX-2 with other microsomal factors (e.g. PGE synthase). The present results indicate that tea polyphenols can affect arachidonic acid metabolism in human colon mucosa and colon tumors, and this action may alter the risk for colon cancer in humans.

162. Biochem Biophys Res Commun. 2001 Nov 16;288(5):1200-6.

Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase.

Wang X, Tian W.

Department of Biology, Graduate School of Chinese Academy of Sciences, Beijing 100039, China.

We discover that epigallocatechin gallate (EGCG) from green tea is an inhibitor of fatty-acid synthase (FAS) from chicken liver. Its inhibition of FAS is composed of reversible fast-binding inhibition, through which 52 microM EGCG can inhibit 50% of the activity of FAS, and irreversible slow-binding inactivation following saturation kinetics with the dissociation constant of 0.352 mM and limiting rate constant of 0.0168 min(-1). The marked inhibition of ketoacyl reduction shows that the inhibition is related to beta-ketoacyl reductase of FAS. The observable protection of NADPH and competitive inhibition of NADPH for ketoacyl reduction indicate that EGCG may compete with NADPH for the same binding site. The synthetic inhibitor C75 does not show obvious fast-binding inhibition, but does exhibit irreversible slow-binding biphasic inactivation, which is demonstrated to be a second-order reaction. That the inactivation by C75 is protected by malonyl-CoA indicates C75 is similar to cerulenin in being a covalent inactivator of the beta-ketoacyl synthase. Copyright 2001 Academic Press.

163. J Biol Chem. 2002 Jan 18;277(3):1828-36. Epub 2001 Nov 06.

Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes.

Balasubramanian S, Efimova T, Eckert RL.

Department of Physiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.

(-)-Epigallocatechin-3-gallate (EGCG) is an important bioactive constituent of green tea that efficiently reduces epidermal cancer cell proliferation. This inhibition is associated with a reduction in activator protein 1 (AP1) transcription factor level and activity. However, its effects on AP1 function in normal epidermal cells have not been extensively explored. Our present studies show that EGCG regulates normal keratinocyte function. To understand the mechanism of action, we examined the effects of EGCG on AP1 factor activity, MAPK signal transduction, and expression of the AP1 factor-regulated human involucrin (hINV) gene. EGCG increases hINV promoter activity in a concentration-dependent manner that requires the presence of an intact hINV promoter AP1 factor binding site. This response appears to be physiologic, as endogenous hINV gene expression is also increased. Fra-1, Fra-2, FosB, JunB, JunD, c-Jun, and c-Fos levels are increased by EGCG treatment, as is AP1 factor binding to hINV promoter AP1 site. Gel mobility shift studies show that this complex contains Fra-1 and JunD. Signal transduction analysis indicates that the EGCG response requires Ras, MEKK1, MEK3, and p38 kinases. Kinase assays and inhibitor studies suggest that p38delta is the p38 isoform responsible for the regulation. These changes are also associated with a cessation of cell proliferation and enhanced cornified envelope formation. These studies show that in normal human keratinocytes EGCG markedly increases, via a MAPK signaling mechanism, AP1 factor-associated responses.

164. Epidemiology. 2001 Nov;12(6):695-700.

A population-based case-control study of lung cancer and green tea consumption among women living in Shanghai, China.

Zhong L, Goldberg MS, Gao YT, Hanley JA, Parent ME, Jin F.

Gilead Sciences, Forest City, California, USA.

Epidemiologic evidence regarding the association between the consumption of green tea and lung cancer is limited and inconclusive, although experimental studies have shown consistently that tea preparations and tea polyphenols may inhibit the induction of a variety of cancers, including lung cancer. In this population-based case-control study, we examined the association between past consumption of green tea and the risk of lung cancer. We identified 649 incident cases of primary lung cancer among women diagnosed from February 1992 through January 1994 using the population-based Shanghai Cancer Registry. We randomly selected a control group of 675 women from the Shanghai Residential Registry, frequency-matched to the expected age distribution of the cases. Green tea consumption was ascertained through face-to-face interviews. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. Among nonsmoking women, consumption of green tea was associated with a reduced risk of lung cancer (OR = 0.65; 95% CI = 0.45-0.93), and the risks decreased with increasing consumption. We found little association, however, among women who smoked (OR = 0.94; 95% CI = 0.40-2.22). The inconsistency in the association between drinking tea and the risk of lung cancer reported in previous studies may in part be due to inadequate control of confounding of active smoking.

165. Mutat Res 2001 Sep 1;480-481:147-51 Protective effect of green tea against benzo[a]pyrene-induced mutations in the liver of Big Blue transgenic mice. Jiang T, Glickman BW, de Boer JG. Laboratory of Industrial Hygiene, Ministry of Health, Beijing, PR China.

We assessed the ability of green tea to protect against benzo[a]pyrene (B[a]P)-induced mutations in the liver of lacI transgenic male C57BL/6 Big Blue mice. The mice were given a 2% Japanese green tea hot water extract as their sole source of drinking water for 10 weeks. After 7 weeks, they received a total dose of 150 mg/kg B[a]P. Treatment with B[a]P resulted in a two-fold higher lacI mutant frequency than the untreated controls (8.6+/-0.8 x 10(-5) versus 4.0+/-0.7 x 10(-5), P=0.01). B[a]P increased the frequency of its characteristic mutation (GC-->TA transversions) nearly five-fold, from 0.75 x 10(-5) to 3.7 x 10(-5). In mice treated with green tea, the induced B[a]P mutant frequency decreased by 63%, while GC-->TA transversions were reduced by 54%. Thus, we report evidence that green tea extract significantly suppressed B[a]P-induced mutation by lowering its specific transversion mutation in the lacI transgene in vivo. Further studies will address the correlation between the modulation of metabolic enzymes and the protection against induced mutation by green tea.

166. J Nutr 2001 May;131(5):1560-7 Green tea suppresses lipopolysaccharide-induced liver injury in d-galactosamine-sensitized rats. He P, Noda Y, Sugiyama K. Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan.

We conducted a series of in vivo experiments to clarify the hepatoprotective activity of green tea against lipopolysaccharide (LPS) + D-galactosamine (GalN)-induced liver injury and to elucidate the mechanism by which green tea exerts its effect in 7-wk-old male Wistar rats. Liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities. Green tea extract significantly suppressed LPS + GalN-induced liver injury when added to the diet (30 or 35 g/kg) and fed to rats for 14 d or when force-fed alone (0.4-1.2 g/kg body) 1.5 h before the injection of drugs. Although all five of the fractions extracted from green tea extract with different organic solvents had significant suppressive effects, the caffeine-containing fraction exhibited the strongest effect, suggesting that the protective effect of green tea against LPS + GalN-induced liver injury is attributable mainly to caffeine. Authentic caffeine also significantly suppressed LPS + GalN-induced liver injury when added to the diet (2 g/kg) and fed to rats for 14 d. Dietary green tea suppressed LPS + GalN-induced apoptosis of liver cells, as assessed by DNA fragmentation. However, dietary green tea did not suppress LPS-induced enhancement of plasma concentration of tumor necrosis factor (TNF)-alpha, the cytokine that is thought to play a pivotal role in the pathogenesis of LPS-induced liver injury, although it significantly suppressed plasma concentrations of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10 and interferon (IFN)-gamma. TNF-alpha + GalN-induced liver injury and apoptosis were also suppressed by dietary green tea. In contrast, dietary caffeine significantly suppressed LPS-induced enhancement not only of plasma IL-1beta, IL-6, IL-10 and IFN-gamma concentrations, but also of TNF-alpha concentration. The results suggest that green tea might suppress LPS + GalN-induced liver injury mainly through the inhibition of TNF-alpha-induced apoptosis of hepatocytes, rather than through the suppression of TNF-alpha production, although the suppressed production of TNF-alpha may be associated with the hepatoprotective effect of caffeine.

167. Chem Biol Interact 2001 Mar 14;134(1):41-54 Stereospecificity in membrane effects of catechins. Tsuchiya H Department of Dental Pharmacology, Asahi University School of Dentistry, 1851 Hozumi, Hozumi-cho, Motosu-gun, 501-0296, Gifu, Japan

Green tea catechins consisting of catechin stereoisomers and their derivatives have been suggested to show biological activities through the interactions with cellular membranes. Their effects on membrane fluidity were comparatively studied by measuring fluorescence polarization of liposomal membranes prepared with phospholipids and cholesterol. All catechin stereoisomers reduced membrane fluidity by acting on the hydrophilic and hydrophobic regions of membrane bilayers at 20-500 ?M. Both epicatechins in a cis form were more effective for reducing membrane fluidity than both catechins in a trans form. (-)-Epicatechin, (+)-epicatechin, (-)-catechin and (+)-catechin reduced membrane fluidity in increasing order of intensity. Such difference between optical isomers was increased by chiral cholesterol added to membrane lipids. In reversed-phase chromatographic evaluation, (-)-epicatechin and (+)-epicatechin were more hydrophobic than (-)-catechin and (+)-catechin, although hydrophobicity was not distinguishable between optical isomers. Stereospecificity in the membrane effects of catechin stereoisomers may be induced by the different hydrophobicity of geometrical isomers and the chirality of membrane lipid components. At lower concentrations (5-100 ?M), (-)-epigallocatechin gallate and (-)-epicatechin gallate reduced membrane fluidity more significantly than (-)-epicatechin, suggesting that the intensive membrane effect contributes to the potent medicinal utility of (-)-epigallocatechin gallate.

168. Mutat Res 2001 Mar 1;474(1-2):71-85

Antimutagenic activity of green tea and black tea extracts studied in a dynamic in vitro gastrointestinal model.

Krul C, Luiten-Schuite A, Tenfelde A, van Ommen B, Verhagen H, Havenaar R

TNO Nutrition and Food Research, P.O. Box 360, 3700, AJ Zeist, The Netherlands

[Medline record in process]

An in vitro gastrointestinal model, which simulates the conditions in the human digestive tract, was used to determine potential antimutagenic activity of extracts of black tea and green tea. In this paper, results are presented on the availability for absorption of potential antimutagenic compounds present in tea and on the influence of the food matrix on this activity. Between 60 and 180min after the tea was introduced into the model, antimutagenic activity was recovered from the jejunal compartment by means of dialysis: the dialysate appeared to inhibit the mutagenicity of the food mutagen MeIQx in the direct plate assay with Salmonella typhimurium (Ames test). The maximum inhibition was measured at 2h after the start of the experiment and was comparable for black tea and green tea extract. To determine the influence of food matrices on the antimutagenic activity of tea, the model was loaded with black tea together with milk or a homogenized standard breakfast. The maximum inhibition observed with black tea was reduced by 22, 42 and 78% in the presence of whole milk, semi-skimmed milk, and skimmed milk, respectively. Whole milk and skimmed milk abolished the antimutagenic activity of green tea by more than 90%; for semi-skimmed milk the inhibition was more than 60%. When a homogenized breakfast was added into the model together with the black tea extract, the antimutagenic activity was completely eliminated. When tea and MeIQx were added together into the digestion model, MeIQx mutagenicity was efficiently inhibited, with green tea showing a slightly stronger antimutagenic activity than black tea. In this case, the addition of milk had only a small inhibiting effect on the antimutagenicity.Antioxidant capacity and the concentration of catechins were also measured in the jejunal dialysates. The reduction in antimutagenic activity corresponded with reduction in antioxidant capacity and with a decrease of concentration of three catechins, viz. catechin, epigallocatechin gallate and epigallocatechin. The in vitro gastrointestinal model appears to be a useful tool to study the antimutagenicity of food components.

169. Comp Biochem Physiol C Toxicol Pharmacol 2001 Feb;128(2):153-64

Tea catechins inhibit cholesterol oxidation accompanying oxidation of low density lipoprotein in vitro.

Osada K, Takahashi M, Hoshina S, Nakamura M, Nakamura S, Sugano M

Department of Applied Life Science, Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Hirosaki, 036-8561, Aomori, Japan

[Medline record in process]

Endogenous oxidized cholesterols are potent atherogenic agents. Therefore, the antioxidative effects of green tea catechins (GTC) against cholesterol oxidation were examined in an in vitro lipoprotein oxidation system. The antioxidative potency of GTC against copper catalyzed LDL oxidation was in the decreasing order (-)-epigalocatechin gallate (EGCG)=(-)-epicatechin gallate (ECG)>(-)-epicatechin (EC)=(+)-catechin (C)>(-)-epigallocatechin (EGC). Reflecting these activities, both EGCG (74%) and ECG (70%) inhibited the formation of oxidized cholesterol, as well as the decrease of linoleic and arachidonic acids, in copper catalyzed LDL oxidation. The formation of oxidized cholesterol in 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH)-mediated oxidation of rat plasma was also inhibited when the rats were given diets containing 0.5% ECG or EGCG. In addition, EGCG and ECG highly inhibited oxygen consumption and formation of conjugated dienes in AAPH-mediated linoleic acid peroxidative reaction. These two species of catechin also markedly lowered the generation of hydroxyl radical and superoxide anion. Thus, GTC, especially ECG and EGCG, seem to inhibit cholesterol oxidation in LDL by combination of interference with PUFA oxidation, the reduction and scavenging of copper ion, hydroxyl radical generated from peroxidation of PUFA and superoxide anion.

170. Life Sci 2001 Jan 26;68(10):1207-14

Induction of apoptosis by green tea catechins in human prostate cancer DU145 cells.

Chung LY, Cheung TC, Kong SK, Fung KP, Choy YM, Chan ZY, Kwok TT

Department of Biochemistry, The Chinese University of Hong Kong, Shatin.

Green tea catechins (GTCs) including (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) and (-)-epicatechin (EC) were shown to suppress cell growth and induce apoptosis in various cell systems in addition to their chemo-preventive effect. In this study, except EC which was inactive, green tea extract (TE) and other 3 GTCs were found to suppress the growth and induce apoptosis in human prostate cancer DU145 cells largely through an increase in reactive oxygen species formation and mitochondrial depolarization. The conclusion was supported by the fact that the profiles for different GTCs in growth suppression, apoptosis induction, ROS formation and mitochondrial depolarization are in a similar order, i.e. ECG > EGCG > EGC > EC. Although the molecular mechanisms are still not clear, apoptosis induced by GTCs is not related to the members of BCL-2 family as EGCG did not alter the expression of BCL-2, BCL-X(L) and BAD in DU145 cells.

171. J Nutr 2001 Jan;131(1):27-32

Tea catechins Prevent the Development of Atherosclerosis in Apoprotein E-Deficient Mice.

Miura Y, Chiba T, Tomita I, Koizumi H, Miura S, Umegaki K, Hara Y, Ikeda M, (daggerdagger) 2;

School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Shizuoka, 422-8526, Japan. Shizuoka Sangyo University, 4-1-1, Surugadai, Fujieda, Shizuoka, 426-8668, Japan. Central Pharmaceutical Research Institute, Japan Tobacco Incorporated 23, Nukogi, Hatano, Kanagawa, 257-0024, Japan. National Institute of Nutrition and Health, 1-23-1, Toyama, Shinjuku-ku, Tokyo, Japan. Food Research Laboratories, Mitsui Nohrin Company Limited, 223-1, Miyahara, Fujieda, 426-0133, Japan. University of Shizuoka, Graduate School of Health Sciences, 52-1, Yada, Shizuoka, 422 8526, Japan.

[Record supplied by publisher]

Green tea contains various antioxidative flavan-3ols (tea catechins), such as (-)-epigallocatechin gallate (EGCg, the major catechin), which exert potent inhibitory effects on LDL oxidation in vitro and ex vivo in humans. In this study, the antiatherogenic effects of tea catechins were examined in atherosclerosis-susceptible C57BL/6J, apoprotein (apo)E-deficient mice. Male apoE-deficient mice (10 wk old) were fed an atherogenic diet for 14 wk; during that time, one group (tea) was supplied drinking water supplemented with green tea extract (0.8 g/L), and another group (control) was offered the vehicle only. The tea extract consisted of the following (g/100 g): EGCg, 58.4; (-)-epigallocatechin (EGC), 11.7; (-)-epicatechin (EC), 6.6; (-)-gallocatechingallate (GCg), 1.6; (-)-epicatechin gallate (ECg), 0.5; and caffeine, 0.4. The estimated actual intake of tea catechin was 1.7 mg/(d. mouse). Tea ingestion did not influence plasma cholesterol or triglyceride concentrations. Plasma lipid peroxides were reduced in the tea group at wk 8, suggesting that the in vivo oxidative state is improved by tea ingestion. Atheromatous areas in the aorta from the arch to the femoral bifurcation and aortic weights were both significantly attenuated by 23% in the tea group compared with the control group. Aortic cholesterol and triglyceride contents were 27 and 50% lower, respectively, in the tea group than in the control group. These results suggest that chronic ingestion of tea extract prevents the development of atherosclerosis without changing the plasma lipid level in apoE-deficient mice, probably through the potent antioxidative activity of the tea.

172. Cancer Epidemiol Biomarkers Prev 2001 Jan;10(1):53-8

Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E.

Chow HH, Cai Y, Alberts DS, Hakim I, Dorr R, Shahi F, Crowell JA, Yang CS, Hara Y

Arizona Cancer Center, The University of Arizona, Tucson 85724, USA. schow@azcc.arizona.edu

[Medline record in process]

Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its principal active components include epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin (EC), and epicatechin gallate, of which EGCG is the most abundant and possesses the most potent antioxidative activity. We performed a Phase I pharmacokinetic study to determine the systemic availability of green tea catechins after single oral dose administration of EGCG and Polyphenon E (decaffeinated green tea catechin mixture). Twenty healthy subjects (five subjects/dose level) were randomly assigned to one of the dose levels (200, 400, 600, and 800 mg based on EGCG content). All subjects were randomly crossed-over to receive the two catechin formulations at the same dose level. Blood and urine samples were collected for up to 24 h after oral administration of the study medication. Tea catechin concentrations in plasma and urine samples were determined using high-performance liquid chromatography with the coulometric electrode array detection system. After EGCG versus Polyphenon E administration, the mean area under the plasma concentration-time curves (AUC) of unchanged EGCG were 22.5 versus 21.9, 35.4 versus 52.2, 101.9 versus 79.7, and 167.1 versus 161.4 min x microg/ml at the 200-, 400-, 600-, and 800-mg dose levels, respectively. EGC and EC were not detected in plasma after EGCG administration and were present at low/undetectable levels after Polyphenon E administration. High concentrations of EGC and EC glucuronide/sulfate conjugates were found in plasma and urine samples after Polyphenon E administration. There were no significant differences in the pharmacokinetic characteristics of EGCG between the two study medications. The AUC and maximum plasma concentration (Cmax) of EGCG after the 800-mg dose of EGCG were found to be significantly higher than those after the 200- and 400-mg dose. The AUC and Cmax of EGCG after the 800-mg dose of Polyphenon E were significantly higher than those after the three lower doses. We conclude that the two catechin formulations resulted in similar plasma EGCG levels. EGC and EC were present in the body after the Polyphenon E administration; however, they were present predominantly in conjugated forms. The systemic availability of EGCG increased at higher doses, possibly due to saturable presystemic elimination of orally administered green tea polyphenols.

173. Arch Pharm Res 2000 Dec;23(6):605-12

Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death.

Chen C, Yu R, Owuor ED, Kong AN

Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, IL 60607-7173, USA.

[Medline record in process]

Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase II gene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 microM with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 microM to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP

174. Planta Med 2000 Dec;66(8):762-4

Protective effects of green tea catechins against asbestos-induced cell injury.

Kostyuk VA, Potapovich AI, Vladykovskaya EN, Hiramatsu M

[Medline record in process]

Green tea extract was found to provide a strong protective effect against asbestos-induced injury of peritoneal macrophages and red blood cells in vitro. The main polyphenolic constituents of green tea extract, (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG), were also efficient in preventing injury of cells following exposure to asbestos fibers. The protective efficacies of EGCG and ECG expressed as IC50 values were, respectively, 10 microM and 12 microM if peritoneal macrophages were injured by chrysotile and 4 microM and 5 microM in the case of crocidolite-induced cell injury. Antiradical and chelating properties of ECG and EGCG were evaluated and it was concluded that the protective effect of catechins against asbestos-induced injury may be related to both scavenger properties towards to superoxide anion and the ability to chelate iron ions.

175. J Agric Food Chem 2000 Nov;48(11):5768-72

Protection against nitric oxide toxicity by tea.

Paquay JB, Haenen GR, Stender G, Wiseman SA, Tijburg LB, Bast A

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

It is found that green tea and black tea are able to protect against nitric oxide (NO(*)) toxicity in several ways. Both green tea and black tea scavenge NO(*) and peroxynitrite, inhibit the excessive production of NO(*) by the inducible form of nitric oxide synthase (iNOS), and suppress the LPS-mediated induction of iNOS. The NO(*) scavenging activity of tea was less than that of red wine. The high activity found in the polyphenol fraction of black tea (BTP) could not be explained by the mixed theaflavin fraction (MTF) or catechins [epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate (EGCG)], which were tested separately. Synergistic effects between the compounds, or the presence of a potent, unidentified NO(*) scavenger, may explain the high activity of BTP. The peroxynitrite scavenging of tea was comparable to that of red wine. The main activity was found in the polyphenol fraction. MTF and the catechins were found to be potent peroxynitrite scavengers. Tea and tea components were effective inhibitors of iNOS. Of the tea components tested, only MTF had an activity higher than that of the tea powders. The polyphenol fractions of tea were much more active than the tea powders in suppressing the induction of iNOS. On the basis of its abundance and activity, EGCG was the most active inhibitor. The protective effect of tea on NO(*) toxicity is discussed in relation to the beneficial effect of flavonoid intake on the occurrence of cardiovascular heart disease.

176. Eur J Med Res 2000 Nov 30;5(11):463-7

The effect of sugar-free green tea chew candies on the degree of inflammation of the gingiva.

Krahwinkel T, Willershausen B

Policlinic for Restorative Dentistry, Johannes Gutenberg-University Mainz, Augustusplatz 2, D-55131 Mainz, Germany. krahwink@mail.uni-mainz.de

The components of green tea extracts such as catechins and polyphenols gain increasing significance in tumor research and immunology. - The clinical double blind study presented here was aimed at the investigation on how green tea catechins and polyphenols in the form of green tea dragees may influence the inflammatory behaviour of the gingiva. A total of 47 test persons with a mean age of 25.76 years (23 males, 24 females) were randomly divided into two groups: one group (n = 22: 11 males, 11 females) received chew candies containing green tea extracts, the other group (n = 25: 12 males, 13 females) received placebos with the same flavour but without active substances. At the beginning of the four week investigation period, a professional dental cleaning was carried out on all test persons. Then the persons were instructed to do their usual dental cleaning and chew eight candies distributed over the day. The API (approximal plaque index) and the SBI (sulcus bleeding index) were determined after seven days (API-1, SBI-1) and after another 21 days (API-2, SBI-2). Within the verum group, a mean value of 33.2% +/- 18.3% was determined for API-1, and 29.6% +/- 17.5% for API-2. The mean SBI-1 was 5.9% +/- 7.6%, and 3.6% +/- 5.8% for SBI-2. The clinical data within the placebo group were different: The plaque index values changed from API-1 30.3% +/- 16.3% after one week to API-2 31.8% +/- 17.2% after another three weeks. The values for the inflammatory degree of the gingiva had also changed to the negative: from SBI-1 3.4% +/- 4.1% after seven days to SBI-2 4.7% +/- 6.4% after another 21 days. Whereas in the verum group a distinct improvement in both API and SBI values could be stated, slight worsening of the values were determined for the placebo group. The results indicate that the oral application of green tea catechins and polyphenols might have a positive influence on the inflammatory reaction of periodontal structures.

177. J Nutr Biochem 2000 Nov;11(11-12):536-542

Chemical composition and antioxidant activity of Strobilanthes crispus leaf extract.

Ismail M, Manickam E, Danial AM, Rahmat A, Yahaya A

Department of Nutrition & Health Science, Faculty of Medicine & Health Sciences, University Putra Malaysia, Serdang, Selangor, Malaysia

[Record supplied by publisher]

This study investigated the components present in and the total antioxidant activity of leaves of Strobilanthes crispus (L.) Bremek or Saricocalyx crispus (L.) Bremek (Acanthacea). Proximate analyses and total antioxidant activity using ferric thiocyanate and thiobarbituric acid methods were employed. Minerals content was determined using the atomic absorption spectrophotometer, whereas the water-soluble vitamins were determined by means of the UV-VIS spectrophotometer (vitamin C) and fluorimeter (vitamins B(1) and B(2)). Catechin, tannin, caffeine, and alkaloid contents were also studied. All data were compared to the previously reported results of Yerbamate, green tea, black tea, and Indian tea. The dried leaves contained a high amount of total ash (21.6%) as a result of a high amount of minerals including potassium (51%), calcium (24%), sodium (13%), iron (1%), and phosphorus (1%). High content of water-soluble vitamins (C, B(1), and B(2)) contributed to the high antioxidant activity of the leaves. The leaves also contained a moderate amount of other proximate composition as well as other compounds such as catechins, alkaloids, caffeine, and tannin, contributing further to the total antioxidant activity. Catechins of Strobilanthes crispus leaves showed highest antioxidant activity when compared to Yerbamate and vitamin E. Consumption of the leafy extract daily (5 g/day) as an herbal tea could contribute to the additional nutrients and antioxidants needed in the body to enhance the defense system, especially toward the incidence of degenerative diseases.

178. Chem Biol Interact 2000 Nov 1;128(3):211-29

Comparative studies on the effects of green tea extracts and individual tea catechins on human CYP1A gene expression.

Williams SN, Shih H, Guenette DK, Brackney W, Denison MS, Pickwell GV, Quattrochi LC

Section of Medical Toxicology, Department of Medicine, University of Colorado Health Sciences Center, B146, 4200 East 9th Avenue, 80262, Denver, CO, USA.

Green tea possesses significant anticancer activity in numerous experimental animal models, including demonstrated protection against aryl hydrocarbon induced cancers. The aryl hydrocarbon receptor (AhR) mediates the transcriptional activation of CYP1A1 and CYP1A2. In the present study, we investigated the effects of commercially available green tea extracts (GTEs) and individual tea catechins on the function of the AhR and on CYP1A gene expression in human hepatoma HepG2 cells and primary cultures of human hepatocytes. GTEs inhibited the transcription of a human CYP1A1 promoter-driven reporter gene induced by the AhR ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in a concentration-dependent manner and inhibited the induced accumulation of both CYP1A1 and CYP1A2 mRNAs. GTEs blocked TCDD-induced binding of the AhR to DNA in HepG2 cells and in vitro in isolated hepatic cytosol. To determine if the observed effects were due to a single green tea component, we examined the four major catechins present in GTEs. Only (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea, was able to inhibit TCDD-induced binding of the AhR to DNA and subsequent CYP1A transcription, however EGCG alone was less effective than GTEs. We next examined GTEs and catechins for AhR agonist activity. GTEs caused a concentration-dependent increase in CYP1A1-promoter driven reporter gene activity and caused accumulation of CYP1A1 mRNA and protein, but we found that individual catechins were unable to induce the expression of CYP1A1. Our results demonstrate that GTEs as a whole exert mixed agonist/antagonist activity on the AhR, while EGCG functions as a strict AhR antagonist. Therefore, modulation of human CYP1A expression by green tea extracts can not be attributed to the action of a single tea catechin, but rather is due to the effects of a complex mixture. These findings may be useful in future studies concerning green tea as a cancer preventive agent.

179. Carcinogenesis 2000 Sep;21(9):1671-6 Prevention of the down-regulation of gap junctional intercellular communication by green tea in the liver of mice fed pentachlorophenol. Sai K, Kanno J, Hasegawa R, Trosko JE, Inoue T. Division of Cellular and Molecular Toxicology and Division of Risk Assessment, National Institute of Health Sciences, 1-18-1 Kamiyohga, Setagayaku, Tokyo 158-8501, Japan.

Much evidence has been documented supporting the hypothesis that the down-regulation of gap junctional intercellular communication (GJIC) is a cellular event underlying the tumor promotion process and that treatment to prevent the down-regulation or to up-regulate GJIC is important in preventing tumor promotion. We explored the potential preventive effects of green tea against the promoting action of pentachlorophenol (PCP) in mouse hepatocarcinogenesis, examining whether drinking green tea prevents the down-regulation of GJIC inhibition in the liver caused by tumorigenic doses of PCP. We used a modified in vivo GJIC assay, the incision loading/dye transfer method. Male B6C3F1 mice were given a green tea infusion for 1 week and then PCP was fed at a dose of 300 or 600 p.p.m. in the diet for the following 2 weeks, along with green tea treatment. A dose-related inhibition of GJIC in the hepatocytes was evident in the mice treated with PCP alone that was associated with a reduction in connexin32 (Cx32) plaques in the plasma membrane and an increase in the cell proliferation index. Drinking green tea significantly protected mice against GJIC inhibition, the reduction in Cx32 and the elevation of the labeling index. These findings suggest that green tea might act as an anti-promoter against PCP-induced mouse hepatocarcinogenesis via its ability to prevent down-regulation of GJIC.

180. Chem Res Toxicol 2000 Sep;13(9):801-10

Antioxidant chemistry of green tea catechins. New oxidation products of (-)-epigallocatechin gallate and (-)-epigallocatechin from their reactions with peroxyl radicals.

Valcic S, Burr JA, Timmermann BN, Liebler DC

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.

The green tea catechins (-)-epigallocatechin gallate (EGCG) and (-)-epigallocatechin (EGC) react with peroxyl radicals generated by thermolysis of the azo initiator 2,2'-azobis(2, 4-dimethylvaleronitrile) (AMVN) to produce several oxidation products. Structure elucidation of these products can provide insights into specific mechanisms of antioxidant reactions. We isolated and identified a previously unreported reaction product of EGCG and three reaction products of EGC. In the EGCG product, the B-ring was transformed into a ring-opened unsaturated dicarboxylic acid moiety. The EGC products include a seven-membered B-ring anhydride and a symmetrical EGC dimer, both analogues of previously described EGCG oxidation products. The third EGC product was an unsymmetrical dimer. In all identified products, changes occurred solely in the B-ring of EGCG or EGC. This confirmed our previous observation that the principal site of antioxidant reactions in EGCG and EGC is the trihydroxyphenyl B-ring, regardless of the presence of a 3-galloyl moiety. A stoichiometric factor n of 4.16 +/- 0.51 was measured for EGCG, whereas factors of 2.20 +/- 0.26 was found for EGC and 2.33 +/- 0.18 measured for methyl gallate. These values represent the net peroxyl radical trapping per catechin molecule by several competing reactions. EGCG and EGC oxidation involves addition of oxygen, which is not derived from water, but most likely from atmospheric oxygen via peroxyl radicals. Characteristic oxidation products may be useful markers for antioxidant actions in living systems.

181. Expert Opin Investig Drugs 2000 Sep;9(9):2103-19

The therapeutic potential of flavonoids.

Wang HK

University of North Carolina at Chapel Hill, Room 323, Beard Hill, Chapel Hill, NC 27599-7360, USA. hwang@email.unc.edu

Four most widely investigated flavonoids, flavopiridol, catechins, genistein and quercetin are reviewed in this article. Flavopiridol is a novel semisynthetic flavone analogue of rohitukine, a leading anticancer compound from an Indian tree. Flavopiridol inhibits most cyclin-dependent kinases and displays unique anticancer properties. It is the first cyclin-dependent kinase inhibitor to be tested in Phase II clinical trials. catechin and its gallate are major ingredients in green tea and their anti-oxidant and cancer preventive effects have been widely investigated. A Phase I study of green tea extract GTE-TP91 has been conducted in adult patients with solid tumours. Similarly, genistein is a major ingredient in soybean and has been shown to prevent cancer and have antitumour, anti-oxidant and anti-inflammatory effects. Two antibody-genistein conjugates, B43-genistein and EGF-genistein, are currently in clinical development for the treatment of acute lymphoblastic leukaemia and breast cancer, respectively. Finally, most recent updates of quercetin are briefly described.

182.J Toxicol Sci 2000 Aug;25(3):199-204

Protective effects of (-)-epigallocatechin gallate and (+)-catechin on paraquat-induced genotoxicity in cultured cells.

Tanaka R

Akita Keijo Junior College, Japan.

The protective effects of green tea polyphenols on paraquat-induced genotoxicity in cultured cells were studied. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, and (+)-catechin (CT), a minor constituent, equivalently decreased the frequencies of sister-chromatid exchanges (SCE) induced by paraquat (PQ), which is a generator of reactive oxygen species. These polyphenols were effective at concentrations of 1.0 microM and above. A reduction of the effect on the cell cycle rate caused by PQ was found when EGCG and CT were added at concentrations of more than 10.0 microM. These concentrations of EGCG and CT alone had no effect on cell cycle rate, which is used as index of cell proliferation. Decreases in the cell cycle rate were found at 200 microM EGCG and CT in the 24 hr exposure period. The equivalent effectiveness of EGCG and CT suggested the possibility of other mechanisms, apart from acting as reactive oxygen species scavengers, because it has been reported that EGCG is the most potent scavenger among tea catechins. From the present study, it was suggested that green tea and foods containing these polyphenols may be beneficial to human health by protecting against reactive oxygen species-induced genotoxicity.

183. Altern Med Rev 2000 Aug;5(4):372-5

Green tea.

Tea is one of the most widely consumed beverages in the world today, second only to water, and its medicinal properties have been widely explored. The tea plant, Camellia sinensis, is a member of the Theaceae family, and black, oolong, and green tea are produced from its leaves. It is an evergreen shrub or tree and can grow to heights of 30 feet, but is usually pruned to 2-5 feet for cultivation. The leaves are dark green, alternate and oval, with serrated edges, and the blossoms are white, fragrant, and appear in clusters or singly. Unlike black and oolong tea, green tea production does not involve oxidation of young tea leaves. Green tea is produced from steaming fresh leaves at high temperatures, thereby inactivating the oxidizing enzymes and leaving the polyphenol content intact. The polyphenols found in tea are more commonly known as flavonols or catechins and comprise 30-40 percent of the extractable solids of dried green tea leaves. The main catechins in green tea are epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate (EGCG), with the latter being the highest in concentration. green tea polyphenols have demonstrated significant antioxidant, anticarcinogenic, anti-inflammatory, thermogenic, probiotic, and antimicrobial properties in numerous human, animal, and in vitro studies.

184. J Agric Food Chem 2000 Aug;48(8):3072-6

Oxidative stability of conjugated linoleic acid isomers.

Yang L, Leung LK, Huang Y, Chen ZY

Department of Chemistry, Henan Normal University, Xinxiang, Henan, The Chinese University of Hong Kong, Shatin, New Territories.

Conjugated linoleic acids (CLAs) have been shown to be a strong anticarcinogen in a number of animal models. Our previous study demonstrated that CLA as a whole was extremely unstable in air. The present study was undertaken further to examine the oxidative stability of individual CLA isomers using the combination of gas-liquid chromatography (GLC) and silver ion high-performance liquid chromatography (Ag-HPLC). It was found that CLA as a whole oxidized rapidly and more than 80% was degraded within 110 h in air at 50 degrees C. Four c,c-CLA isomers were most unstable followed by four c,t-CLA isomers. In contrast, four t,t-CLA isomers were relatively stable under the same experimental conditions. Both the oxygen consumption and the GLC analysis revealed that 200 ppm jasmine green tea catechins (GTCs) exhibited protection to CLA and were even stronger than 200 ppm butylated hydroxytoluene (BHT) when added to either CLA or canola oil containing 10% CLA. The present study emphasized that oxidative unstability of CLA should not be overlooked although CLA has many biological effects.

185. Biol Pharm Bull 2000 Jun;23(6):695-9

Inhibitory effects of green tea and grape juice on the phenol sulfotransferase activity of mouse intestines and human colon carcinoma cell line, Caco-2.

Tamura H, Matsui M

Kyoritsu College of Pharmacy, Tokyo, Japan. tamura-hr@kyoritsu-ph.ac.jp

Tea and fruit juices are beverages consumed daily all over the world. The present study reports the inhibitory effects of these beverages on the activity of mammalian intestinal phenol sulfotransferases (P-STs). green tea strongly inhibited the E. coli-expressed mouse intestinal P-ST activity in vitro. (-)-Epigallocatechin gallate (EGCG) was found to be the most potent inhibitor among the catechins tested (IC50=0.93 microM). (-)EGCG also inhibited the P-ST activity of the human colon carcinoma cell line, Caco-2. Kinetic analysis showed that the inhibition was competitive. Among fruit juices examined (apple, grape, grapefruit and orange), grape juice exhibited the most potent inhibitory action on the P-ST activity of mouse intestines and human colon carcinoma cells. The inhibitory activity of grape juice was located mainly in the skin and seeds. Flavonols, such as quercetin and kaempferol, inhibited the P-ST activity at low concentrations. These observations suggest the possible inhibition of P-ST activity in human intestines by green tea or grape juice.

186. Phytother Res 2000 Jun;14(4):250-3

Application of flow injection--chemiluminescence to the study of radical scavenging activity in plants.

Choi HY, Jhun EJ, Lim BO, Chung IM, Kyung SH, Park DK

Department of Biochemistry, Konkuk University, Chungju, Chungbuk, Korea, 380-701.

Chemiluminescence (CL) was observed during the oxidation of luminol (2 mg/L). mediated by 0.06% hydrogen peroxide (H(2)O(2)) and cytochrome c (10 mg/L). CL intensity was decreased by the presence of radical scavengers and the reduction was linearly proportional to the concentration and ability of scavengers; butylated hydroxytoluene (BHT), caffeic acid and gallic acid. The order of effectiveness as radical scavengers was gallic acid > caffeic acid > BHT, which shows that the number of hydroxyl groups (OH) in the B-ring of flavonoids plays a key role in a good radical scavenging activity. Of eight catechins obtained from green tea extracts, (-)-catechin was the least effective and (-)-epigallocatechin gallate (EGCg) showed the strongest activity. This result indicates that the stereoscopic structure between the C-3 group and the B ring of flavonoids as well as substituents at the C-3 position make a contribution to radical scavenging activity. Of the tested Chinese herbal ingredients, five species of ingredients represented more than 90% of the radical scavenging activity.

187. Biofactors 2000;13(1-4):81-5

Tea catechins and related polyphenols as anti-cancer agents.

Isemura M, Saeki K, Kimura T, Hayakawa S, Minami T, Sazuka M

Laboratory of Cellular Biochemistry, Graduate School of Nutritional and Environmental Sciences, The University of Shizuoka, Japan.

[Medline record in process]

Epigallocatechin gallate (EGCg) and theaflavins, a major constituent of green tea infusion and the constituents of black tea, respectively, were found to inhibit matrix metalloproteinases (MMPs) which are intimately associated with tumor invasion and metastasis. EGCg and related polyphenols exhibited apoptosis-inducing activity for several cancer cell lines including human stomach and colon cancer cells. Comparison of the activity of these compounds revealed the importance of the number and the steric disposition of hydroxyl groups. A pyrogallol-type structure in a molecule is a minimum requirement for apoptosis induction of catechin compounds and that in the B ring has an important role in the activity. These data would provide useful information for designing anti-cancer agents on the basis of anti-inhibitory activity for MMPs and/or apoptosis-inducing activity.

188. FEBS Lett 2000 Apr 7;471(1):51-5

Green tea compounds inhibit tyrosine phosphorylation of PDGF beta-receptor and transformation of A172 human glioblastoma.

Sachinidis A, Seul C, Seewald S, Ahn H, Ko Y, Vetter H

Medizinische Universitats-Poliklinik, Wilhelmstr. 35-37, 53111, Bonn, Germany. sachinidis@uni-bonn.de

The effect of the green tea compounds 2-(3,4-dihydroxyphenyl)-3, 4-dihydro-2H-1-benzopyran-3,5,7-triol (catechin), epicathechin (EC), epigallocathechin-3 gallate (EGCG), epicathechin-3 gallate (ECG) and catechin-3 gallate (CG) on the tyrosine phosphorylation of PDGF beta-receptor (PDGF-Rbeta) and on the anchorage-independent growth of A172 glioblastoma cells in semisolid agar has been investigated. Treatment of A172 glioblastoma with 50 microM CG, ECG, EGCG and 25 microM Tyrphostin 1296 resulted in an 82+/-17%, 77+/-21%, 75+/-8% and 55+/-11%, respectively (mean+/-S.D., n=3) inhibition of the PDGF-BB-induced tyrosine phosphorylation of PDGF-Rbeta. The PDGF-Rbeta downstream intracellular transduction pathway including tyrosine phosphorylation of phospholipase C-gamma1 (PLC-gamma1) and phosphatidylinositol 3'-kinase (PI 3'-K) was also inhibited. Spheroid formation was completely inhibited by 50 microM ECG, CG, EGCG and by 25 microM Tyrphostin 1296. We conclude that catechins of the green tea possessing the gallate group in their chemical structure act as anticancer agents probably partly via their ability to suppress the tyrosine kinase activity of the PDGF-Rbeta.

189. Biochim Biophys Acta 2000 Mar 16;1478(1):51-60

Matrix metalloproteinase inhibition by green tea catechins.

Demeule M, Brossard M, Page M, Gingras D, Beliveau R

Laboratoire de Medecine Moleculaire, Hopital Sainte-Justine - UQAM, C.P. 8888, Succursale centre-ville, Montreal, QC, Canada.

We have investigated the effects of different biologically active components from natural products, including green tea polyphenols (GTP), resveratrol, genistein and organosulfur compounds from garlic, on matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 activities. GTP caused the strongest inhibition of the three enzymes, as measured by fluorescence assays using gelatin or elastin as substrates. The inhibition of MMP-2 and MMP-9 caused by GTP was confirmed by gelatin zymography and was observed for MMPs associated with both various rat tissues and human brain tumors (glioblastoma and pituitary tumors). The activities of MMPs were also measured in the presence of various catechins isolated from green tea including (-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate(ECG), (-)-epigallocatechin (EGC), (-)-epicatechin (EC) and (+)-catechin (C). The most potent inhibitors of these activities, as measured by fluorescence and by gelatin or casein zymography, were EGCG and ECG. GTP and the different catechins had no effect on pancreatic elastase, suggesting that the effects of these molecules on MMP activities are specific. Furthermore, in vitro activation of proMMP-2 secreted from the glioblastomas cell line U-87 by the lectin concanavalin A was completely inhibited by GTP and specifically by EGCG. These results indicate that catechins from green tea inhibit MMP activities and proMMP-2 activation.

190. Endocrinology 2000 Mar;141(3):980-7

Modulation of endocrine systems and food intake by green tea epigallocatechin gallate.

Kao YH, Hiipakka RA, Liao S

Ben May Institute for Cancer Research, Department of Biochemistry and Molecular Biology, and Tang Center for Herbal Medicine Research, University of Chicago, Illinois 60637, USA.

Green tea polyphenols, especially the catechin, (-)-epigallocatechin gallate (EGCG), have been proposed as a cancer chemopreventative based on a variety of laboratory studies. For clear assessment of the possible physiological effects of green tea consumption, we injected pure green tea catechins ip into rats and studied their acute effects on endocrine systems. We found that EGCG, but not related catechins, significantly reduced food intake; body weight; blood levels of testosterone, estradiol, leptin, insulin, insulin-like growth factor I, LH, glucose, cholesterol, and triglyceride; as well as growth of the prostate, uterus, and ovary. Similar effects were observed in lean and obese male Zucker rats, suggesting that the effect of EGCG was independent of an intact leptin receptor. EGCG may interact specifically with a component of a leptin-independent appetite control pathway. Endocrine changes induced by parenteral administration of EGCG may relate to the observed growth inhibition and regression of human prostate and breast tumors in athymic mice treated with EGCG as well as play a role in the mechanism by which EGCG inhibits cancer initiation and promotion in various animal models of cancer.

191. Eur J Clin Nutr 2000 Jan;54(1):87-92

A single dose of tea with or without milk increases plasma antioxidant activity in humans.

Leenen R, Roodenburg AJ, Tijburg LB, Wiseman SA

Unilever Nutrition Centre, Unilever Research Vlaardingen, PO Box 114, 3130 AC Vlaardingen, The Netherlands.

OBJECTIVE: To investigate the effect of black and green tea consumption, with and without milk, on the plasma antioxidant activity in humans. DESIGN: In a complete cross-over design, 21 healthy volunteers (10 male, 11 female) received a single dose of black tea, green tea (2 g tea solids in 300 ml water) or water with or without milk. Blood samples were obtained at baseline and at several time points up to 2 h post-tea drinking. Plasma was analysed for total catechins and antioxidant activity, using the ferric reducing ability of plasma (FRAP) assay. RESULTS: Consumption of black tea resulted in a significant increase in plasma antioxidant activity reaching maximal levels at about 60 min. A larger increase was observed after consumption of green tea. As anticipated from the higher catechin concentration in green tea, the rise in plasma total catechins was significantly higher after consumption of green tea when compared to black tea. Addition of milk to black or green tea did not affect the observed increases in plasma antioxidant activity. CONCLUSIONS: Consumption of a single dose of black or green tea induces a significant rise in plasma antioxidant activity in vivo. Addition of milk to tea does not abolish this increase. Whether the observed increases in plasma antioxidant activity after a single dose of tea prevent in vivo oxidative damage remains to be established. European Journal of Clinical Nutrition (2000) 54, 87-92

192. Food Chem Toxicol 2000 Jan;38(1):7-13

Inhibitory effects of tea extracts on the mutagenicity of 1-methyl-1, 2,3,4-tetrahydro-beta-carboline-3-carboxylic acid on treatment with nitrite in the presence of ethanol.

Higashimoto M, Akada Y, Sato M, Kinouchi T, Kuwahara T, Ohnishi Y

Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.

It has been shown that the mutagenicity of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid (MTCCA), a major mutagen precursor in soy sauce on treatment with nitrite and ethanol, was strongly decreased by the addition of hot water extracts of green, black and oolong teas in the reaction mixture when it was treated with 50mM nitrite at pH3.0, 37 degrees C for 60min in the presence of 7.5% ethanol. The mutagenicity-decreasing activity of the teas was scarcely decreased by washing the teas with chloroform and benzene and was partly decreased by butanol and ethyl acetate. Typical polyphenols such as catechins were shown to have the antimutagenicity dose dependently. The antimutagenicity and the reducing power of tea extracts gave a positive good correlation. The results suggest that the mutagenicity of MTCCA on treatment with nitrite in the presence of ethanol may be decreased by the mixed fractions of lyophilic components such as polyphenols, which have high reducing power such as catechins and the other compounds which have little reducing power including the derivatives of the catechins and so on. Although the antimutagenicity of teas and catechins was also considerably effective when they were added after the nitrosation, that of black tea and some catechins was less effective.

193.Atherosclerosis 2000 Jan;148(1):67-73

Inhibitory effect of Chinese green tea on endothelial cell-induced LDL oxidation.

Yang TT, Koo MW

Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, 1/F Li Shu Fan Building, 5 Sassoon Road, Hong Kong.

Green tea has been shown to inhibit Cu(2+)-induced LDL oxidation and suppress lipoxygenase activity. Since LDL oxidation is a characteristic feature of atherogenesis and lipoxygenase is involved in the disease process, the effect of Lung Chen Tea, a non-fermented Chinese green tea, on LDL oxidation induced by human umbilical cord vascular endothelial cell was investigated in the present study. Lung Chen Tea was extracted with methanol and the dried powder was redissolved in water before extraction with chloroform and then ethyl acetate. Lung Chen Tea, chloroform and ethyl acetate fractions dose-dependently reduced LDL oxidation and decreased its relative electrophoretic mobility (P<0.001) when compared to the oxidized LDL. The lipid peroxidation products, thiobarbituric acid reactive substances, and cellular cholesterol were also significantly lowered by 5 and 10 microg/ml Lung Chen Tea (P<0.001) in a dose-dependent manner. The remaining aqueous layer, which was devoid of catechins after chloroform and ethyl acetate extractions, did not prevent LDL oxidation. The results of this study demonstrated that Lung Chen Tea and catechin-rich fractions significantly prevented endothelial cell induced LDL oxidation. The consumption of Lung Chen Tea may therefore lower the risk of coronary heart diseases.

194. Biofactors 2000;13(1-4):73-9

Mechanisms of inhibition of carcinogenesis by tea.

Yang CS, Chung JY, Yang GY, Li C, Meng X, Lee MJ

Laboratory Cancer Research, College of Pharmacy Rutgers, The State University of New Jersey, Piscataway 08854-8020, USA. csyang@rci.rutgers.edu

[Medline record in process]

Tea (Camellia sinensis) preparations have been shown to inhibit tumorigenesis at the initiation, promotion, and progression stages in different animal models. The anti-proliferative effects of tea polyphenols may be a key mechanism, especially in the NNK-induced lung tumorigenesis model with mice. Studies with cell lines have demonstrated that tea polyphenols inhibit cell proliferation and induce apoptosis. The effective concentrations used in these studies (20-100 microM) are usually higher than those observed in blood and tissues of humans and animals, which are in the low micromolar range. Glucuronide and sulfate conjugated and methylated catechins as well as ring fission products (due to intestinal microflora) have been observed in human plasma and urine. Purified green and black tea polyphenols inhibited the H-ras induced milogen-activated protein kinases, AP-1 activities, and the growth of 30.7b Ras 12 and BES21 cells. Among the catechins, both the galloyl structure on the B ring and the gallate moiety are important for the inhibition. Both (-)-epigallocatechin-3-gallate and theaflavin-3,3'-digallate inhibited the phosphorylation of c-jun and p44/42 (ERK 1/2). More mechanistic and human studies in these areas will help us to understand the possible inhibitory action of tea against carcinogenesis in humans.

195. Biofactors 2000;13(1-4):61-5

Regulation of intestinal glucose transport by tea catechins.

Shimizu M, Kobayashi Y, Suzuki M, Satsu H, Miyamoto Y

Department of Applied Biological Chemistry, The University of Tokyo, Japan.

[Medline record in process]

Intestinal glucose uptake is mainly performed by its specific transporters, such as SGLT 1, GLUT 2 and 5 expressed in the intestinal epithelial cells. By using human intestinal epithelial Caco-2 cells we observed that intestinal glucose uptake was markedly inhibited by tea extracts. While several substances in green tea seem to be involved in this inhibition, catechins play the major role and epicatechin gallate (ECg) showed the highest inhibitory activity. Since our Caco-2 cells did not express enough amount of SGLT 1, the most abundant intestinal glucose transporter, the effect of ECg on SGLT 1 was evaluated by using brush border membrane vesicles obtained from the rabbit small intestine. ECg inhibited SGLT 1 in a competitive manner, although ECg itself was not transported via the glucose transporters. These results suggest that tea catechins could play a role in controlling the dietary glucose uptake at the intestinal tract and possibly contribute to blood glucose homeostasis.

196. Biofactors 2000;13(1-4):55-9

Absorption, metabolism and antioxidative effects of tea catechin in humans.

Miyazawa T

Biodynamics Chemistry, Lab., Tohoku University Graduate School of Life Science & Agriculture, Sendai, Japan. miyazawa@biochem.tohoku.ac.jp

[Medline record in process]

Green tea is consumed as a popular beverage in Japan and throughout the world. During the past decade, epidemiological studies have shown that tea catechin intake is associated with lower risk of cardiovascular disease. In vitro biochemical studies have reported that catechins, particularly epigallocatechin-3-gallate (EGCg), help to prevent oxidation of plasma low-density lipoprotein (LDL). LDL oxidation has been recognized to be an important step in the formation of atherosclerotic plaques and subsequent cardiovascular disease. Metabolic studies have shown that EGCg supplement is incorporated into human plasma at a maximum concentration of 4400 pmol/mL. Such concentrations would be enough to exert antioxidative activity in the blood stream. The potent antioxidant property of tea catechin may be beneficial in preventing the oxidation of LDL. It is of interest to examine the effect of green tea catechin supplementation on antioxidant capacity of plasma in humans by measuring plasma phosphatidylcholine hydroperoxide (PCOOH) as a marker of oxidized lipoproteins.

197. Biofactors 2000;12(1-4):45-51

Role of diet modification in cancer prevention.

Abdulla M, Gruber P

Trace Element-Institute for UNESCO, Lyon, France.

[Medline record in process]

Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and include both genetic and biochemical changes in the cells. At each of these levels, there are several possibilities of intervention in order to prevent, slow down or even halt the gradual march of healthy cells towards malignancy. Diet modification is one such possibility. A number of natural foodstuffs, especially fruits and vegetables contain substantial quantities of molecules that have chemopreventive potential against cancer development. Such compounds include vitamins, trace elements and a variety of other molecules with antioxidant properties. Carotenoids, flavanoid polyphenols, isoflavones, catechins, and several other components that found in cruciferous vegetables are molecules that are known to protect against the deleterious effect of reactive oxygen species. A number of epidemiological and experimental studies have shown that vitamin C and E, Beta-carotene and the essential trace element selenium can reduce the risk of cancer. Consistent observations during the last few decades that cancer risk is reduced by a diet rich in vegetables, fruits, legumes, grains and green tea have encouraged research to identify several plant components especially phytochemicals that protect against DNA damage. Many of these substances block specific carcinogen pathways. Dietary supplements are part of an overall health program, along with a high intake of fruits and vegetables that help to combat damage to cells, which in turn may initiate cancer development. This paper will review current knowledge concerning diet modification and cancer prevention with special reference to minerals and trace elements.

198. J Mol Med 2000;78(6):333-6

Molecular mechanisms of anticancer activity of natural dietetic products.

Colic M, Pavelic K

R&D Division, Molecutec Corporation, Goleta, CA 93117, USA.

The efficiency of dietetic supplements in cancer prevention and treatment is a popular and controversial subject of research. New in vitro and in vivo research results indicate that some dietetic supplements do indeed show anticancer activity. The strongest anticancer action has been demonstrated by natural compounds with multifunctional activity. For instance, antioxidants, which also bind to and modulate the activity of protein kinases involved in signal transduction cascades show both cytostatic and cytotoxic activity towards cancer cells. Other activities such as angiogenesis inhibition, nitric oxide synthase inhibition, and pro-oxidants production have also been observed. catechins and polyphenols from plant extracts such as green tea show the strongest anticancer activity. The initial clinical trials with some flavonoid molecules are already underway.

199. Nutr Cancer 2000;37(1):41-8

Plasma and tissue levels of tea catechins in rats and mice during chronic consumption of green tea polyphenols.

Kim S, Lee MJ, Hong J, Li C, Smith TJ, Yang GY, Seril DN, Yang CS

Laboratory for Cancer Research, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08854-8020, USA.

[Medline record in process]

To understand the relationship between tea consumption and its biological effects, plasma and tissue levels of (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin (EC) were measured after rats and mice were given a 0.6% green tea polyphenol preparation as the drinking fluid for different periods of time. EGC and EC levels in rat plasma increased over time and reached peak values (3 times the Day 1 values) on Day 14. Then the plasma levels of tea catechins decreased, to Day 1 values on Day 28. The plasma concentrations of EGCG were much lower than those of EGC or EC. High levels of EGC and EC were found in urine, whereas high levels of EGCG were found in feces. The changes in the urinary and fecal excretions of tea catechins could not account for the above-described changes in the plasma levels. The amounts of catechins in different tissues reflected the ingestion, absorption, and excretion pattern. When the green tea polyphenol preparation was given to mice, the "increase-and-then-decrease" pattern of catechin levels was also observed in the plasma, lung, and liver; the EGCG levels were much higher than in the rats. The results suggest that consumption of tea by rodents could induce adaptive responses affecting blood and tissue levels of tea catechins with time and that investigation of a similar phenomenon in humans is warranted.

200. J Nutr 1999 Dec;129(12):2130-4

Supplementation of Jurkat T cells with green tea extract decreases oxidative damage due to iron treatment.

Erba D, Riso P, Colombo A, Testolin G

Department of Food Science and Microbiology, Division of Human Nutrition, University of Milan, Milan, Italy.

Regular tea consumption has been associated with a reduced risk of cancer. As demonstrated in vitro, green tea contains catechins with antioxidant properties. We evaluated the effect of the supplementation of the Jurkat T-cell line with green tea extract on oxidative damage. Cells grown in medium with or without green tea extract (10 mg/L) were treated with Fe(2+) (100 &mgr;mol/L) as an oxidative stimulus for 2 h. Cell membrane lipid peroxidation was evaluated by fatty acids pattern analysis and malondialdehyde production in alpha-linolenic acid-loaded cells. Furthermore, oxidative DNA damage (single strand breaks) was detected in cells by the Comet assay and quantified as relative tail moment (RTM). Supplementation with green tea extract significantly decreased malondialdehyde production (1.6 +/- 0.3 vs. 0.6 +/- 0.1 nmol/mg protein, P < 0.05) and DNA damage (0.32 +/- 0.07 vs. 0.12 +/- 0.04 RTM, P < 0.05) after Fe(2+) oxidative treatment. In control cells, there was no effect on membrane distribution of (n-3) fatty acids due to Fe(2+) treatment. Cell enrichment with alpha-linolenic acid increased total membrane (n-3) fatty acids. However, the oxidative treatment did not modify the distribution of polyunsaturated fatty acids. It is likely that the observed protective effects can be attributed to epigallocatechin gallate, which is present mainly (670 g/kg) in green tea extract; however, we cannot exclude contributions by other catechins. These data support a protective effect of green tea against oxidative damage.