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LDL oxidation

1. Clin Chem. 2000 Nov;46(11):1818-29.

Influence of increased fruit and vegetable intake on plasma and lipoprotein carotenoids and LDL oxidation in smokers and nonsmokers.

Chopra M, O'Neill ME, Keogh N, Wortley G, Southon S, Thurnham DI.

Northern Ireland Centre for Diet and Health, School of Biomedical Sciences, University of Ulster, Coleraine, County Londonderry, Northern Ireland BT52 1SA, United Kingdom. M.Chopra@ulst.ac.uk

BACKGROUND: Epidemiological studies suggest a cardioprotective role for carotenoid-rich foods. Smokers have a high risk of cardiovascular disease and low dietary intake and plasma concentrations of carotenoids. The aim of this study was to determine the carotenoid response of smokers and nonsmokers to increased intake of 300-400 g of vegetables and its effect on LDL oxidation. METHODS: After a depletion period of 8 days, 34 healthy females (18 nonsmokers, 16 smokers) were supplemented with beta-carotene- and lutein-rich (green) and lycopene-rich (red) vegetable foods, each for 7 days. RESULTS: Baseline concentrations (mean +/- SD) of plasma beta-carotene (0.203+/-0.28 micromol/L vs. 0.412+/-0.34 micromol/L; P <0.005) and lutein (0.180 +/-0.10 vs. 0.242+/-0.11 micromol/L; P<0.05) but not lycopene (0.296+/-0.10 vs. 0.319+/-0.33 micromol/L) were significantly lower in smokers compared with nonsmokers. After supplementation, the change (supplementation minus depletion) in plasma beta-carotene (0.152+/- 0.43 vs. 0.363+/-0.29 micromol/L in smokers vs. nonsmokers; P = 0.002) and LDL lutein (0.015+/-0.03 vs. 0.029+/-0.03 micromol/mmol cholesterol; P = 0.01) was significantly lower in smokers than nonsmokers. Green-vegetable supplementation had no effect on the resistance of LDL to oxidation (lag-phase) in either group. After red-vegetable supplementation, plasma and LDL lycopene concentrations were increased in both groups, but only nonsmokers showed a significant increase in the lag-phase (44.9+/-9.5 min at baseline, 41.4+/-6.5 min after depletion, and 49.0+/-8.9 min after supplementation; P<0.01) compared with depletion. CONCLUSIONS: In this short-term intervention study, a dietary intake of >40 mg/day of lycopene by a group of nonsmoking individuals significantly reduced the susceptibility of LDL to oxidation, whereas an equivalent increase in lycopene by a group of smokers showed no such effect.

2. Antioxid Redox Signal. 2000 Fall;2(3):491-506.

Lycopene synergistically inhibits LDL oxidation in combination with vitamin E, glabridin, rosmarinic acid, carnosic acid, or garlic.

Fuhrman B, Volkova N, Rosenblat M, Aviram M.

Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.

Several lines of evidence suggest that oxidatively modified low-density lipoprotein (LDL) is atherogenic, and that atherosclerosis can be attenuated by natural antioxidants, which inhibit LDL oxidation. This study was conducted to determine the effect of tomato lycopene alone, or in combination with other natural antioxidants, on LDL oxidation. LDL (100 microg of protein/ml) was incubated with increasing concentrations of lycopene or of tomato oleoresin (lipid extract of tomatoes containing 6% lycopene, 0.1% beta-carotene, 1% vitamin E, and polyphenols), after which it was oxidized by the addition of 5 micromol/liter of CuSO4. Tomato oleoresin exhibited superior capacity to inhibit LDL oxidation in comparison to pure lycopene, by up to five-fold [97% vs. 22% inhibition of thiobarbituric acid reactive substances (TBARS) formation, and 93% vs. 27% inhibition of lipid peroxides formation, respectively]. Because tomato oleoresin also contains, in addition to lycopene, vitamin E, flavonoids, and phenolics, a possible cooperative interaction between lycopene and such natural antioxidants was studied. A combination of lycopene (5 micromol/liter) with vitamin E (alpha-tocopherol) in the concentration range of 1-10 micromol/liter resulted in an inhibition of copper ion-induced LDL oxidation that was significantly greater than the expected additive individual inhibitions. The synergistic antioxidative effect of lycopene with vitamin E was not shared by gamma-to-cotrienol. The polyphenols glabridin (derived from licorice), rosmarinic acid or carnosic acid (derived from rosemary), as well as garlic (which contains a mixture of natural antioxidants) inhibited LDL oxidation in a dose-dependent manner. When lycopene (5 micromol/liter) was added to LDL in combination with glabridin, rosmarinic acid, carnosic acid, or garlic, synergistic antioxidative effects were obtained against LDL oxidation induced either by copper ions or by the radical generator AAPH. Similar interactive effects seen with lycopene were also observed with beta-carotene, but, however, to a lesser extent of synergism. Because natural antioxidants exist in nature in combination, the in vivo relevance of lycopene in combination with other natural antioxidants was studied. Four healthy subjects were administered a fatty meal containing 30 mg of lycopene in the form of tomato oleoresin. The lycopene concentration in postprandial plasma was elevated by 70% in comparison to plasma obtained before meal consumption. Postprandial LDL isolated 5 hr after meal consumption exhibited a significant (p < 0.01) reduced susceptibility to oxidation by 21%. We conclude that lycopene acts synergistically, as an effective antioxidant against LDL oxidation, with several natural antioxidants such as vitamin E, the flavonoid glabridin, the phenolics rosmarinic acid and carnosic acid, and garlic. These observations suggest a superior antiatherogenic characteristic to a combination of different natural antioxidants over that of an individual one.

3. Diabetes Care. 2000 Jun;23(6):733-8.

Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.

Upritchard JE, Sutherland WH, Mann JI.

Department of Human Nutrition, University of Otago, Dunedin, New Zealand.

OBJECTIVE: To compare the effects of short-term dietary supplementation with tomato juice, vitamin E, and vitamin C on susceptibility of LDL to oxidation and circulating levels of C-reactive protein (C-RP) and cell adhesion molecules in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 57 patients with well-controlled type 2 diabetes aged <75 years treated with placebo for 4 weeks and then randomized to receive tomato juice (500 ml/day), vitamin E (800 U/day), vitamin C (500 mg/day), or continued placebo treatment for 4 weeks. Susceptibility of LDL to oxidation (lag time) and plasma concentrations of lycopene, vitamin E, vitamin C, C-RP, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 were measured at the beginning of the study, after the placebo phase, and at the end of the study. RESULTS: Plasma lycopene levels increased nearly 3-fold (P = 0.001), and the lag time in isolated LDL oxidation by copper ions increased by 42% (P = 0.001) in patients during supplementation with tomato juice. The magnitude of this increase in lag time was comparable with the corresponding increase during supplementation with vitamin E (54%). Plasma C-RP levels decreased significantly (-49%, P = 0.004) in patients who received vitamin E. Circulating levels of cell adhesion molecules and plasma glucose did not change significantly during the study. CONCLUSIONS: This study indicates that consumption of commercial tomato juice increases plasma lycopene levels and the intrinsic resistance of LDL to oxidation almost as effectively as supplementation with a high dose of vitamin E, which also decreases plasma levels of C-RP, a risk factor for myocardial infarction, in patients with diabetes. These findings may be relevant to strategies aimed at reducing risk of myocardial infarction in patients with diabetes.

Lipids. 1998 Oct;33(10):981-4.

Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study.

4. Agarwal S, Rao AV.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Ontario, Canada.

Increase in low density lipoprotein (LDL) oxidation is hypothesized to be causally associated with increasing risk of atherosclerosis and coronary heart disease. In recent epidemiological studies, tissue and serum levels of lycopene, a carotenoid available from tomatoes, have been found to be inversely related to risk of coronary heart disease. A study was undertaken to investigate the effect of dietary supplementation of lycopene on LDL oxidation in 19 healthy human subjects. Dietary lycopene was provided using tomato juice, spaghetti sauce, and tomato oleoresin for a period of 1 wk each. Blood samples were collected at the end of each treatment. Serum lycopene was extracted and measured by high-performance liquid chromatography using an absorbance detector. Serum LDL was isolated by precipitation with buffered heparin, and thiobarbituric acid-reactive substances (TBARS) and conjugated dienes (CD) were measured to estimate LDL oxidation. Both methods, to measure LDL oxidation LDL-TBARS and LDL-CD, were in good agreement with each other. Dietary supplementation of lycopene significantly increased serum lycopene levels by at least twofold. Although there was no change in serum cholesterol levels (total, LDL, or high-density lipoprotein), serum lipid peroxidation and LDL oxidation were significantly decreased. These results may have relevance for decreasing the risk for coronary heart disease.

Lung Cancer/function

5. Am J Clin Nutr. 2000 Oct;72(4):990-7.

Comment in: Am J Clin Nutr. 2000 Oct;72(4):901-2. Am J Clin Nutr. 2001 Aug;74(2):273-4.

Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts.

Michaud DS, Feskanich D, Rimm EB, Colditz GA, Speizer FE, Willett WC, Giovannucci E.

Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.

BACKGROUND: Carotenoids may reduce lung carcinogenesis because of their antioxidant properties; however, few studies have examined the relation between intakes of individual carotenoids and lung cancer risk. OBJECTIVE: The aim of this study was to examine the relation between lung cancer risk and intakes of alpha-carotene, beta-carotene, lutein, lycopene, and beta-cryptoxanthin in 2 large cohorts. DESIGN: During a 10-y follow-up period, 275 new cases of lung cancer were diagnosed in 46924 men; during a 12-y follow-up period, 519 new cases were diagnosed in 77283 women. Carotenoid intakes were derived from the reported consumption of fruit and vegetables on food-frequency questionnaires administered at baseline and during follow-up. The data were analyzed separately for each cohort and the results were pooled to compute overall relative risks (RRs). RESULTS: In the pooled analyses, alpha-carotene and lycopene intakes were significantly associated with a lower risk of lung cancer; the association with beta-carotene, lutein, and beta-cryptoxanthin intakes were inverse but not significant. Lung cancer risk was significantly lower in subjects who consumed a diet high in a variety of carotenoids (RR: 0.68; 95% CI: 0.49, 0.94 for highest compared with lowest total carotenoid score category). Inverse associations were strongest after a 4-8-y lag between dietary assessment and date of diagnosis. In subjects who never smoked, a 63% lower incidence of lung cancer was observed for the top compared with the bottom quintile of alpha-carotene intake (RR: 0.37; 95% CI: 0.18, 0.77). CONCLUSION: Data from 2 cohort studies suggest that several carotenoids may reduce the risk of lung cancer.

6. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):790-5.

Serum carotenoids, alpha-tocopherol, and lung function among Dutch elderly.

Grievink L, de Waart FG, Schouten EG, Kok FJ.

Division of Human Nutrition and Epidemiology, Wageningen University and Research Center, Wageningen, The Netherlands.

Antioxidant vitamins (provitamins) may protect against loss of lung function over time. We studied the association between serum carotenoids (alpha-carotene, beta-carotene, lycopene, beta-cryptoxanthin, zeaxanthin, and lutein), alpha-tocopherol, and lung function among noninstitutionalized Dutch elderly age 65 to 85 yr (n = 528). Multiple linear regression analysis was performed with FEV(1) or FVC as dependent variables and serum levels of antioxidants in quintiles as independent variables. We adjusted for age, gender, height, and pack-years of smoking. Subjects in the fifth quintile of serum beta-carotene had a 195 ml (95% confidence interval [95% CI]: 40 to 351 ml) higher and those in the fifth quintile of alpha-carotene had a 257 ml (95% CI: 99 to 414 ml) higher FEV(1) compared with subjects in the first quintile of these carotenoids. Significant (p < 0.05) positive trends were observed between alpha-carotene, beta-carotene, lycopene, and FEV(1) and between alpha-carotene, beta-carotene, and FVC. Subjects in the highest quintile of the other carotenoids or alpha-tocopherol did not have significantly higher FEV(1) or FVC compared with subjects in the first quintile of these antioxidants. In conclusion, this study shows that from the six major serum carotenoids and alpha-tocopherol studied, particularly alpha-carotene, beta-carotene, and lycopene were positively associated with lung function in the elderly and may be considered as candidates for further investigations.

Gastric ulcer

7. J Clin Gastroenterol. 2000 Jun;30(4):381-5.

Comment in: J Clin Gastroenterol. 2000 Jun;30(4):341-2. J Clin Gastroenterol. 2001 Jan;32(1):91-2.

Micronutrient antioxidants in gastric mucosa and serum in patients with gastritis and gastric ulcer: does Helicobacter pylori infection affect the mucosal levels?

Nair S, Norkus EP, Hertan H, Pitchumoni CS.

Division of Gastroenterology, Johns Hopkins University School of Medicine Baltimore, Maryland, USA.

Free radicals (FRs) play an important role in the pathogenesis of gastroduodenal mucosal inflammation, peptic ulcer disease, and probably even gastric cancer. Various micronutrients protect the gastric mucosa by scavenging FRs. Only limited data is available regarding the concentration of micronutrients in the gastric mucosa in patients with gastritis and peptic ulcer disease. Our aim was to analyze micronutrient antioxidant concentrations in the antral mucosa in patients with gastritis and gastric ulcer and to determine the influence of Helicobacter pylori infection on gastric mucosal antioxidants in patients with gastritis and gastric ulcer. Patients who underwent upper endoscopy for evaluation of dyspepsia were included in the study. Ascorbic acid, alpha-tocopherol, alpha-carotene, beta-carotene, total carotenoids, lutein, cryptoxanthin, and lycopene levels were measured in the sera and antral mucosal biopsies in these patients. The diagnosis of H. pylori was confirmed by histology, urease test (CLO) and serology. Patients with negative endoscopic findings and normal histology and no H. pylori infection served as controls. In patients with gastritis, alpha-tocopherol levels were reduced in serum and mucosa irrespective of H. pylori status, whereas carotenoids and ascorbic acid levels were similar to controls. However, in patients with gastric ulcer, serum and mucosal levels of all micronutrient antioxidants were markedly decreased compared with both controls and patients with gastritis. The degree of depletion of antioxidants was similar in patients with either H. pylori-induced or nonsteroidal antiinflammatory drug (NSAID)-induced ulcers. Patients with gastric ulcer have very low gastric antioxidant concentrations compared to patients with gastritis and normal mucosa. This depletion in antioxidants seems to be a nonspecific response and was not related to H. pylori infection.

Homocysteine

8. J Nutr. 2000 Jun;130(6):1578-83.

Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans.

Broekmans WM, Klopping-Ketelaars IA, Schuurman CR, Verhagen H, van den Berg H, Kok FJ, van Poppel G.

TNO Nutrition and Food Research, 3700 AJ Zeist, The Netherlands.

Observational epidemiologic studies have shown that a high consumption of fruits and vegetables is associated with a decreased risk of chronic diseases. Little is known about the bioavailability of constituents from vegetables and fruits and the effect of these constituents on markers for disease risk. Currently, the recommendation is to increase intake of a mix of fruits and vegetables ("five a day"). We investigated the effect of this recommendation on plasma carotenoids, vitamins and homocysteine concentrations in a 4-wk dietary controlled, parallel intervention study. Male and female volunteers (n = 47) were allocated randomly to either a daily 500-g fruit and vegetable ("high") diet or a 100-g fruit and vegetable ("low") diet. Analyzed total carotenoid, vitamin C and folate concentrations of the daily high diet were 13.3 mg, 173 mg and 228.1 microg, respectively. The daily low diet contained 2.9 mg carotenoids, 65 mg vitamin C and 131.1 microg folate. Differences in final plasma levels between the high and low group were as follows: lutein, 46% [95% confidence interval (CI) 28-64]; beta-cryptoxanthin, 128% (98-159); lycopene, 22% (8-37); alpha-carotene, 121% (94-149); beta-carotene, 45% (28-62); and vitamin C, 64% (51-77) (P < 0.05). The high group had an 11% (-18 to -4) lower final plasma homocysteine and a 15% (0.8-30) higher plasma folate concentration compared with the low group (P < 0.05). This is the first trial to show that a mix of fruits and vegetables, with a moderate folate content, decreases plasma homocysteine concentrations in humans.

Diabetes

9. Diabetes Metab Res Rev. 2000 Jan-Feb;16(1):15-9.

Plasma levels of lipophilic antioxidants in very old patients with type 2 diabetes.

Polidori MC, Mecocci P, Stahl W, Parente B, Cecchetti R, Cherubini A, Cao P, Sies H, Senin U.

Institute of Gerontology and Geriatrics, Perugia University Hospital, Perugia, Italy. polidori@uni-duesseldorf.de

BACKGROUND: Experimental research indicates that oxidative stress is implicated in aging and in the pathogenesis of diabetes and its complications. This evidence is limited in elderly patients with non-insulin dependent diabetes, in which age- and disease-related production of reactive oxygen species might exert synergistic damaging effects on tissues and organs. METHODS: Plasma levels of lipid-soluble compounds with antioxidant properties including vitamin A, vitamin E and carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) were measured by HPLC in 72 elderly patients with non-insulin dependent diabetes (75.7+/-0.8 years, 40 F, 32 M) and in 75 age-matched controls (77.2+/-1.2 years, 48 F, 27 M). RESULTS: All compounds measured were significantly lower in plasma from diabetic patients as compared to controls (p<0.0001). Plasma levels of vitamins A and E and of carotenoids did not significantly correlate with dietary intake and lipid profile in both groups. In patients, significant inverse correlations were found between age and levels of vitamin E, beta-cryptoxanthin, lycopene and beta-carotene. CONCLUSIONS: We conclude that patients of very old age with Type 2 diabetes show a poor plasma status of vitamins A and E and carotenoids, which negatively correlates with age. Further studies are needed to explore the possible therapeutic role of lipid-soluble vitamin supplements in elderly diabetic subjects. Copyright 2000 John Wiley & Sons, Ltd.

10. Am J Clin Nutr. 2001 Jan;73(1):68-74.

Differences in body fat distribution and antioxidant status in Korean men with cardiovascular disease with or without diabetes.

Jang Y, Lee JH, Cho EY, Chung NS, Topham D, Balderston B.

Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University, Seoul, Korea.

BACKGROUND: Abnormal body fat distribution and reduced antioxidant status have been shown to be effective markers of risk of cardiovascular disease (CVD). OBJECTIVE: The objective of this study was to determine the differences in body fat distribution and antioxidant status in healthy men (control subjects) and in men with CVD with or without diabetes. DESIGN: An oral-glucose-tolerance test was performed and CVD patients were subdivided into groups according to the presence or absence of diabetes. Adipose tissue areas were calculated from computed tomography scans made at the L1 and L4 vertebrae. Fasting serum concentrations of lipids, testosterone, insulin-like growth factor I, antioxidants, and plasma homocysteine were determined. RESULTS: There were no significant differences in mean age, body mass index (in kg/m(2)), or blood pressure between the groups. The visceral fat area at the L1 vertebra was nonsignificantly greater in CVD patients without diabetes than in control subjects, whereas it was significantly greater in CVD patients with diabetes than in control subjects at both the L1 and L4 vertebrae. Both groups of CVD patients had higher plasma concentrations of homocysteine and lower serum insulin-like growth factor I concentrations and superoxide dismutase activities than did control subjects. Serum ss-carotene and lycopene concentrations were lowest in the CVD patients with diabetes. CONCLUSION: The concurrent presence of CVD and diabetes is associated with a greater negative effect on the risk factors typically associated with significant declines in health status.

Heart

11. J Nutr. 2003 Jul;133(7):2336-41.

Dietary lycopene, tomato-based food products and cardiovascular disease in women.

Sesso HD, Liu S, Gaziano JM, Buring JE.

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. hsesso@hsph.harvard.edu

In addition to the inverse association of dietary lycopene with various cancers, studies suggest a role for lycopene in cardiovascular disease (CVD) prevention. We determined whether the intake of lycopene or tomato-based foods is associated with the risk of CVD in a prospective cohort of 39,876 middle-aged and older women initially free of CVD and cancer. Participants completed a food-frequency questionnaire and provided self-reports of coronary risk factors. Dietary lycopene levels were divided into quintiles, and primary lycopene food sources (total tomato-based products, including tomatoes, tomato juice, tomato sauce and pizza) were categorized. During 7.2 y of follow-up, 719 CVD cases (including myocardial infarction, stroke, revascularization and CVD death) occurred. Compared with women in the 1st quintile of lycopene, those in increasing quintiles had multivariate relative risks (RR) of CVD of 1.11, 1.14, 1.15 and 0.90 (P for trend = 0.34). For the consumption of tomato-based products, women consuming 1.5 to <4, 4 to <7, 7 to <10 and >or=10 servings/wk had RR (95% CI) of CVD of 1.02 (0.82-1.26), 1.04 (0.82-1.31), 0.68 (0.49-0.96) and 0.71 (0.42-1.17) (P for trend = 0.029) compared with women consuming <1.5 servings/wk. Among lycopene food sources, those in the highest levels of tomato sauce (>or=2 servings/wk) and pizza intake (>or=2 servings/wk), with multivariate RR of 0.76 (0.55-1.05) and 0.66 (0.37-1.18), respectively, had potential reductions in CVD risk. Dietary lycopene was not strongly associated with the risk of CVD. However, the possible inverse associations noted for higher levels of tomato-based products, particularly tomato sauce and pizza, with CVD suggest that dietary lycopene or other phytochemicals consumed as oil-based tomato products confer cardiovascular benefits.

12. Am J Clin Nutr. 2003 Jan;77(1):133-8.

Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Rissanen TH, Voutilainen S, Nyyssonen K, Salonen R, Kaplan GA, Salonen JT.

Research Institute of Public Health, Department of Public Health and General Practice, University of Kuopio, Kuopio, Finland.

BACKGROUND: Interest in lycopene is growing rapidly following the recent publication of epidemiologic studies in which high circulating lycopene concentrations were associated with reductions in cardiovascular disease. Lycopene is one of the major carotenoids in the Western diet and is probably one of the protective factors in a vegetable-rich diet. OBJECTIVE: We studied the hypothesis that the intima-media thickness of the common carotid artery (CCA-IMT) would be greater in men with low serum lycopene concentrations. DESIGN: We investigated the relation between serum lycopene concentration and CCA-IMT in 1028 middle-aged men (aged 46-64 y) in eastern Finland who were participants in the Kuopio Ischaemic Heart Disease Risk Factor study and who were examined in 1991-1993. The subjects were classified into quarters according to serum lycopene concentration. RESULTS: In a covariance analysis with adjustment for covariates, the men in the lowest quarter of serum lycopene concentration had a significantly higher mean CCA-IMT and maximal CCA-IMT (P = 0.005 and P = 0.001 for the difference, respectively) than did the other men. The mean and maximal CCA-IMT increased linearly across the quarters of serum lycopene concentration. CONCLUSIONS: A low serum lycopene concentration is associated with a higher CCA-IMT in middle-aged men from eastern Finland. This finding suggests that the serum lycopene concentration may play a role in the early stages of atherosclerosis. Increased thickness of the intima-media has been shown to predict coronary events; thus, lycopene intakes and serum concentrations may have clinical and public health relevance.

13. Am Heart J. 2002 Mar;143(3):467-74.

Inverse association between carotid intima-media thickness and the antioxidant lycopene in atherosclerosis.

Gianetti J, Pedrinelli R, Petrucci R, Lazzerini G, De Caterina M, Bellomo G, De Caterina R.

C. N. R. Institute of Clinical Physiology, University of Pisa, Pisa, Italy.

BACKGROUND: Antioxidants may prevent atherosclerosis by interfering with endothelial activation, which involves the expression of endothelial adhesion molecules. The aim of this study was to explore the relationship between plasma levels of some lipid-soluble antioxidants (gamma-tocopherol, alpha-tocopherol, lycopene, beta-carotene, and ubiquinone), carotid maximum intima-media thickness (IMTmax), an index of atherosclerotic extension/severity, and soluble adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and E-selectin), which are taken as a reflection of vascular cell expression of adhesion molecules. METHODS: We studied 11 healthy control subjects, 11 patients with uncomplicated hypertension (UH), and 11 patients with essential hypertension plus peripheral vascular disease (PVD) who were matched for age, sex, smoking habit, and body mass index. RESULTS: Patients with PVD had elevated IMTmax (2.7 [1.1-3.1] mm, median [range]) compared with both patients with UH(1.2 [0.8-2.4] mm) and control subjects (1.0 [0.6-2] mm). In patients with PVD, soluble (s)VCAM-1 and sICAM-1 were also significantly higher than in the 2 other categories. Plasma levels of lycopene had a trend toward lower values in patients with PVD compared with other groups (P =.13). A statistically significant correlation was found between lycopene and IMTmax (r = 0.42, P =.014) at univariate analysis, which persisted at multivariate analysis (P <.05) and was independent of low-density lipoprotein cholesterol, creatinine clearance, and plasma insulin. Plasma lycopene did not significantly correlate with any of the soluble adhesion molecules tested. CONCLUSIONS: We conclude that the inverse relationship of plasma lycopene with IMTmax is compatible with a protective role of this natural dietary antioxidant in atherosclerosis, although the mechanism of protection does not apparently involve a decrease in endothelial activation measured through soluble adhesion molecules.

14. Free Radic Biol Med. 2002 Jan 15;32(2):148-52.

Plasma lipophilic antioxidants and malondialdehyde in congestive heart failure patients: relationship to disease severity.

Polidori MC, Savino K, Alunni G, Freddio M, Senin U, Sies H, Stahl W, Mecocci P.

Institute of Physiological Chemistry I, Heinrich-Heine University, Dusseldorf, Germany. polidori@uni-duesseldorf.de

Plasma levels of malondialdehyde (MDA), vitamin A, and of antioxidant micronutrients including vitamin E, lutein, zeaxanthin, beta-cryptoxanthin, lycopene, and alpha- and beta-carotene were measured in 30 patients with class II and III congestive heart failure (CHF) according to the New York Heart Association (NYHA) classification and in 55 controls. Ejection fraction was evaluated by echocardiography in all patients as a measure of the emptying capacity of the heart. Plasma levels of all measured compounds were significantly lower and MDA significantly higher in patients compared to controls (p <.001). Class II NYHA patients showed significantly lower MDA levels and significantly higher levels of vitamin A, vitamin E, lutein, and lycopene than class III patients. Ejection fraction was inversely correlated with MDA levels and directly correlated with vitamin A, vitamin E, lutein, and lycopene levels in patients. The present study supports the concept that an increased consumption of vitamin-rich fruits and vegetables might help in achieving cardiovascular health.

15. J Am Coll Cardiol. 2001 Dec;38(7):1788-94.

Comment in: J Am Coll Cardiol. 2001 Dec;38(7):1795-8.

Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS).

McQuillan BM, Hung J, Beilby JP, Nidorf M, Thompson PL.

Gairdner Campus of the Heart Research Institute of Western Australia, Western, Nedlands, Perth, Australia.

OBJECTIVES: This study examined whether dietary intake or plasma levels of antioxidant vitamins were independently associated with common carotid artery intima-media (wall) thickness (IMT) or focal plaque, or both, in a large, randomly selected community population. BACKGROUND: Oxidation of low-density lipoprotein (LDL) cholesterol is thought to be important in early atherogenesis. Antioxidant micronutrients may therefore protect against lipid peroxidation and atherosclerotic vascular disease. METHODS: We studied 1,111 subjects (558 men and 553 women; age 52 +/- 13 years [mean +/- SD], range 27 to 77). We measured dietary vitamin intake and fasting plasma levels of vitamins A, C and E, lycopene and alpha- and beta-carotene and performed bilateral carotid artery B-mode ultrasound imaging. RESULTS; After adjustment for age and conventional risk factors, there was a progressive decrease in mean IMT, with increasing quartiles of dietary vitamin E intake in men (p = 0.02) and a nonsignificant trend in women (p = 0.10). Dietary vitamin E levels accounted for 1% of the variance in measured IMT in men. For plasma antioxidant vitamins, there was an inverse association between carotid artery mean IMT and plasma lycopene in women (p = 0.047), but not in men. None of the other dietary or plasma antioxidant vitamins, nor antioxidant vitamin supplements, were associated with carotid artery IMT or focal carotid artery plaque. CONCLUSIONS: This study provides limited support for the hypothesis that increased dietary intake of vitamin E and increased plasma lycopene may decrease the risk of atherosclerosis. No benefit was demonstrated for supplemental antioxidant vitamin use.

16. J Nutr Sci Vitaminol (Tokyo). 2001 Jun;47(3):213-21.

Effects of tomato juice consumption on plasma and lipoprotein carotenoid concentrations and the susceptibility of low density lipoprotein to oxidative modification.

Maruyama C, Imamura K, Oshima S, Suzukawa M, Egami S, Tonomoto M, Baba N, Harada M, Ayaori M, Inakuma T, Ishikawa T.

Department of Food and Nutrition, Japan Women's University, Tokyo.

Effects of tomato juice supplementation on the carotenoid concentration in lipoprotein fractions and the oxidative susceptibility of LDL were investigated in 31 healthy Japanese female students. These subjects were randomized to one of three treatment groups; Control, Low and High. The Control, Low and High groups consumed 480 g of a control drink, 160 g of tomato juice plus 320 g of the control drink, and 480 g of tomato juice, providing 0, 15 and 45 mg of lycopene, respectively, for one menstrual cycle. The ingestion of tomato juice, rich in lycopene but having little beta-carotene, increased both lycopene and beta-carotene. Sixty-nine percent of lycopene in plasma was distributed in the LDL fraction and 24% in the HDL fraction. In the Low group, the lycopene concentration increased 160% each in the VLDL+IDL, LDL and HDL fractions (p<0.01). In the High group, the lycopene concentration increased 270% each in the VLDL+IDL and LDL fractions, and 330% in the HDL fraction (p<0.01). Beta-carotene also increased 120% and 180% in LDL fractions of the Low and the High groups, respectively. Despite these carotenoid increases in LDL, the lag time before oxidation was not prolonged as compared with that of the Control group. The propagation rate decreased significantly after consumption in the High group. Multiple regression analysis showed a positive correlation between lag time changes and changes in the alpha-tocopherol concentration per triglyceride in LDL, and a negative correlation between propagation rate changes and changes in the lycopene concentration per phospholipid in LDL. These data suggest that alpha-tocopherol is a major determinant in protecting LDL from oxidation, while lycopene from tomato juice supplementaion may contribute to protect phospholipid in LDI, from oxidation. Thus, oral intake of lycopene might be beneficial for ameliorating atherosclerosis.

17. Br J Nutr. 2001 Jun;85(6):749-54.

Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Rissanen TH, Voutilainen S, Nyyssonen K, Lakka TA, Sivenius J, Salonen R, Kaplan GA, Salonen JT.

Research Institute of Public Health, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland.

A number of epidemiological studies have shown an association between beta-carotene and the risk of cardiovascular diseases, whereas only a few studies are available concerning the association of lycopene with the risk of coronary events, and no studies have been undertaken concerning lycopene and stroke. Thus, we tested the hypothesis that low serum levels of lycopene are associated with increased risk of acute coronary events and stroke in middle-aged men previously free of CHD and stroke. The subjects were 725 men aged 46-64 years examined in 1991-3 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Forty-one men had either a fatal or a non-fatal acute coronary event or a stroke by December 1997. In a Cox' proportional hazard's model adjusting for examination years, age, systolic blood pressure and three nutritional factors (serum folate, beta-carotene and plasma vitamin C), men in the lowest quarter of serum lycopene levels (< or =0.07 micromol/l) had a 3.3-fold (95 % CI 1.7, 6.4, risk of acute coronary events or stroke compared with the others. Our study suggests that a low serum level of lycopene is associated with an increased risk of atherosclerotic vascular events in middle-aged men previously free of CHD and stroke.

18. Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):2677-81.

Low plasma lycopene concentration is associated with increased intima-media thickness of the carotid artery wall.

Rissanen T, Voutilainen S, Nyyssonen K, Salonen R, Salonen JT.

Research Institute of Public Health, University of Kuopio, Kuopio, Finland.

Although a number of epidemiological studies have evaluated the association between ss-carotene and the risk of cardiovascular diseases, there has been little research on the role of lycopene, an acyclic form of ss-carotene, with regard to the risk of cardiovascular disease. We investigated the relationship between plasma concentrations of lycopene and intima-media thickness of the common carotid artery wall (CCA-IMT) in 520 middle-aged men and women (aged 45 to 69 years) in eastern Finland. They were examined from 1994 to 1995 at the baseline of the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, a randomized trial concerning the effect of vitamin E and C supplementation on atherosclerotic progression. The subjects were classified into 2 categories according to the median concentration of plasma lycopene (0.12 micromol/L in men and 0.15 micromol/L in women). Mean CCA-IMT of the right and left common carotid arteries was 1.18 mm in men and 0.95 mm in women with plasma lycopene levels lower than the median and 0.97 mm in men (P:<0.001 for difference) and 0.89 mm in women (P:=0.027 for difference) with higher levels of plasma lycopene. In ANCOVA adjusting for cardiovascular risk factors and intake of nutrients, in men, low levels of plasma lycopene were associated with a 17.8% increment in CCA-IMT (P:=0.003 for difference). In women, the difference did not remain significant after the adjustments. We conclude that low plasma lycopene concentrations are associated with early atherosclerosis, manifested as increased CCA-IMT, in middle-aged men living in eastern Finland.

Sources

19. J Nutr. 2003 Apr;133(4):1043-50.

Consumption of watermelon juice increases plasma concentrations of lycopene and beta-carotene in humans.

Edwards AJ, Vinyard BT, Wiley ER, Brown ED, Collins JK, Perkins-Veazie P, Baker RA, Clevidence BA.

U.S. Department of Agriculture, Agricultural Research Service, Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, MD 20705, USA.

Watermelon is a rich natural source of lycopene, a carotenoid of great interest because of its antioxidant capacity and potential health benefits. Assessment of bioavailability of lycopene from foods has been limited to tomato products, in which heat processing promotes lycopene bioavailability. We examined the bioavailability of lycopene from fresh-frozen watermelon juice in a 19-wk crossover study. Healthy, nonsmoking adults (36-69 y) completed three 3-wk treatment periods, each with a controlled, weight-maintenance diet. Treatment periods were preceded by "washout" periods of 2-4 wk during which lycopene-rich foods were restricted. All 23 subjects consumed the W-20 (20.1 mg/d lycopene, 2.5 mg/d beta-carotene from watermelon juice) and C-0 treatments (controlled diet, no juice). As a third treatment, subjects consumed either the W-40 (40.2 mg/d lycopene, 5.0 mg/d beta-carotene from watermelon juice, n = 12) or T-20 treatment (18.4 mg/d lycopene, 0.6 mg/d beta-carotene from tomato juice, n = 10). After 3 wk of treatment, plasma lycopene concentrations for the W-20, W-40, T-20 and C-0 treatments were (least squares means +/- SEM) 1078 +/- 106, 1183 +/- 139, 960 +/- 117 and 272 +/- 27 nmol/L, respectively. Plasma concentrations of beta-carotene were significantly greater after W-20 (574 +/- 49 nmol/L) and W-40 (694 +/- 73 nmol/L) treatments than after the C-0 treatment (313 +/- 27 nmol/L). Plasma lycopene concentrations did not differ at wk 3 after W-20, W-40 and T-20 treatments, indicating that lycopene was bioavailable from both fresh-frozen watermelon juice and canned tomato juice, and that a dose-response effect was not apparent in plasma when the watermelon dose was doubled.

20. J Agric Food Chem. 2002 Apr 10;50(8):2214-9.

Liquid chromatography-mass spectrometry of cis- and all-trans-lycopene in human serum and prostate tissue after dietary supplementation with tomato sauce.

van Breemen RB, Xu X, Viana MA, Chen L, Stacewicz-Sapuntzakis M, Duncan C, Bowen PE, Sharifi R.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA. breemen@uic.edu

Several epidemiological studies suggest a lower incidence of prostate cancer in men who routinely consume tomato products. Tomatoes are the primary dietary source of lycopene, which is among the most potent antioxidants of the carotenoids. Men with clinical stage T1 or T2 prostate adenocarcinoma were recruited (n = 32) and consumed tomato sauce based pasta dishes for 3 weeks (equivalent to 30 mg of lycopene per day) before radical prostectomy. Prostate tissue from needle biopsy just before intervention and prostectomy after supplementation from a subset of 11 subjects was evaluated for both total lycopene and lycopene geometrical isomer ratios. A gradient HPLC system using a C(18) column with UV-vis absorbance detection was used to measure total lycopene. Because the absorbance detector was insufficiently sensitive, HPLC with a C(30) column and positive ion atmospheric pressure chemical ionization mass spectrometric (LC-MS) detection was developed as a new assay to measure the ratio of lycopene cis/trans isomers in these samples. The limit of detection of the LC-MS method was determined to be 0.93 pmol of lycopene on-column, and a linear response was obtained over 3 orders of magnitude. Total lycopene in serum increased 2.0-fold from 35.6 to 69.9 microg/dL (from 0.664 to 1.30 microM) as a result of dietary supplementation with tomato sauce, whereas total lycopene in prostate tissue increased 3.0-fold from 0.196 to 0.582 ng/mg of tissue (from 0.365 to 1.09 pmol/mg). all-trans-Lycopene and at least 14 cis-isomer peaks were detected in prostate tissue and serum. The mean proportion of all-trans-lycopene in prostate tissue was approximately 12.4% of total lycopene before supplementation but increased to 22.7% after dietary intervention with tomato sauce. In serum there was only a 2.8% but statistically significant increase in the proportion of all-trans-lycopene after intervention. These results indicate that short-term supplementation with tomato sauce containing primarily all-trans-lycopene (83% of total lycopene) results in substantial increases in total lycopene in serum and prostate and a substantial increase in all-trans-lycopene in prostate but relatively less in serum.

Antioxidant

21. Biochem Biophys Res Commun. 2003 Apr 11;303(3):745-50.

Lycopene attenuates arachidonic acid toxicity in HepG2 cells overexpressing CYP2E1.

Xu Y, Leo MA, Lieber CS.

Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Veterans Affairs Medical Center (151-2), Mt Sinai School of Medicine, 130 West Kingsbridge Rd, Bronx, NY, USA.

Arachidonic acid (AA) was shown to be toxic to HepG2 cells expressing cytochrome P4502E1 (CYP2E1) because of oxidative stress. The aim of this study was to investigate whether lycopene, a carotenoid with high anti-oxidant capacity, protects HepG2 cells expressing CYP2E1 against AA toxicity. In preliminary experiments, lycopene as well as placebo (vehicle) were not toxic in the three types of cells tested: HepG2 cells, HepG2 cells transfected with pCI-neo (Neo) or pCI-neo/2E1 (2E1). AA produced toxic effects, especially in the 2E1 cells, and caused a remarkable increase in hydrogen peroxide production and lipid peroxidation compared to the Neo and HepG2 cells. Lycopene had a protective effect whereas the placebo did not. This was due, at least in part, to inhibition of hydrogen peroxide production and of the resulting lipid peroxidation, confirming the potent anti-oxidant properties of lycopene and its suitability for clinical studies.

22. J Nutr. 2003 Mar;133(3):727-32.

The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage.

Hadley CW, Clinton SK, Schwartz SJ.

The Department of Food Science and Technology, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA.

Lycopene, the predominant carotenoid in tomatoes, is hypothesized to mediate the health benefits of tomato products. We designed a study to examine the change in plasma lycopene and resistance of lipoproteins to ex vivo oxidative stress. Healthy individuals (n = 60; age >40 y; 30 men/30 women) consumed a lycopene-free diet for 1 wk and were subsequently randomized to receive 35 +/- 1, 23 +/- 1 or 25 +/- 1 mg lycopene/d from Campbell's Condensed Tomato Soup (CS), Campbell's Ready To Serve Tomato Soup (RTS) or V8 Vegetable Juice (V8), respectively, for 15 d. Total plasma lycopene concentrations decreased from 0.499 +/- 0.044 to 0.322 +/- 0.027 (35%, P < 0.0001) micro mol/L for the 60 participants during the 7-d washout period. After intervention, total lycopene concentrations increased for those consuming CS, RTS and V8 (compared with the washout period for each group) to 0.784 +/- 0.083 (123%, P < 0.0001), 0.545 +/- 0.061 (57%, P < 0.01) and 0.569 +/- 0.061 (112%, P < 0.0001) micro mol/L, respectively. The concentrations of all lycopene isomers decreased during the washout period. As a percentage of plasma total lycopene isomers for the 60 subjects, all-trans-lycopene decreased from 44.4 +/- 1.2 to 39.6 +/- 1.2 (P < 0.0001), whereas total cis-lycopene isomers increased from 55.6 +/- 1.2 to 60.4 +/- 1.2 (P < 0.0001) during the washout period, a shift that was reversed by consumption of tomato products for 15 d. The ex vivo lipoprotein oxidation lag period, used as a measure of antioxidant capacity, increased significantly from 64.7 +/- 2.4 min at the end of the washout period (all groups) to 70.1 +/- 4.0 (P < 0.05), 68.3 +/- 2.4 (P < 0.05) and 71.7 +/- 4.0 min (P < 0.01) after treatment for the CS, RTS and V8 groups, respectively. This study shows that lycopene concentrations and isomer patterns change rapidly with variation in dietary intake. In addition, 15 d of tomato product consumption significantly enhanced the protection of lipoproteins to ex vivo oxidative stress.

23. Eur J Nutr. 2002 Dec;41(6):237-43.

Paraoxonase 1 Q192R (PON1-192) polymorphism is associated with reduced lipid peroxidation in R-allele-carrier but not in QQ homozygous elderly subjects on a tomato-rich diet.

Bub A, Barth S, Watzl B, Briviba K, Herbert BM, Luhrmann PM, Neuhauser-Berthold M, Rechkemmer G.

Federal Research Centre for Nutrition, Institute of Nutritional Physiology, Haid-und-Neu-Str. 9, 76131 Karlsruhe, Germany. achim.bub@bfe.uni-karlsruhe.de

BACKGROUND: The oxidative modification of LDL is considered to play a central role in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Paraoxonase (PON1) protects LDL from oxidation and may therefore retard the development of atherosclerosis. The PON1-192 polymorphism is associated with diminished PON1 concentrations and an increased risk for CHD in RR-allele subjects. AIM OF THE STUDY: To investigate the effect of tomato juice consumption on PON1 activity and other parameters related to oxidative stress in healthy elderly subjects. Furthermore, the PON1-192 genotype has been determined in the volunteers in order to see whether possible treatment effects are related to the PON1-192 polymorphism. METHODS: Fifty elderly subjects were randomly assigned to control (mineral water) or intervention group (tomato juice). Subjects of the tomato juice group consumed daily 330 mL tomato juice for 8 weeks. Antioxidant status was measured as LDL oxidation, plasma malondialdehyde, ferric reducing ability of plasma (FRAP) and PON1 activity. The PON1-192 polymorphism was determined by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). Plasma carotenoids were analyzed by HPLC. RESULTS: Tomato juice consumption reduced LDL-oxidation and improved antioxidant status in R-allele carriers, but not in the QQ genotype group. PON1 activity increased irrespective of the genotype in both, control and intervention group. CONCLUSIONS: The changes in antioxidant status after tomato juice consumption seem to depend on the PON1-192 genotype. Healthy elderly, carrying the R-allele, could specifically reduce their higher cardiovascular risk by changing dietary habits.

24. Free Radic Res. 2002 Aug;36(8):875-82.

Independent and interactive association of blood antioxidants and oxidative damage in elderly people.

Lasheras C, Huerta JM, Gonzalez S, Brana AF, Patterson AM, Fernandez S.

Departamento de Biologia Funcional, Facultad de Medicina, Universidad de Oviedo, Spain. lasheras@correo.uniovi.es

Oxidative stress is recognized as one of the major contributors to the increased risk of several diseases. Many recent population studies have established a close link between antioxidant defense and lowered risk of morbidity and mortality from cancer and heart disease, but little is known about the cooperative interactions of antioxidants. We examined the cross-sectional independent and interactive association of serum lipid-soluble antioxidant levels and free radical scavenging enzymes to serum malondialdehyde (MDA) levels, as a marker of oxidative damage. The participants were 160 nonsmoker institutionalized elderly. Upper tertile values of erythrocyte-superoxide-dismutase (E-SOD) constituted the strongest-associated single compound with a 74% decreased risk of high MDA. Upper tertiles of carotenoids and alpha-tocopherol independently showed a similar lowering of risk of about 57%. The highest tertiles of lycopene and either beta-carotene or alpha-tocopherol simultaneously reveal a higher decreased risk for oxidative damage (74 and 71%, respectively), very similar to those in the upper tertiles of all these three vitamins (75%). This study represents one of the few attempts to date to understand the interactive effect between antioxidants and suggests that lipid-soluble antioxidants act not individually, but rather cooperatively with each other. The efficacy of this interaction is more effective when lycopene is present.

25. J Photochem Photobiol B. 2001 Nov 15;64(2-3):176-8.

Dietary uptake of lycopene protects human cells from singlet oxygen and nitrogen dioxide - ROS components from cigarette smoke.

Bohm F, Edge R, Burke M, Truscott TG.

Meclinic Berlin, Friedrichstrasse 71, 10117 Berlin, Germany. info@meoclinic.de

There is current interest in the health benefits of dietary carotenoids and the possible deleterious effects on certain sub-populations such as smokers. Here we report in vivo protection of human lymphocytes, conferred by dietary supplementation of lycopene rich foods against the reactive oxygen species, NO(2)(*) radical (by electron transfer) and 1(O)(2) (by energy transfer). It was found that a lycopene rich diet, maintained for 14 days, increased the serum lycopene level 10 fold compared to serum obtained after the same period, where a typical western European diet had been consumed. Relative lymphocyte protection factors of 17.6 and 6.3 against NO(2)(*) radical and 1(O)(2), respectively, were obtained, which re-enforce epidemiological data, showing protection against several chronic diseases by tomato lycopene.

26. Eur J Nutr. 2001 Apr;40(2):78-83.

Relationship between dietary intake, antioxidant status and smoking habits in female Austrian smokers.

Rust P, Lehner P, Elmadfa I.

Institute of Nutritional Sciences, Vienna, Austria. petra.rust@univie.ac.at

BACKGROUND: Previous studies have shown that cigarette smoke contains many oxidants and free radicals, which can increase lipid peroxidation. AIM OF THE STUDY: The association between smoking, food pattern, especially vitamin intake and plasma concentrations of important antioxidants, as well as lipid peroxidation products was assessed in this cross-sectional study. SUBJECTS and METHODS: Sixty Austrian women aged 18-40 y were enrolled in the study. Twenty-nine women were allocated to the smoking group; thirty-one women served as nonsmoking controls. Plasma concentrations of alpha- and gamma-tocopherol, alpha- and beta-carotene, lycopene, cryptoxanthin, retinol, ascorbate and malondialdehyde were determined by HPLC; dietary intake and food pattern had been assessed by four 24-h dietary intake recalls and one food frequency questionnaire. RESULTS: Generally, food intake patterns were not different between smoking and nonsmoking women. But, a significantly higher intake of alcohol was observed in the smoking group (P < 0.05). Plasma ascorbic acid concentration of the smoking group did not differ from the nonsmoking women. Despite the increased utilization because of the oxidative stress in smokers, this result might be explained by the high dietary intake of vitamin C in our smoking group. Significantly lower plasma concentrations of alpha-,beta-carotene and lycopene have been partly ascribed to the enhanced metabolic turnover resulting from smoking-induced oxidative stress. Our results confirm that smoking had no effects on plasma tocopherol and plasma retinol concentrations. CONCLUSIONS: The poor supply with the carotenoids alpha-, beta-carotene and lycopene may result from the increased metabolism of antioxidants caused by oxidative stress and may be responsible for significantly higher levels of lipid peroxidation products in smokers compared to nonsmokers (P < 0.05).

27. Free Radic Biol Med. 2000 Nov 15;29(10):1051-5. Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma.

Lee A, Thurnham DI, Chopra M.

Northern Ireland Centre for Diet and Health, School of Biomedical Sciences, University of Ulster, Northern Ireland, Coleraine, UK.

Health benefits of lycopene from tomato products have been suggested to be related to its antioxidant activity. Dietary fat may influence the absorption and hence the plasma levels and antioxidant activity of lycopene. In the present study, we have compared the effect of consumption of tomato products with extra-virgin olive oil vs. tomato products plus sunflower oil on plasma lycopene and antioxidant levels. Results show that the oil composition does not affect the absorption of lycopene from tomato products because similar levels of plasma lycopene (mean +/- SD) were obtained on feeding tomatoes (providing approximately 46 mg lycopene/d) for 7 d with either olive oil (0.66 +/- 0.26 vs 1.20 +/- 0.20 micromol/l, p <.002) or sunflower oil (0.67 +/- 0.27 vs. 1.14 micromol/l, p <.001). However, consumption of tomato products with olive oil significantly raised the plasma antioxidant activity (FRAP) from 930 +/- 150 to 1118 +/- 184 micromol/l, p <.01) but no effect was observed when the sunflower oil was used. The change (supplementation minus start values) in FRAP following the consumption of tomato products with oil was significantly higher for olive oil (190 +/- 101) than for sunflower oil (-9.6 +/- 99, p <. 005). In conclusion, the results of the study show that consumption of tomato products with olive oil but not with sunflower oil improves the antioxidant activity of the plasma.

28. Arch Latinoam Nutr. 1999 Sep;49(3 Suppl 1):12S-20S.

Lycopene entrapped in human albumin protects 2'-deoxyguanosine against singlet oxygen damage.

Yamaguchi LF, Martinez GR, Catalani LH, Medeiros MH, Di Mascio P.

Departamento de Bioquimica, Universidade de Sao Paulo, Brasil.

The generation of electronically excited molecular oxygen 1O2 has been shown to occur in several biological systems, such as photooxidation of a variety of biological compounds and xenobiotics ("photodynamic action") and also enzymatic reactions. The high reactivity of 1O2 with unsaturated compounds, sulfides and amino groups arises from its electrophilicity and relatively long lifetime. Thus, biological targets for 1O2 having the above functional groups include unsaturated fatty acids, proteins, enzymes and DNA. There is interest in the role of nutrition in the prevention and pathogenesis of cancer. Epidemiological studies in humans have suggested that carotenoids aid in cancer prevention. Lycopene and oxycarotenoids are present at significant levels in cells and plasma. Extensively conjugated biomolecules such as carotenoids act largely on physical quenching of 1O2 and in much lesser extent on chemical reaction. In this study we observed the protective effect of beta-carotene and lycopene entrapped in human albumin (HSA) against the oxidative 1O2 attack of 2'-deoxyguanosine (dGuo). Photosensitization with methylene blue associated with Chelex resine or Polymer-Rose bengal (Sensitox) and thermodecomposition of water-soluble endoperoxide 3,3'-(1,4-naphthylidene)dipropionate were employed to generate 1O2. The detection of 8-oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodGuo) and 4-hydroxy-8-oxo-7,8-dihydro-2'-deoxyguanosine(4-OH-8-oxodGuo) were performed using reversed phase HPLC with UV, electrochemical detection and by electrospray ionization mass spectrometry. Results showed a significant decrease in the amount of 8-oxodGuo in the presence of lycopene. The percentages of 4-OH-8-oxodGuo and 8-oxodGuo measured were 50% and 70% lower than the control, respectively. These data indicate that carotenoids entrapped in albumin can be an efficient quencher of 1O2 and may be of interest in protecting against the deleterious effect of this excited state molecule.

29. J Nutr. 2000 Feb;130(2):189-92.

Lymphocyte lycopene concentration and DNA protection from oxidative damage is increased in women after a short period of tomato consumption.

Porrini M, Riso P.

Department of Food Science and Technology, University of Milan, Italy.

Several epidemiologic studies have suggested a role of tomato products in protecting against cancer and chronic diseases. In nine adult women, we evaluated whether the consumption of 25 g tomato puree (containing 7 mg lycopene and 0.3 mg beta-carotene) for 14 consecutive days increased plasma and lymphocyte carotenoid concentration and whether this was related to an improvement in lymphocyte resistance to an oxidative stress (500 micromol/L hydrogen peroxide for 5 min). Before and after the period of tomato intake, carotenoid concentrations were analyzed by HPLC and lymphocyte resistance to oxidative stress by the Comet assay, which detects DNA strand breaks. Intake of tomato puree increased plasma (P <0.001) and lymphocyte (P<0.005) lycopene concentration and reduced lymphocyte DNA damage by approximately 50% (P<0.0001). Beta-carotene concentration increased in plasma (P<0.05) but not in lymphocytes after tomato puree consumption. An inverse relationship was found between plasma lycopene concentration (r = -0.82, P<0.0001) and lymphocyte lycopene concentration (r = -0.62, P<0.01) and the oxidative DNA damage. In conclusion, small amounts of tomato puree added to the diet over a short period can increase carotenoid concentrations and the resistance of lymphocytes to oxidative stress.

30. Am J Clin Nutr. 1999 Apr;69(4):712-8.

Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage?

Riso P, Pinder A, Santangelo A, Porrini M.

Department of Food Science and Technology, University of Milan, Italy. nutr_lab@imiucca.csi.unimi.it

BACKGROUND: Lycopene, the main carotenoid in tomato, has been shown to be a potent antioxidant in vitro. However, there is no significant evidence of its antioxidant action in vivo. OBJECTIVE: We evaluated the effect of tomato intake on plasma carotenoid concentrations and lymphocyte resistance to oxidative stress. DESIGN: Ten healthy women (divided into 2 groups of 5 subjects each) ate a diet containing tomato puree (providing 16.5 mg lycopene) and a tomato-free diet for 21 d each in a crossover design. Before and after each diet period, plasma carotenoid concentrations and primary lymphocyte resistance to oxidative stress (evaluated by means of single-cell gel electrophoresis) were analyzed. RESULTS: After the first 21-d experimental period, total plasma lycopene concentrations increased by 0.5 micromol/L (95% CI: 0.14, 0.87) in the group that consumed the tomato diet and decreased by 0.2 micromol/L (95% CI: -0.11, -0.30) in the group that consumed the tomato-free diet (P < 0.001). Tomato consumption also had an effect on cellular antioxidant capacity: lymphocyte DNA damage after ex vivo treatment with hydrogen peroxide decreased by 33% (95% CI: 0.8%, 61%; P < 0.05) and by 42% (95% CI: 5.1%, 78%; P < 0.05) in the 2 groups of subjects after consumption of the tomato diet. CONCLUSION: The consumption of tomato products may reduce the susceptibility of lymphocyte DNA to oxidative damage.

Prostate Cancer

31. J Med Food. 2002 Winter;5(4):181-7.

Effect of lycopene on prostate LNCaP cancer cells in culture.

Kim L, Rao AV, Rao LG.

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Epidemiological studies have shown an inverse relationship between serum lycopene levels and the risk of prostate cancer. The objective of this study was to measure the effect of lycopene on the proliferation of LNCaP human prostate cancer cells in culture. A new, water-dispersible lycopene in an appropriate vehicle was used. The stock solution was diluted in the medium to obtain lycopene concentrations of 10(-6), 10(-5), and 10(-4) M; their corresponding vehicles were similarly diluted to be used as controls. Cells were grown for 48 hours in RPMI-1640 medium supplemented with 10% fetal bovine serum and antibiotics. Lycopene was then added at different concentrations, and the cells were allowed to grow for 24, 48, 72, and 96 hours. Lycopene at concentrations of 10(-6) and 10(-5) M significantly reduced the growth of LNCaP cells after 48, 72, and 96 hours of incubation, by 24.4% to 42.8% (P <.05). The inhibitory effect of lycopene was significantly higher than that of the corresponding vehicle controls. In a follow-up experiment, a lower range of lycopene concentrations (10(-9) to 10(-7) M) was used to determine whether there was a dose-response effect. Lycopene significantly decreased the growth of cells in a dose-dependent manner when cells were incubated for 24, 48, 72, or 96 hours (F = 3.150, 11.27, 54.51, and 297.5, respectively; P <.05). The growth inhibitory effect of lycopene on human prostate cancer cells observed in this study suggests a possibly important role for lycopene as an antioxidant in human prostate cancer; however, investigations of other mechanisms are warranted.

32. Exp Biol Med (Maywood). 2002 Nov;227(10):881-5.

Effects of lycopene supplementation in patients with localized prostate cancer.

Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, Khachik F, Banerjee M, Bertram JS, Wood DP Jr.

Division of Hematology and Oncology, 3990 John R, Barbara Ann Karmanos Cancer Institute, Wayne State University, 5 Hudson, Detroit, MI 48201, USA. kucuko@karmanos.org

Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.

33. Am J Epidemiol. 2002 Jun 1;155(11):1023-32.

Serum lycopene, other serum carotenoids, and risk of prostate cancer in US Blacks and Whites.

Vogt TM, Mayne ST, Graubard BI, Swanson CA, Sowell AL, Schoenberg JB, Swanson GM, Greenberg RS, Hoover RN, Hayes RB, Ziegler RG.

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA. vogtt@exchange.nih.gov

Epidemiologic studies investigating the relation between individual carotenoids and risk of prostate cancer have produced inconsistent results. To further explore these associations and to search for reasons prostate cancer incidence is over 50% higher in US Blacks than Whites, the authors analyzed the serum levels of individual carotenoids in 209 cases and 228 controls in a US multicenter, population-based case-control study (1986-1989) that included comparable numbers of Black men and White men aged 40-79 years. Lycopene was inversely associated with prostate cancer risk (comparing highest with lowest quartiles, odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.36, 1.15; test for trend, p = 0.09), particularly for aggressive disease (comparing extreme quartiles, OR = 0.37, 95% CI: 0.15, 0.94; test for trend, p = 0.04). Other carotenoids were positively associated with risk. For all carotenoids, patterns were similar for Blacks and Whites. However, in both the controls and the Third National Health and Nutrition Examination Survey, serum lycopene concentrations were significantly lower in Blacks than in Whites, raising the possibility that differences in lycopene exposure may contribute to the racial disparity in incidence. In conclusion, the results, though not statistically significant, suggest that serum lycopene is inversely related to prostate cancer risk in US Blacks and Whites.

34. J Natl Cancer Inst. 2002 Mar 6;94(5):391-8.

A prospective study of tomato products, lycopene, and prostate cancer risk.

Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. edward.giovannucci@channing.harvard.edu

BACKGROUND: Some data, including our findings from the Health Professionals Follow-Up Study (HPFS) from 1986 through January 31, 1992, suggest that frequent intake of tomato products or lycopene, a carotenoid from tomatoes, is associated with reduced risk of prostate cancer. Overall, however, the data are inconclusive. We evaluated additional data from the HPFS to determine if the association would persist. METHODS: We ascertained prostate cancer cases from 1986 through January 31, 1998, among 47 365 HPFS participants who completed dietary questionnaires in 1986, 1990, and 1994. We used pooled logistic regression to compute multivariate relative risks (RR) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: From 1986 through January 31, 1998, 2481 men in the study developed prostate cancer. Results for the period from 1992 through 1998 confirmed our previous findings---that frequent tomato or lycopene intake was associated with a reduced risk of prostate cancer. Similarly, for the entire period of 1986 through 1998, using the cumulative average of the three dietary questionnaires, lycopene intake was associated with reduced risk of prostate cancer (RR for high versus low quintiles = 0.84; 95% CI = 0.73 to 0.96; P(trend) =.003); intake of tomato sauce, the primary source of bioavailable lycopene, was associated with an even greater reduction in prostate cancer risk (RR for 2+ servings/week versus <1 serving/month = 0.77; 95% CI = 0.66 to 0.90; P(trend)<.001), especially for extraprostatic cancers (RR = 0.65; 95% CI = 0.42 to 0.99). These associations persisted in analyses controlling for fruit and vegetable consumption and for olive oil use (a marker for Mediterranean diet) and were observed separately in men of Southern European or other Caucasian ancestry. CONCLUSION: Frequent consumption of tomato products is associated with a lower risk of prostate cancer. The magnitude of the association was moderate enough that it could be missed in a small study or one with substantial errors in measurement or based on a single dietary assessment.

35. J Natl Cancer Inst. 2001 Dec 19;93(24):1872-9.

Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention.

Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, van Breemen R, Ashton D, Bowen PE.

Department of Human Nutrition, University of Illinois at Chicago, 60612, USA.

BACKGROUND: Human prostate tissues are vulnerable to oxidative DNA damage. The risk of prostate cancer is lower in men reporting higher consumption of tomato products, which contain high levels of the antioxidant lycopene. We examined the effects of consumption of tomato sauce-based pasta dishes on lycopene uptake, oxidative DNA damage, and prostate-specific antigen (PSA) levels in patients already diagnosed with prostate cancer. METHODS: Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for the 3 weeks (30 mg of lycopene per day) preceding their scheduled radical prostatectomy. Serum and prostate lycopene concentrations, serum PSA levels, and leukocyte DNA oxidative damage (ratio of 8-hydroxy-2'-deoxyguanosine [8-OHdG] to 2'-deoxyguanosine [dG]) were assessed before and after the dietary intervention. DNA oxidative damage was assessed in resected prostate tissue from study participants and from seven randomly selected prostate cancer patients. All statistical tests were two-sided. RESULTS: After the dietary intervention, serum and prostate lycopene concentrations were statistically significantly increased, from 638 nM (95% confidence interval [CI] = 512 to 764 nM) to 1258 nM (95% CI = 1061 to 1455 nM) (P<.001) and from 0.28 nmol/g (95% CI = 0.18 to 0.37 nmol/g) to 0.82 nmol/g (95% CI = 0.57 to 1.11 nmol/g) (P <.001), respectively. Compared with preintervention levels, leukocyte oxidative DNA damage was statistically significantly reduced after the intervention, from 0.61 8-OHdG/10(5) dG (95% CI = 0.45 to 0.77 8-OHdG/10(5) dG) to 0.48 8-OHdG/ 10(5) dG (95% CI = 0.41 to 0.56 8-OHdG/10(5) dG) (P =.005). Furthermore, prostate tissue oxidative DNA damage was also statistically significantly lower in men who had the intervention (0.76 8-OHdG/10(5) dG [95% CI = 0.55 to 0.96 8-OHdG/10(5) dG]) than in the randomly selected patients (1.06 8-OHdG/10(5) dG [95% CI = 0.62 to 1.51 8-OHdG/10(5) dG]; P =.03). Serum PSA levels decreased after the intervention, from 10.9 ng/mL (95% CI = 8.7 to 13.2 ng/mL) to 8.7 ng/mL (95% CI = 6.8 to 10.6 ng/mL) (P<.001). CONCLUSION: These data indicate a possible role for a tomato sauce constituent, possibly lycopene, in the treatment of prostate cancer and warrant further testing with a larger sample of patients, including a control group.

36. J Nutr. 2001 Dec;131(12):3303-6.

Carotenoids affect proliferation of human prostate cancer cells.

Kotake-Nara E, Kushiro M, Zhang H, Sugawara T, Miyashita K, Nagao A.

Department of Bioresources Chemistry, Graduate School of Fisheries Science, Hokkaido University, 3-1-1 Hakodate 041-8611, Japan.

We investigated whether various carotenoids present in foodstuffs were potentially involved in cancer-preventing action on human prostate cancer. The effects of 15 kinds of carotenoids on the viability of three lines of human prostate cancer cells, PC-3, DU 145 and LNCaP, were evaluated. When the prostate cancer cells were cultured in a carotenoid-supplemented medium for 72 h at 20 micromol/L, 5,6-monoepoxy carotenoids, namely, neoxanthin from spinach and fucoxanthin from brown algae, significantly reduced cell viability to 10.9 and 14.9% for PC-3, 15.0 and 5.0% for DU 145, and nearly zero and 9.8% for LNCaP, respectively. Acyclic carotenoids such as phytofluene, zeta-carotene and lycopene, all of which are present in tomato, also significantly reduced cell viability. On the other hand, phytoene, canthaxanthin, beta-cryptoxanthin and zeaxanthin did not affect the growth of the prostate cancer cells. DNA fragmentation of nuclei in neoxanthin- and fucoxanthin-treated cells was detected by in situ TdT-mediated dUTP nick end labeling (TUNEL) assay. Neoxanthin and fucoxanthin were found to reduce cell viability through apoptosis induction in the human prostate cancer cells. These results suggest that ingestion of leafy green vegetables and edible brown algae rich in neoxanthin and fucoxanthin might have the potential to reduce the risk of prostate cancer.

37. Cancer Epidemiol Biomarkers Prev. 2001 Aug;10(8):861-8.

Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.

Kucuk O, Sarkar FH, Sakr W, Djuric Z, Pollak MN, Khachik F, Li YW, Banerjee M, Grignon D, Bertram JS, Crissman JD, Pontes EJ, Wood DP Jr.

Division of Hematology and Oncology, Wayne State University, and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA. kucuko@karmanos.org

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = 0.22). Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = 0.05). Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = 0.25). Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = 0.13). Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = 0.0002 and P = 0.0003, respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size.

38. Altern Med Rev. 1999 Jun;4(3):162-9.

An ecologic study of dietary links to prostate cancer.

Grant WB.

NASA Langley Research Center, Hampton, VA, USA. wbgrant@norfolk.infi.net

BACKGROUND: The etiology of prostate cancer has not been fully resolved in the scientific and medical literature, although the non-fat portion of milk and calcium are emerging as leading dietary risk factors, with lycopene (found in tomatoes) and vitamin D apparently being risk reduction factors. METHODS: The ecologic (multi-country statistical) approach is used to study dietary links to prostate cancer. Mortality data from 1986 for various age groups in 41 countries are compared with national consumer macronutrient supply values for 1983 and tomato supply values for 1985. RESULTS: For 28 countries with more than five Kcal/day of tomatoes in the consumer supply, a linear combination of non-fat milk (risk factor) and tomatoes (risk reduction factor) was found to have the highest statistical association with prostate cancer mortality rates for men over the age of 35, with the Pearson regression coefficient (R2) for those aged 65-74 years = 0.67 and p < 0.001. For the 13 countries with fewer than six Kcal/day of tomatoes, non-fat milk had the highest association (R2 = 0.92, p < 0.001 for men aged 65-74 years). For 41 countries combined, the non-fat portion of milk had the highest association with prostate cancer mortality rates (R2 = 0.73, p < 0.001 for men aged 65-74 years). CONCLUSIONS: These results support the results of several cohort studies which found the non-fat portion of milk to have the highest association with prostate cancer, likely due to the calcium, and tomatoes to reduce the risk of prostate cancer, most likely due to lycopene.

39. Nutr Cancer. 1999;33(2):159-64.

Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study.

Rao AV, Fleshner N, Agarwal S.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada. v.rao@utoronto.ca

Dietary intake of tomatoes and tomato products containing lycopene, an antioxidant carotenoid, has been shown in recent studies to reduce the risk of cancer. This study was conducted to investigate the serum and prostate tissue lycopene and other major carotenoid concentrations in cancer patients and their controls. Serum lipid and protein oxidation was also measured. Twelve prostate cancer patients and 12 age-matched subjects were used in the study. Significantly lower serum and tissue lycopene levels (44%, p = 0.04; 78%, p = 0.050, respectively) were observed in the cancer patients than in their controls. Serum and tissue beta-carotene and other major carotenoids did not differ between the two groups (p = 0.395 and p = 0.280, respectively). Although there was no difference (p = 0.760) in serum lipid peroxidation between cancer patients and their controls (7.09 +/- 0.74 and 6.81 +/- 0.56 mumol/l, respectively), serum protein thiol levels were significantly lower among the cancer patients (p = 0.026). This study demonstrates that the status of lycopene but not other carotenoids in prostate cancer patients is different from controls. The role of dietary lycopene in preventing oxidative damage of biomolecules and thereby reducing the risk of prostate cancer needs to be evaluated in future studies.

40. Cancer Res. 1999 Mar 15;59(6):1225-30.

Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.

Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ.

Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA. pgann@nwu.edu

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.

41. Biochem Biophys Res Commun. 1998 Sep 29;250(3):582-5.

Lycopene in association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells.

Pastori M, Pfander H, Boscoboinik D, Azzi A.

Institute for Biochemistry and Molecular Biology, University of Bern, Bern, CH-3012, Switzerland.

The effect of lycopene alone or in association with other antioxidants was studied on the growth of two different human prostate carcinoma cell lines (the androgen insensitive DU-145 and PC-3). It was found that lycopene alone was not a potent inhibitor of prostate carcinoma cell proliferation. However, the simultaneous addition of lycopene together with alpha-tocopherol, at physiological concentrations (less than 1 microM and 50 microM, respectively), resulted in a strong inhibitory effect of prostate carcinoma cell proliferation, which reached values close to 90 %. The effect of lycopene with alpha-tocopherol was synergistic and was not shared by beta-tocopherol, ascorbic acid and probucol. Copyright 1998 Academic Press.

42. Cancer Epidemiol Biomarkers Prev. 1996 Oct;5(10):823-33.

cis-trans lycopene isomers, carotenoids, and retinol in the human prostate.

Clinton SK, Emenhiser C, Schwartz SJ, Bostwick DG, Williams AW, Moore BJ, Erdman JW Jr.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115-6084, USA.

An evaluation of the Health Professionals Follow-Up Study has detected a lower prostate cancer risk associated with the greater consumption of tomatoes and related food products. Tomatoes are the primary dietary source of lycopene, a non-provitamin A carotenoid with potent antioxidant activity. Our goal was to define the concentrations of lycopene, other carotenoids, and retinol in paired benign and malignant prostate tissue from 25 men, ages 53 to 74, undergoing prostatectomy for localized prostate cancer. The concentrations of specific carotenoids in the benign and malignant prostate tissue from the same subject are highly correlated. Lycopene and all-trans beta-carotene are the predominant carotenoids observed, with means +/- SE of 0.80 +/- 0.08 nmol/g and 0.54 +/- 0.09, respectively. Lycopene concentrations range from 0 to 2.58 nmol/g, and all-trans beta-carotene concentrations range from 0.09 to 1.70 nmol/g. The 9-cis beta-carotene isomer, alpha-carotene, lutein, alpha-cryptoxanthin, zeaxanthin, and beta-cryptoxanthin are consistently detectable in prostate tissue. No significant correlations between the concentration of lycopene and the concentrations of any other carotenoid are observed. In contrast, strong correlations between prostate beta-carotene and alpha-carotene are noted (correlation coefficient, 0.88; P < 0.0001), as are correlations between several other carotenoid pairs, which reflects their similar dietary origins. Mean vitamin A concentration in the prostate is 1.52 nmol/g, with a range of 0.71 to 3.30 nmol/g. We further evaluated tomato-based food products, serum, and prostate tissue for the presence of geometric lycopene isomers using high-performance liquid chromatography with a polymeric C30 reversed phase column. All-trans lycopene accounts for 79 to 91% and cis lycopene isomers for 9 to 21% of total lycopene in tomatoes, tomato paste, and tomato soup. Lycopene concentrations in the serum of men range between 0.60 and 1.9 nmol/ml, with 27 to 42% all-trans lycopene and 58 to 73% cis-isomers distributed among 12 to 13 peaks, depending upon their chromatographic resolution. In striking contrast with foods, all-trans lycopene accounts for only 12 to 21% and cis isomers for 79 to 88% of total lycopene in benign or malignant prostate tissues. cis Isomers of lycopene within the prostate are distributed among 14 to 18 peaks. We conclude that a diverse array of carotenoids are found in the human prostate with significant intra-individual variation. The presence of lycopene in the prostate at concentrations that are biologically active in laboratory studies supports the hypothesis that lycopene may have direct effects within the prostate and contribute to the reduced prostate cancer risk associated with the reduced prostate cancer risk associated with the consumption of tomato-based foods. The future identification and characterization of geometric lycopene isomers may lead to the development of novel agents for chemoprevention studies.

Skin

43. J Nutr. 2003 Jan;133(1):98-101.

Supplementation with beta-carotene or a similar amount of mixed carotenoids protects humans from UV-induced erythema.

Heinrich U, Gartner C, Wiebusch M, Eichler O, Sies H, Tronnier H, Stahl W.

Institut fur Experimentelle Dermatologie, Universitat Witten-Herdecke, Germany.

Carotenoids are useful oral sun protectants, and supplementation with high doses of beta-carotene protects against UV-induced erythema formation. We compared the erythema-protective effect of beta-carotene (24 mg/d from an algal source) to that of 24 mg/d of a carotenoid mix consisting of the three main dietary carotenoids, beta-carotene, lutein and lycopene (8 mg/d each). In a placebo-controlled, parallel study design, volunteers with skin type II (n = 12 in each group) received beta-carotene, the carotenoid mix or placebo for 12 wk. Carotenoid levels in serum and skin (palm of the hand), as well as erythema intensity before and 24 h after irradiation with a solar light simulator were measured at baseline and after 6 and 12 wk of treatment. Serum beta-carotene concentration increased three- to fourfold (P < 0.001) in the beta-carotene group, whereas in the mixed carotenoid group, the serum concentration of each of the three carotenoids increased one- to threefold (P < 0.001). No changes occurred in the control group. The intake of either beta-carotene or a mixture of carotenoids similarly increased total carotenoids in skin from wk 0 to wk 12. No changes in total carotenoids in skin occurred in the control group. The intensity of erythema 24 h after irradiation was diminished in both groups that received carotenoids and was significantly lower than baseline after 12 wk of supplementation. Long-term supplementation for 12 wk with 24 mg/d of a carotenoid mix supplying similar amounts of beta-carotene, lutein and lycopene ameliorates UV-induced erythema in humans; the effect is comparable to daily treatment with 24 mg of beta-carotene alone.

Oral cancers

44. J Nutr. 2002 Dec;132(12):3754-9.

Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells.

Livny O, Kaplan I, Reifen R, Polak-Charcon S, Madar Z, Schwartz B.

Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.

Cell-cell interaction via gap junctions is considered to be a key factor in tissue homeostasis, and its alteration is associated with the neoplastic phenotype. Experimental and epidemiologic data suggest that carotenoids, particularly lycopene and beta-carotene, can reduce the risk of certain cancers. The aim of this study was to assess whether lycopene and beta-carotene interfere at some stage with the carcinogenic processes in human cancer cells derived from the oral cavity. KB-1 cells, originating from a human oral cavity tumor, were incubated with different concentrations of lycopene or beta-carotene delivered via the cell culture media from stock solutions in tetrahydrofuran. Lycopene strongly and dose dependently inhibited proliferation of KB-1 human oral tumor cells. beta-Carotene was a far less effective growth inhibitor. Lycopene (3 and 7 micro mol/L) significantly upregulated both the transcription (P < 0.005) and the expression (P < 0.05) of connexin 43, a key protein in the formation of gap-junctional communication. beta-Carotene (3 micro mol/L) tended to upregulate connexin 43 expression (P = 0.07) and significantly affected transcription of connexin 43 at 7 micro mol/L (P < 0.05). Gap-junctional communication measured by scrape-loading dye transfer and electron microscopy showed that lycopene enhanced gap-junctional communication between the cancer cells, whereas beta-carotene was less effective in this regard. The pattern of cellular uptake and incorporation into cancer KB-1 cells differed significantly between the carotenoids. beta-Carotene was avidly and rapidly incorporated into KB-1 cells, whereas lycopene uptake into the cells took place after longer incubation periods and only at the highest concentrations. The results of the present study further support the hypothesis that carotenoids in general, and lycopene in particular, may be effective anticarcinogenic agents in oral carcinogenesis.

Cancer

45. Exp Biol Med (Maywood). 2002 Nov;227(10):860-3.

Tomatoes, lycopene intake, and digestive tract and female hormone-related neoplasms.

La Vecchia C.

Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. garimoldi@marionegri.it

Tomato consumption showed a consistent inverse relation with the risk of digestive tract neoplasms in Italy in an integrated series of studies conducted in the 1980s. Another series of case-control studies was conducted between 1992 and 1999 in different areas of Italy. Cases were patients below age 80 with incident, histologically confirmed cancer of the oral cavity and pharynx (n = 754), esophagus (n = 304), colorectum (n = 1953), breast (n = 2529), and ovary (n = 1031). The comparison group involved, overall, over 5000 patients below age 80 with acute, non-neoplastic, nonhormone-related diseases, unrelated to long-term diet modifications and admitted to the same network of hospitals. Information was collected in hospital by trained interviewers using a validated food frequency questionnaire, including 78 foods or groups of foods, various alcoholic beverage, and fat-intake pattern. The multivariate relative risk (RR) of oral, pharyngeal, and esophageal cancer decreased across subsequent levels of lycopene intake to reach 0.7 (95% confidence interval [CI] 0.4-1.0) for oral and pharyngeal, and 0.7 (95% CI 0.4-1.1) for esophageal cancer in the highest quintile of intake. Both trends in risk were of borderline statistical significance. With reference to colorectal, breast, and ovarian cancer, although no consistent association was observed for lycopene (RR = 1.0 for colorectal, 1.2 for breast, and 1.1 for ovary in the highest quintile), tomato intake was inversely and significantly related with colorectal cancer (RR = 0.8). The inverse relation between lycopene and upper digestive tract neoplasms was not explained by alcohol or tobacco, sociodemographic factors, or total energy intake. The interpretation of such an inverse relation, however, remains open to discussion because it may be related to an effect of lycopene due to its antioxidant effect and/or a potential role of lycopene in decreasing insulin growth factor I, which is a promoter in the process of carcinogenesis.

46. Int J Vitam Nutr Res. 2002 Jul;72(4):237-50.

Serum antioxidants and subsequent mortality rates of all causes or cancer among rural Japanese inhabitants.

Ito Y, Suzuki K, Suzuki S, Sasaki R, Otani M, Aoki K.

Department of Public Health, Fujita Health University School of Health Sciences, Toyoake, Japan. yoshiito@fujita-hu.ac.jp

The purpose of this study was to investigate whether a relationship exists between mortality rates and serum antioxidant levels among Japanese inhabitants. The follow-up subjects, who participated in comprehensive health examinations, consisted of 2444 inhabitants (949 males and 1495 females) of a rural area in Hokkaido, Japan. Between 1991 and December 2000, 146 subjects (94 males and 52 females) died, with cancer accounting for 76 of these deaths (48 males and 28 females). Serum samples at fasting were collected at entry into the study, and serum levels of beta- and alpha-carotenes, lycopene, beta-cryptoxanthin, canthaxanthin, zeaxanthin/lutein, tocopherols, and retinol were measured separately by high-performance liquid chromatography (HPLC). The statistical analyses were conducted using the Cox proportional hazard model. Age- and gender-adjusted hazard ratios of the groups with high serum levels of lycopene, beta-carotene, zeaxanthin/lutein, and total carotenoids compared to those with low serum levels were 0.36 (95% C.I: 0.19-0.69), 0.53 (0.29-0.95), 0.73 (0.43-1.25), and 0.52 (0.30-0.92) for cancers of all sites, and 0.44 (95% C.I: 0.28-0.69), 0.59 (0.39-0.90), 0.61 (0.40-0.93), and 0.50 (0.33-0.76) for all causes, respectively. Similar results were found after adjusting for gender, age, smoking habits, alcohol consumption, and serum levels of total cholesterol and glutamic pyruvic transaminase (GPT) activity. Moreover, after excluding mortality within the first three years of follow-up, the hazard ratios of subjects with high serum levels of lycopene, total carotenes, and total carotenoids were significantly and inversely associated with subsequent mortality from all causes and cancers of all sites after adjusting for gender, age, and serum levels of total cholesterol, alpha-tocopherol, and retinol. These results suggest that high serum levels of antioxidants, such as lycopene, beta-carotene and zeaxanthin/lutein, play roles in preventing death from cancer and from all causes. However, high serum levels of tocopherols and retinol did not demonstrate clear associations with either low mortality rates from all causes or cancer of all sites.

47. Nutr Cancer. 2000;38(1):23-9.

Vegetables, fruits, related dietary antioxidants, and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay.

De Stefani E, Brennan P, Boffetta P, Ronco AL, Mendilaharsu M, Deneo-Pellegrini H.

Registro Nacional de Cancer, Montevideo, Uruguay.

In 1998-1999, a case-control study on esophageal cancer was conducted in Uruguay. For this purpose, 111 cases with squamous cell carcinoma of the esophagus and 444 controls with conditions unrelated to tobacco smoking, alcohol drinking, or recent changes in the diet were frequency matched on age, gender, residence, and urban/rural status. Vegetables and, more markedly, fruits were associated with strong reductions in risk. On the other hand, 12 of 15 dietary antioxidants displayed significant inverse associations with esophageal cancer risk. The strongest effect was observed for high intake of beta-cryptoxanthin (odds ratio = 0.16, 95% confidence interval = 0.08-0.36). Also, alpha-carotene, lycopene, and beta-sitosterol were associated with significant reductions in risk. Most antioxidants lost their effect when they were further adjusted for a term for all vegetables and fruits. beta-Carotene showed an increased risk with high intakes. On the other hand, vegetables and fruits remained as significant variables after adjustment for each antioxidant, suggesting that other substances or other mechanisms could explain this effect.

48. Oral Oncol. 2000 Jan;36(1):47-53.

Tomatoes, tomato-rich foods, lycopene and cancer of the upper aerodigestive tract: a case-control in Uruguay.

De Stefani E, Oreggia F, Boffetta P, Deneo-Pellegrini H, Ronco A, Mendilaharsu M.

Registro Nacional de Cancer, Montevideo, Uruguay.

In order to study the relationship between tomatoes, tomato products, lycopene and cancers of the upper aerodigestive tract (UADC; oral cavity, pharynx, larynx, esophagus) a case-control study was carried out in Uruguay, in the time period 1996-98. Two-hundred and thirty eight cases and 491 hospitalized controls were frequency matched on age, sex, residence and urban/rural status. Both series were submitted to a detailed questionnaire, including tobacco smoking, alcohol drinking and queries on 64 food items. These data were analyzed by unconditional logistic regression, after adjusting by total energy intake. Tomato intake was associated with a reduction in risk of 0.30 (95% confidence interval [CI], 0.18-0.51), whereas tomato sauce-rich foods displayed a protective effect of 0.57 (95% CI, 0.33-0.96 for the highest quartile of intake). The food group composed of raw tomato and tomato-rich foods showed a strong inverse association with UADC (odds ratio [OR], 0.23; 95% CI, 0.13-0.39 for the highest quartile of intake). Lycopene was also strongly associated with a reduced risk of 0.22 (95% CI, 0.13-0.37). Adjustment of tomato intake for several phytochemicals explained almost completely its protective effect, which disappears in this model. Finally, the joint effect of lycopene and total phytosterols was associated with a significant reduction in risk (OR, 0.11; 95% CI, 0.05-0.23).

49. Nutr Cancer. 1999;33(1):105-12.

Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells.

Amir H, Karas M, Giat J, Danilenko M, Levy R, Yermiahu T, Levy J, Sharoni Y.

Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Lycopene, the major tomato carotenoid, has been found to inhibit proliferation of several types of cancer cells, including those of breast, lung, and endometrium. By extending the work to the HL-60 promyelocytic leukemia cell line, we aimed to evaluate some mechanistic aspects of this effect. Particularly, the possibility was examined that the antiproliferative action of the carotenoid is associated with induction of cell differentiation. Lycopene treatment resulted in a concentration-dependent reduction in HL-60 cell growth as measured by [3H]thymidine incorporation and cell counting. This effect was accompanied by inhibition of cell cycle progression in the G0/G1 phase as measured by flow cytometry. Lycopene alone induced cell differentiation as measured by phorbol ester-dependent reduction of nitro blue tetrazolium and expression of the cell surface antigen CD14. Results of several recent intervention studies with beta-carotene, which have revealed no beneficial effects of this carotenoid, suggest that a single dietary component cannot explain the anticancer effect of diets rich in vegetables and fruits. Thus another goal of our study was to examine whether lycopene has the ability to synergize with other natural anticancer compounds, such as 1,25-dihydroxyvitamin D3, which when used alone are therapeutically active only at high and toxic concentrations. The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibited a synergistic effect on cell proliferation and differentiation and an additive effect on