Vitamin E Regulation of Mitochondrial Superoxide Generation.

Chow CK Graduate Center for Nutritional Sciences, and Kentucky Agricultural Experiment Station, University of Kentucky, Lexington, Ky., USA.

Biol Signals Recept 2001 Jan;10(1-2):112-124

The mitochondrion is the greatest source, as well as the target, of reactive oxygen species (ROS). Increasing evidence indicates that vitamin E can act as a biological modifier independently of its antioxidant activity. Experimental evidence available shows that vitamin E is capable of dose-dependently regulating mitochondrial generation of superoxide and hydrogen peroxide. Vitamin E may modulate mitochondrial production and levels of superoxide by preventing electron leakage, by mediating the superoxide generation systems directly and/or by scavenging superoxide generated. By downregulating mitochondrial generation of superoxide and related ROS, vitamin E not only attenuates oxidative damage but also modulates the expression and activation of signal transduction pathways and other redox-sensitive biological modifiers. Copyright 2001 S. Karger AG, Basel

Antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree-bark powder: a randomised placebo-controlled trial.

Gupta R, Singhal S, Goyle A, Sharma VN Department of Medicine, Monilek Hospital and Research Centre, Jaipur.

J Assoc Physicians India 2001 Feb;49:231-5

OBJECTIVE: To evaluate the antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree bark (a popular cardiotonic substance in Indian pharmacopoeia) and to compare it with a known antioxidant, vitamin E, we performed a randomized controlled trial. METHODS: One hundred and five successive patients with coronary heart disease (CHD) presenting to our centre were recruited and using a Latin-square design divided into 3 groups of 35 each. The groups were matched for age, lifestyle and dietary variables, clinical diagnosis and drug treatment status. None of the patients was on lipid-lowering drugs. Supplemental vitamins were stopped for one month before study began and American Heart Association Step II dietary advice was given to all. At baseline, total cholesterol, triglycerides, HDL and LDL cholesterol and lipid peroxide estimated as thiobarbituric acid reactive substances (TBARS) were determined. Group I received placebo capsules; Group II vitamin E capsules 400 units/day; and Group III received finely pulverized T. arjuna tree bark-powder (500 mg) in capsules daily. Lipids and lipid peroxide levels were determined at 30 days follow-up. RESULTS: Response rate in various groups varied from 86% to 91%. No significant changes in total, HDL, LDL cholesterol and triglycerides levels were seen in Groups I and II (paired t-test p > 0.05). In Group III there was a significant decrease in total cholesterol (-9.7 +/- 12.7%), and LDL cholesterol (-15.8 +/- 25.6%) (paired t-test p < 0.01). Lipid peroxide levels decreased significantly in both the treatment groups (p < 0.01). This decrease was more in vitamin E group (-36.4 +/- 17.7%) as compared to the T. arjuna group (-29.3 +/- 18.9%). CONCLUSIONS: Terminalia arjuna tree bark powder has significant antioxidant action that is comparable to vitamin E. In addition, it also has a significant hypocholesterolaemic effect.

Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin.

Yam D, Peled A, Shinitzky M Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.

Cancer Chemother Pharmacol 2001;47(1):34-40

PURPOSE: The anticancer activity of omega-3 polyunsaturated fatty acids (omega-3 PUFA) has been shown in a large number of studies. This study was undertaken to analyze the combined effect of omega-3 PUFA and antioxidative vitamins on the level of spontaneous metastatic dissemination. The supportive effect of this dietary combination on chemotherapy with cisplatin (CP) was determined in parallel. METHODS: C57BL/6J mice bearing the Lewis lung carcinoma 3LL were fed ad libitum one of three isocaloric diets containing 5% soybean oil supplemented with 40 mg/kg alpha-tocopherol acetate (SO diet), or 4% fish oil plus 1% corn oil, and basal amounts of vitamin E (FO diet) or FO diet supplemented with vitamins E and C (FO+E+C diet). These diets were tested in combination with the conventional cytotoxic agent CP in a series of regimens. Tumor growth, feed consumption, body weight, lung metastasis and lung histology were followed. RESULTS: Both the FO dietary groups showed significantly lower tumor development than the SO group in all examined parameters, indicating that omega-3 PUFA have anticancer activity. However, the FO diet, in comparison with the FO+E+C diet induced a significantly slower rate of tumor growth, and lower metastatic load, as reflected in lung weight. The decrease in the anticancer activity of FO by the addition of vitamins E and C suggests that in situ oxidation of omega-3 PUFA underlies their anticancer action. It is thus proposed that oxidized omega-3 PUFA accumulates in the membranes and the cytosol of tumor cells, reducing their vitality and eventually leading to their death. No signs of anorexia or cachexia were observed in either FO group, in contrast to the SO group. CP treatment with the SO diet had no apparent therapeutic effect, while with the FO diets it reduced the metastatic load. The best regimen of this combined treatment was FO diet followed by CP treatment with FO diet supplemented with vitamins E and C after resection of the primary growth. This regimen could be translated to a combined therapy for human cancer. CONCLUSIONS: Diets enriched with omega-3 PUFA may have beneficial anticancer effects in particular when containing only basal amounts of antioxidants such as vitamin E or C. Furthermore, the addition of drugs which promote oxidation of omega-3 PUFA, such as ferrous salts (e.g. as prescribed for the treatment of anemia), may further increase these effects. However, the supportive effect of omega-3 PUFA in chemotherapy (e.g. with CP) increases when vitamins E and C are also included.

Sex bodies and synaptonemal complexes of Balb/C mice: antioxidant intervention of oxyradical insult.

Goldstein P, Raphael D, Ruiloba MC Department of Biological Sciences, University of Texas at El Paso, 79968, USA.

Cytobios 2001;104(405):7-23

Spermatogenesis is inhibited in Balb/C mice as a result of oxyradical insult. However, mammalian spermatocytes and synaptonemal complexes retain their structure and function after oxyradical insult due to protection afforded by the antioxidant vitamin E. Control groups were compared with experimental groups which were fed various vitamin E-deficient diets and subjected to varying times in an humidified 100% oxygen (hyperoxia) chamber. Measurements were made of sex body volume (SBV), nuclear envelope aberrations (NEA), and synaptonemal complex structure in spermatocytes during pachytene of meiosis prophase I. Changes in the volume of the sex body were positively correlated with increased oxyradical insult. The structure of the synaptonemal complex was not altered in any of the experimental groups which is a significant observation. It is suggested that vitamin E affords antioxidant protection and inhibits the alteration of membranes and sex chromosomes in mice during meiosis.

Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.

Rodriguez-Porcel M, Lerman A, Best PJ, Krier JD, Napoli C, Lerman LO Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.

J Am Coll Cardiol 2001 Feb;37(2):608-15

OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.

Vitamin E inhibits renal mRNA expression of COX II, HO I, TGFbeta, and osteopontin in the rat model of cyclosporine nephrotoxicity.

Jenkins JK, Huang H, Ndebele K, Salahudeen AK Department of Medicine, University of Mississippi Medical Center, Jackson 39216-4505, USA.

Transplantation 2001 Jan 27;71(2):331-4

BACKGROUND: In a rat model of cyclosporine (CsA) nephrotoxicity, vitamin E preserves renal function and reduces free radicals, vasoconstrictive thromboxanes, and tubulointerstitial fibrosis. We examined the effect of vitamin E on tubule gene expression in this model. METHODS: In two of three groups, rats were treated with either CsA, or CsA plus vitamin E, whereas the control group received vehicles. We pooled purified tubules or whole kidney tissue in a novel manner to represent each treatment group, harvested RNA, and performed rigorously controlled qualitative reverse transcription-polymerase chain reaction. RESULTS: Cyclooxygenase (COX) I mRNA was detectable in control animals, was increased by CsA, but was unchanged by vitamin E. COX II mRNA was detected in controls, was inhibited in the CsA group, and was further inhibited with vitamin E. Hemeoxygenase I and TGF-beta and osteopontin mRNA were increased in the CsA-treated group and were inhibited by vitamin E. CONCLUSIONS: Our data support the involvement of free radicals, COX pathways, and pro-fibrotic genes in cyclosporine nephrotoxicity and suggest that the salutary effect of vitamin E involves the suppression of some of these genes.

Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.

Grant CA, Berson EL Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.

Int Ophthalmol Clin 2001 Winter;41(1):103-10

In this chapter; we have described the role of nutritional supplements or selective dietary restriction (or both) on the maintenance and function of the retina and nervous system in some diseases. Oral vitamin A therapy has proven to be effective in the treatment of the common forms of retinitis pigmentosa. Bassen-Kornzweig disease can be treated with vitamin A and vitamin E and, in some cases, with vitamin K. Vitamin E therapy for Friedreich-like ataxia associated with retinitis pigmentosa has been shown to be effective in the short term. Classic Refsum's disease responds to a low phytol-low phytanic acid diet. Undoubtedly, future research will bring more insight into the biochemical pathways responsible for other diseases and, it is hoped, aid in developing treatments for additional retinal degenerations associated with systemic neurological disease.

Vitamin E: Mechanisms of Action as Tumor Cell Growth Inhibitors.

Kline K, Yu W, Sanders BG Division of Nutrition and. School of Biological Sciences, The University of Texas at Austin, Austin, TX 78712.

J Nutr 2001 Jan;131(1):161S-163S

Vitamin E analog modulates UVB-induced signaling pathway activation and enhances cell survival.

Peus D, Meves A, Pott M, Beyerle A, Pittelkow MR Departments of Dermatology and Biochemistry and Molecular Biology, Mayo Clinic and Mayo Foundation, Rochester, MN, USA

Free Radic Biol Med 2001 Feb 15;30(4):425-432

We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H(2)O(2) generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure-increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.

The Effect of alpha-tocopherol on Monocyte Proatherogenic Activity.

Jialal I, Devaraj S, Kaul N Departments of. Pathology and. Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9073.

J Nutr 2001 Feb;131(2):389S-394S

Atherosclerosis is the leading cause of morbidity and mortality in Westernized populations. The monocyte is a crucial cell in the genesis of the atherosclerotic lesion and is present during all stages of atherosclerosis. alpha-tocopherol (AT) is the most active component of the vitamin E family and is the principal and most potent lipid-soluble antioxidant in plasma and LDL. With regard to monocyte function, AT supplementation (1200 IU/d) has been shown to decrease release of reactive oxygen species, lipid oxidation, release of cytokines such as interleukin-1ss (IL-1ss) and tumor necrosis factor-alpha (TNF-alpha) and decrease adhesion of monocytes to human endothelium. The mechanism of inhibition of superoxide and lipid oxidation by monocytes appears to be via inhibition of protein kinase C (PKC), the decrease in IL-1ss and TNF-alpha release by inhibition of 5-lipoxygenase and the inhibition of monocyte-endothelial cell adhesion via decrease in adhesion molecules on monocytes, CD11b and VLA-4 and by decreasing DNA-binding activity of nuclear transcription factor kappaB. Thus, in addition to the decrease in oxidative stress resulting from AT supplementation, as evidenced by decreased F(2)-isoprostanes and LDL oxidizability, AT is anti-inflammatory and exerts beneficial antiatherogenic effects on cells crucial in atherogenesis such as monocytes.

Is there a vitamin E paradox?

Jialal I, Traber M, Devaraj S aCenter for Human Nutrition and Division of Clinical Biochemistry and Human Metabolism, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, and bThe Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA.

Curr Opin Lipidol 2001 Feb;12(1):49-53

[Record supplied by publisher]

In addition to epidemiologic studies that suggest a benefit for high intakes of alpha-tocopherol, studies of supplementation in humans have clearly shown that alpha-tocopherol decreases lipid peroxidation, platelet aggregation, and functions as a potent anti-inflammatory agent. In the five large prospective clinical trials with alpha-tocopherol therapy, four have shown a beneficial effect on cardiovascular end-points (two studies on a primary end-point and two studies on other cardiovascular end-points). Thus, the totality of evidence based on the epidemiologic data, in-vitro studies and animal models, and the clinical trials appears to support a benefit for alpha-tocopherol supplementation in patients with pre-existing cardiovascular disease. However, definitive recommendations must await ongoing clinical trials.

Crux medicorum ulcerated radiation-induced fibrosis - successful therapy with pentoxifylline and vitamin E.

Fischer M, Wohlrab J, Marsch WC Department of Dermatology and Venerology, Martin-Luther-University Halle-Wittenberg, Ernst-Kromayer-Str. 5/6, 06097 Halle, Saale, Germany.

Eur J Dermatol 2001 Jan;11(1):38-40

Case report of a 60 year-old patient with an ulcerated radiation-induced fibrosis after therapy for breast cancer. Treatment with oral administration of pentoxifylline 3 x 400 mg/day and vitamin E 2 x 200 mg/day was started. The ulcers were almost completely healed after 18 months. Sonographic examination showed a reduction in dermal thickness and in the laser Doppler fluxmetry, a regulation in the amplitude and increase in flux was found compared to the measurements made before the start of treatment. The therapy was very well tolerated without any side effects. The treatment of radiation-induced fibrosis with PTX and vitamin E is a practicable and cost-effective regimen, especially for inoperable patients. The efficacy of this treatment is probably due to a combination of blood flow stimulation and immune modulation which lead to a reduction in the fibrosis.

Effects of n-3 Polyunsaturated Fatty Acids and Vitamin E on Colonic Mucosal Leukotriene Generation, Lipid Peroxidation, and Microcirculation in Rats with Experimental Colitis.

Shimizu T, Igarashi J, Ohtuka Y, Oguchi S, Kaneko K, Yamashiro Y Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan.

Digestion 2001;63(1):49-54

Aims: We investigated the effect of n-3 polyunsaturated fatty acids (PUFAs) on mucosal levels of leukotrienes (LTs) and lipid peroxide (LPO), and on mucosal microcirculation, in rats with experimental colitis induced by dextran sulfate sodium (DSS). Methods: We fed Wistar rats a perilla oil-enriched diet containing alpha-linolenic acid (63.2% of total fatty acids) with various doses of vitamin E for 4 weeks, with 4% DSS added to the drinking water during the last week. Control rats were fed a diet produced from soybean oil containing alpha-linolenic acid (5.1% of total fatty acids). Colonic mucosal blood flow was measured with a laser Doppler flowmeter. Results: The mucosal level of arachidonic acid was significantly lower and that of eicosapentaenoic acid was significantly higher in the experimental group. The mucosal level of LPO in the experimental group fed a trace or ordinary dose of vitamin E was significantly higher than that of the controls. The production of LTB(4) and LTC(4) from the colonic mucosa in the experimental group was significantly lower than that in controls. However, only the experimental group fed a vitamin E dose 4-fold higher than that given to the controls showed a significant increase in mucosal blood flow. Conclusion: These results suggest that n-3 PUFAs increase mucosal blood flow by inhibiting LT production when there is sufficient vitamin E to inhibit lipid peroxidation in rats with experimental colitis. Copyright 2001 S. Karger AG, Basel

Neuroprotective effect of vitamin E on the early model of Parkinson's disease in rat: behavioral and histochemical evidence(1).

Roghani M, Behzadi G Department of Physiology, School of Medicine, P.O. Box 19835-181, Shaheed Beheshti University of Medical Sciences, Tehran, Iran

Brain Res 2001 Feb 16;892(1):211-217

There is strong evidence that oxidative stress participates in the etiology of Parkinson's disease (PD). We designed this study to investigate the neuroprotective effect of vitamin E in the early model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (12.5 ?g/5 ?l) lesioned rats were pretreated intramuscularly with D-alpha-tocopheryl acid succinate (24 I.U./kg, i.m.) 1 h before and three times per week for 1 month post-surgery. Apomorphine- and amphetamine-induced rotational behavior was measured postlesion fortnightly. A parallel tyrosine hydroxylase immunoreactivity and wheat germ agglutinin-horse radish peroxidase (WGA-HRP) tract-tracing study was performed to evaluate the vitamin E pretreatment efficacy. Tyrosine hydroxylase-immunohistochemical analyses showed a reduction of 18% in ipsilateral substantia nigra pars compacta (SNC) cell number of the vitamin E-pretreated lesioned (L+E) group comparing with contralateral side. The cell number dropped to 53% in the lesioned (L+V) group. In addition, retrograde-labeled neurons in ipsilateral SNC were reduced by up to 30% in the L+E group and 65% in the L+V group. Behavioral tests revealed that there are 74% and 68% reductions in contraversive and ipsiversive rotations in the L+E group, respectively, as compared with the L+V group. Therefore repeated intramuscular administration of vitamin E exerts a rapid protective effect on the nigrostriatal dopaminergic neurons in the early unilateral model of PD.

Vitamin E, lipid profile, and peroxidation in hemodialysis patients.

Galli F, Varga Z, Balla J, Ferraro B, Canestrari F, Floridi A, Kakuk G, Buoncristiani U "G. Fornaini" Institute of Biological Chemistry, University of Urbino, Urbino, Italy; First Department of Medicine, University Medical School, Debrecen, Hungary; Departments of Internal Medicine and Metabolic and Endocrinologic Sciences, University of Perugia, and Nephrology and Dialysis Unit, "R. Silvestrini" Regional Hospital, Perugia, Italy.

Kidney Int 2001 Feb;59(Suppl 78):148-154

BACKGROUND: Hypertriglyceridemia, lipid peroxidation, and abnormalities of the plasma fatty acid (PUFA) profile may be important risk factors for the atherosclerotic cardiovascular disease in hemodialysis (HD) patients. METHODS: We investigated how these factors are affected by vitamin E supplementation carried out by oral administration (clinical study 1) and dialysis with vitamin E-modified dialyzers (clinical study 2). RESULTS: In the HD patients, conditions of relative vitamin E deficiency were observed [lowered vitamin E/triglyceride (TG) ratio] in the presence of high levels of thiobarbituric acid reactants (TBARs) and decreased levels of the polyunsaturated fraction of PUFAs paired with an increased amount of monounsaturated ones (MUFA). In both studies, vitamin E supplementation significantly increased the levels of vitamin E in the plasma without affecting TG levels and provided a partial correction of TBAR levels. Of note was the relative increase in the PUFA fraction, which gave solid proof of an anti(per)oxidant effect of vitamin E supplementation in HD patients. Vitamin E supplementation was also observed to increase plasma levels of reduced glutathione and NOx (NO2 + NO3). CONCLUSION: The results suggest that vitamin E supplementation may be an effective accessory therapy to combat oxidative stress-lowering lipid peroxidation in HD patients.

A modified dialyzer with vitamin E and antioxidant defense parameters.

Mydlik M, Derzsiova K, Racz O, Sipulova A, Lovasova E, Petrovicova J Nephrological Clinic, University Hospital of L. Pasteur; Institutes of Pathological Physiology, and Experimental Medicine and Medical Informatics, Medical Faculty of P.J. Safarik University, Kosice, Slovak Republic.

Kidney Int 2001 Feb;59(Suppl 78):144-147

BACKGROUND: Oxidative stress, increased lipid peroxidation, and decreased activity of antioxidant systems may contribute to the accelerated development of atherosclerosis in patients receiving hemodialysis therapy for chronic renal failure. We investigated the influence of vitamin E on antioxidant defense parameters in hemodialysis patients who were using a modified dialyzer. METHODS: In eight hemodialyzed patients, erythrocyte antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPX), plasma total antioxidant capacity (TAC), the concentration of plasma malondialdehyde (MDA), and vitamins A, E, and C were investigated. Each parameter was measured before and after hemodialysis. The study was divided into three periods. Each period lasted three weeks, and during this time, 10 hemodialyses were performed. The first and second periods were carried out using the conventional dialyzer, Terumo CL-S15, but during the second period, patients received vitamin E 400 mg perorally after each hemodialysis. The third period was carried out using a modified dialyzer with vitamin E, Terumo CL-E15. All hemodialyzed patients were treated by erythropoietin and received vitamin C 50 mg/day and pyridoxine 20 mg/day during the entire study. RESULTS: The peroral administration of vitamin E led to a significant increase of serum vitamin E (22%), and no influence on other antioxidant defense parameters was found. The modified dialyzer with vitamin E led to a significant increase of serum vitamin E (33%) and TAC and to the significant decrease of plasma MDA. CONCLUSION: The results of our study suggest that the modified dialyzer with vitamin E provided more effective antioxidant defense than peroral administration of vitamin E in our hemodialysis patients.

N-acetyl-serotonin reduces copper (I) ion-induced lipid peroxidation in bovine retinal homogenates.

Siu AW, Cheung JP, To CH, Chan EK, Chan JK, Cheung JC Department of Optometry and Radiography, Faculty of Health & Social Sciences, The Hong Kong Polytechnic University, Kowloon, China.

Acta Ophthalmol Scand 2001 Feb;79(1):69-71

PURPOSE: Chalcosis is an ocular condition caused by penetration injury of copper or its alloy, which leads to extensive ocular inflammation. N-acetyl-serotonin has recently been identified as a potent antioxidant against free radical stress. In this study, we determined the efficacy of N-acetyl-serotonin against the copper (I)-induced retinal lipid peroxidation. METHODS: Copper (I)-treated (100 microM) bovine retinal homogenates were incubated with 6 different concentrations (i.e. 0.00, 0.25, 0.50, 1.00, 2.00 and 4.00 mM) of N-acetyl-serotonin or vitamin E. The malondialdehyde level was measured as an index of lipid peroxidation. RESULTS: Copper (I) ions induced a significant dose-dependent increase in malondialdehyde (p=0.007). Co-incubation with N-acetyl-serotonin or vitamin E significantly suppressed the copper (I)-induced malondialdehyde production (p<0.0001). The concentration to inhibit 50% of damage for N-acetyl-serotonin and vitamin E were found to be 1.54 mM and 0.45 mM, respectively. CONCLUSION: Although N-acetyl-serotonin is only 29% as effective as vitamin E in suppressing the copper (I)-induced lipid peroxidation, the present study supports a pharmacological potential of N-acetyl-serotonin combating free radical oxidative damages in the ocular tissues.

Antioxidants enhance the susceptibility of colon carcinoma cells to 5-fluorouracil by augmenting the induction of the bax protein.

Adeyemo D, Imtiaz F, Toffa S, Lowdell M, Wickremasinghe RG, Winslet M Academic Department of Surgery, Royal Free and University College London Medical School, Pond Street, NW3 2QG, London, UK

Cancer Lett 2001 Mar 10;164(1):77-84

5 Fluorouracil (5 FU), the most effective systemic chemotherapeutic agent in the management of advanced colorectal carcinoma acts by inducing apoptosis. Response rates, approximately 20% is improved by folinic acid. This study investigates similar modulation of 5 FU-induced apoptosis by oxidant quenching. A five-fold reduction of intracellular oxidant levels by antioxidants N-acetylcysteine and vitamin E did not induce apoptosis, it however augmented pro-apoptotic bax protein expression, and apoptotic response to a non-toxic dose of 5 FU in the colorectal cancer cell lines colo 201 and colo 205. This suggests that reduction of intracellular levels of reactive oxygen species enhance susceptibility to 5 FU (apoptotic stimuli) by augmentation of bax expression.

Acute effects of oats and vitamin E on endothelial responses to ingested fat.

Katz DL, Nawaz H, Boukhalil J, Giannamore V, Chan W, Ahmadi R, Sarrel PM Yale Prevention Research Center (Katz, Nawaz, Boukhalil, Giannamore, Chan, Ahmadi, Sarrel), Derby, Connecticut, USA

Am J Prev Med 2001 Feb;20(2):124-129

Objective: To assess the effects of oats and vitamin E on endothelial function following a high-fat meal in healthy adults as measured by brachial artery reactivity studies (BARS).Methods: A total of 25 men and 25 women (N=50) were recruited from a community population to participate in this randomized, crossover study. All subjects were free of known vascular disease, and female subjects were postmenopausal. Subjects underwent BARS before and after a high-fat meal (50 gm fat) on three occasions 1 week apart, one each with vitamin E 800 IU, oatmeal containing 3 gm beta-glucan, or a comparable bowl of wheat cereal serving as a placebo, in random sequence. The ultrasonographer was blinded to treatment status.Results: Endothelial function, as measured by brachial artery peak flow during one minute of post-occlusive hyperemia, declined significantly from baseline when the high-fat meal was consumed with the wheat cereal (-13.4%; p=0.02). There was no difference in brachial artery flow change before and after a high-fat meal with oats (+0.37%; p=0.77) or a high-fat meal with vitamin E (+1.87%; p=0.42). No significant differences in flow-mediated vasodilation before and after the high-fat meal were detected among the three supplements.Conclusions: Endothelial dysfunction induced by acute fat ingestion in healthy adults is apparently prevented by concomitant ingestion of oats or vitamin E, but not wheat. Nutrient distribution and meal composition may have important implications for cardiovascular health.

alpha-tocopherol Inhibits Human Glutathione S-Transferase pi.

van Haaften RI, Evelo CT, Haenen GR, Bast A Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht, 6200 MD, The Netherlands

Biochem Biophys Res Commun 2001 Jan 26;280(3):631-633

alpha-tocopherol is the most important fat-soluble, chain-breaking antioxidant. It is known that interplay between different protective mechanisms occurs. GSTs can catalyze glutathione conjugation with various electrophiles, many of which are toxic. We studied the influence of alpha-tocopherol on the activity of the cytosolic pi isoform of GST. alpha-tocopherol inhibits glutathione S-transferase pi in a concentration-dependent manner, with an IC(50)-value of 0.5 ?M. At alpha-tocopherol additions above 3 ?M there was no GST pi activity left. alpha-tocopherol lowered the V(max) values, but did not affect the K(m) for either CDNB or GSH. This indicates that the GST pi enzyme is noncompetitively inhibited by alpha-tocopherol. An inhibition of GST pi by alpha-tocopherol may have far-reaching implications for the application of vitamin E. Copyright 2001 Academic Press.

Does Vitamin E Decrease Heart Attack Risk? Summary and Implications with Respect to Dietary Recommendations.

Traber MG Department of Nutrition and Food Management, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512 and Division of Critical Care and Pulmonary Medicine, Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento, CA 95817.

J Nutr 2001 Feb;131(2):395S-397S

The hypothesis that oxidative stress has a role in atherosclerosis rests on a large body of experimental work carried out in animal models of heart disease. The situation is more complex in humans, in that the results from vitamin E supplementation trials have been conflicting. Nonetheless, there is emerging information that alpha-tocopherol may play a critical role in maintaining the function of key cellular components in the atherosclerotic process through its ability to inhibit the activity of protein kinase C, a key player in many signal transduction pathways. alpha-tocopherol modulates pathways of platelet aggregation, endothelial cell nitric oxide production, monocyte/macrophage superoxide production and smooth muscle cell proliferation. Regulation of adhesion molecule expression and inflammatory cell cytokine production by alpha-tocopherol has also been reported. More studies are required to relate alpha-tocopherol intakes to optimal tissue responses in humans.

Vitamin E and Macrophage Cyclooxygenase Regulation in the Aged.

Wu D, Hayek MG, Meydani SN Nutritional Immunology Laboratory, Jean Mayer Human Research Center on Aging at Tufts University, Boston, MA 02111. Department of Immunology, Norman Bethune University of Medical Sciences, Changchun, China. Iams Company, Lewisburg, OH 45338.

J Nutr 2001 Feb;131(2):382S-388S

Aging is associated with increased evidence of cardiovascular disease (CVD). Atherosclerosis, a major cause of CVD, is an inflammatory process whose development is influenced by several proinflammatory mediators. Products of arachidonic acid metabolism, in particular, prostaglandin (PG) E(2) and thromboxane (TX) A(2), play an important role in the development of atherosclerosis. We showed previously that the aged have higher PGE(2) production compared with their young counterparts. This age-associated increase in PGE(2) production is mainly a consequence of increased cyclooxygenase (COX) activity. We demonstrated further that increased COX activity in old mice is due to the increased expression of mRNA and protein for the inducible form of COX, COX-2. Vitamin E has been shown to reduce PGE(2) production and risk of CVD. In aged mice, we showed that a vitamin E-induced decrease in PGE(2) production is due to decreased COX activity. However, vitamin E had no effect on COX mRNA and protein levels, indicating a post-translational regulation of COX by vitamin E. Further experiments indicated that vitamin E decreases COX activity through reducing formation of peroxynitrite, a hydroperoxide shown to be involved in the activation of COX-2. Other homologues of tocopherols were also effective in inhibiting COX activity, but their degree of inhibition varied. The varied potency to inhibit COX activity was not explained totally by differences in their antioxidant capacity. Vitamin E-induced inhibition of COX activity might contribute to its effect of reducing CVD risk.

Vitamin E Inhibition of Platelet Aggregation Is Independent of Antioxidant Activity.

Freedman JE, Keaney JF Departments of Pharmacology and Medicine, Georgetown University Medical Center, Washington, DC and the. Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA.

J Nutr 2001 Feb;131(2):374S-377S

Vitamin E is the principal lipid-soluble antioxidant in human plasma, and some studies indicate that it may provide cardiovascular protection. To investigate putative mechanisms for vitamin E in this regard, the effect of vitamin E on vascular function and platelet aggregation was examined. In animal models of endothelial dysfunction, vitamin E improved the activity of endothelium-derived nitric oxide, and this effect was not dependent upon the antioxidant protection of LDL. In fact, vitamin E improved endothelial function in part due to the inhibition of protein kinase C (PKC) stimulation. This activity of vitamin E was examined in platelets, and vitamin E inhibited platelet aggregation in part through a mechanism that involves PKC. Moreover, the platelet inhibitory activity of vitamin E was independent of its antioxidant action because platelet inhibition was still observed with isoforms of vitamin E that were devoid of antioxidant activity.

Molecular Aspects of alpha-Tocotrienol Antioxidant Action and Cell Signalling.

Packer L, Weber SU, Rimbach G Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720-3200.

J Nutr 2001 Feb;131(2):369S-373S

Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922 in the laboratory of Herbert M. Evans (Science 1922, 55: 650). At least eight vitamin E isoforms with biological activity have been isolated from plant sources. Since its discovery, mainly antioxidant and recently also cell signaling aspects of tocopherols and tocotrienols have been studied. Tocopherols and tocotrienols are part of an interlinking set of antioxidant cycles, which has been termed the antioxidant network. Although the antioxidant activity of tocotrienols is higher than that of tocopherols, tocotrienols have a lower bioavailability after oral ingestion. Tocotrienols penetrate rapidly through skin and efficiently combat oxidative stress induced by UV or ozone. Tocotrienols have beneficial effects in cardiovascular diseases both by inhibiting LDL oxidation and by down-regulating 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG CoA) reductase, a key enzyme of the mevalonate pathway. Important novel antiproliferative and neuroprotective effects of tocotrienols, which may be independent of their antioxidant activity, have also been described.

Vitamin E and Atherosclerosis: Beyond Prevention of LDL Oxidation.

Meydani M Vascular Biology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111.

J Nutr 2001 Feb;131(2):366S-368S

Atherosclerosis is a chronic inflammatory disease of the arterial wall. Observational and experimental studies indicate that dietary vitamin E supplementation is associated with reduced risk of atherosclerosis. Evidence indicates that vitamin E, in addition to inhibition of oxidative modification of LDL, may inhibit atherogenesis through several other mechanisms at the molecular and cellular levels, which also include its nonantioxidant functions.

Induction of cancer cell apoptosis by {alpha}-tocopheryl succinate: molecular pathways and structural requirements.

Neuzil J, Weber T, Schroder A, Lu M, Ostermann G, Gellert N, Mayne GC, Olejnicka B, Negre-Salvayre A, Sticha M, Coffey RJ, Weber C Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany;, Medical Center North, Vanderbilt University, Nashville, Tennessee, USA;, Flinders University of South Australia, Adelaide, South Australia, Australia;, Department of Pathology II, University Hospital, Linkoping, Sweden;, Biochemistry Department, INSERM, Toulouse, France; and, Faculty of Science, Charles University, Prague, Czech Republic.

FASEB J 2001 Feb 1;15(2):403-415

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.-Neuzil, J., Weber, T., Schroder, A., Lu, M., Ostermann, G., Gellert, N., Mayne, G. C., Olejnicka, B., Negre-Salvayre, A., Sticha, M., Coffey, R. J., Weber, C. Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements.

Increased circulating lipid peroxides in severe preeclampsia activate NF-{kappa}B and upregulate ICAM-1 in vascular endothelial cells.

Takacs P, Kauma SW, Sholley MM, Walsh SW, Dinsmoor MJ, Green K Departments of Obstetrics and Gynecology, Microbiology and Immunology, Physiology, and, Anatomy, Virginia Commonwealth University, Medical College of Virginia.

FASEB J 2001 Feb 1;15(2):279-281

Preeclampsia is a systemic disease of pregnancy characterized by maternal hypertension, proteinuria, and edema. These clinical pathological findings may be attributed to abnormalities in vascular endothelial activation secondary to increased oxidative stress. To test the hypothesis that increased circulating lipid peroxides in preeclamptic women activate vascular endothelial cells, we determined NF-kB transcriptional activity and ICAM-1 expression in human umbilical vein endothelial cells (HUVEC) cultured with plasma from women with severe preeclampsia (preeclamptic plasma, N = 12) or plasma from normal pregnancies (normal plasma, N = 12). Preeclamptic women had increased circulating lipid peroxides compared with normal pregnant women, as demonstrated by a 4.5-fold higher concentration of plasma malondialdehyde (PkB luciferase reporter construct transfected into HUVEC, preeclamptic plasma was found to up-regulate HUVEC NF-kB activity by 2.5-fold when compared with normal plasma (PkB activation in response to preeclamptic-plasma by 77% (PkB activation and ICAM-1 expression on HUVEC, which can be inhibited by vitamin E and N-acetyl-cysteine.

Doxorubicin toxicity to the skin: possibility of protection with antioxidants enriched yeast.

Korac B, Buzadzic B Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', 29 Novembra 142, 11060, Belgrade, Yugoslavia.

J Dermatol Sci 2001 Jan;25(1):45-52

The possibility of skin protection against doxorubicin toxicity was examined after oral antioxidative pretreatment of the rats with yeast supplemented with selenium and vitamins E, C and A for 15 days. The activity and level of antioxidative defense components were monitored in the skin and blood 48 h after i.v. applied doxorubicin. In the blood, increased glutathione peroxidase activity in the erythrocytes, and amounts of vitamin E and glutathione in the plasma were found after the antioxidative treatment. It also led to an increase of the reductive capacity in the skin (increased thioredoxin reductase activity and reduced glutathione level). Doxorubicin alone, depleted reductive capacity, i.e. decreased the activity of thioredoxin reductase in the skin, as well as the content of reduced glutathione both in the skin and blood plasma. Depletion of reductive capacity represents one of the first harmful doxorubicin effects to the skin at the time when the changes of other antioxidative enzyme activities were not detectable. Reductive capacity in the skin of animals given antioxidative pretreatment was maintained elevated upon doxorubicin application in comparison with the corresponding control. Oral supplementation with antioxidants thus prevents toxic effects of doxorubicin in the skin and may contribute to the alleviation of its secondary cytotoxicity during the chemotherapy.

Circulating autoantibodies to oxidized cardiolipin correlate with isoprostane F(2alpha)-VI levels and the extent of atherosclerosis in ApoE-deficient mice: modulation by vitamin E.

Pratico D, Tangirala RK, Horkko S, Witztum JL, Palinski W, FitzGerald GA The Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, and the Department of Medicine, University of California, San Diego, La Jolla, CA.

Blood 2001 Jan 15;97(2):459-464

Lipid peroxidation plays an important role in atherogenesis. Previous studies suggested that autoantibodies against epitopes of oxidized low-density lipoprotein may indicate the extent or rate of progression of atherosclerosis. The aim of this study was to investigate whether autoantibodies to oxidized phospholipids, such as oxidized cardiolipin (OxCL), correlate with levels of isoprostane F(2alpha)-VI, a sensitive marker of in vivo lipid peroxidation, as well as with the extent of atherosclerosis. Two groups of apolipoprotein E-deficient mice were fed chow with or without vitamin E (2000 IU/kg diet) for 16 weeks. In untreated animals, autoantibodies against OxCL and urinary, plasma, and aortic isoprostane F(2alpha)-VI levels increased significantly. Vitamin E treatment significantly reduced antibody titers, isoprostane levels, and atherosclerosis at the end of the study, compared with untreated mice. Autoantibodies to OxCL correlated with aortic isoprostane F(2alpha)-VI levels (r(2) = 0.42, P =.001 for IgG and r(2) = 0.63, P <.001 for IgM). Both aortic isoprostane F(2alpha)-VI levels (r(2) = 0.59, P <.001) and titers of OxCL antibodies (r(2) = 0.70, P <.001 for IgG and r(2) = 0.68, P <.001 for IgM) correlated with the extent of aortic atherosclerosis. The fact that the levels of autoantibodies to OxCL correlated with a sensitive direct measure of lipid peroxidation in vivo and that both autoantibodies and aortic isoprostane F(2alpha)-VI levels correlated with the extent of atherosclerosis suggests that antibodies to OxCL are a sensitive indicator of in vivo lipid peroxidation and atherosclerosis. (Blood. 2001;97:459-464)

Effect of dietary vitamin E supplementation on vascular reactivity of thoracic aorta in streptozotocin-diabetic rats.

Cinar MG, Ulker S, Alper G, Evinc A Department of Pharmacology, Faculty of Medicine, Ege University, Bornova/Izmir, Turkey.

Pharmacology 2001 Jan;62(1):56-64

The present study evaluated the effect of dietary vitamin E supplementation (1,000 mg/kg chow) on the alterations in vascular reactivity of streptozotocin-diabetic aorta of Wistar rats. After 12 weeks of treatment, thoracic aortic rings of rats were mounted in organ baths and contractile responses to phenylephrine and 5-hydroxytryptamine and relaxant responses to acetylcholine, calcium ionophore and sodium nitroprusside were assessed. Plasma vitamin E concentration as measured by HPLC was markedly decreased in diabetic rats and increased with dietary vitamin E supplementation. Induction of diabetes significantly impaired endothelium-dependent relaxations to acetylcholine and calcium ionophore in aortic rings, but did not change endothelium-independent relaxation to sodium nitroprusside. Vitamin E significantly improved the impaired endothelium-dependent relaxations, further it decreased the enhanced contractile response to phenylephrine and 5-hydroxytryptamine in diabetic rings. The mechanical denudation of endothelium or the chemical inhibition of endothelium-dependent relaxation with N(omega)-nitro-L-arginine methyl ester (100 micromol/l) significantly increased phenylephrine contractility in control rings and the rings of diabetic rats treated with vitamin E; such a difference was not observed in diabetic rats fed with normal diet. Liver and lung malondialdehyde concentrations, as an index of lipid peroxidation, were increased in diabetic rats and significantly decreased with vitamin E supplementation. It is concluded that dietary supplementation of vitamin E improved endothelial dysfunction in insulin-dependent model of uncontrolled diabetes, probably decreasing membranal lipid peroxidation. Copyright 2001 S. Karger AG, Basel

Selective cancer cell killing by alpha-tocopheryl succinate.

Neuzil J, Weber T, Gellert N, Weber C Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Pettenkoferstrasse 9, Munich, 80336, Germany.

Br J Cancer 2001 Jan 5;84(1):87-9

We report that alpha-tocopheryl succinate, a vitamin E analogue with pro-apoptotic properties, selectively kills cells with a malignant or transformed phenotype, i.e. multiple haematopoietic and carcinoma cell lines, while being non-toxic to normal, i.e. primary and non-transformed cells. These findings strongly suggest a potential of this micronutrient in the therapy and/or prevention of cancer without significant side-effects. Copyright 2001 Cancer Research Campaign.

Cypermethrin-induced oxidative stress in rat brain and liver is prevented by vitamin E or allopurinol.

Giray B, Gurbay A, Hincal F Department of Toxicology, Faculty of Pharmacy, University of Hacettepe, 06100, Ankara, Turkey.

Toxicol Lett 2001 Jan 3;118(3):139-46

Considering that the involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides, this study was designed to investigate the possibility of oxidative stress induction by cypermethrin, a Type II pyrethroid. Either single (170 mg/kg) or repeated (75 mg/kg per day for 5 days) oral administration of cypermethrin was found to produce significant oxidative stress in cerebral and hepatic tissues of rats, as was evident by the elevation of the level of thiobarbituric acid reactive substances (TBARS) in both tissues, either 4 or 24 h after treatment. Much higher changes were observed in liver, increasing from a level of 60% at 4 h up to nearly 4 times the control at 24 h for single dose. Reduced levels (up to 20%) of total glutathione (total GSH), and elevation of conjugated dienes ( approximately 60% in liver by single dose at 4 h) also indicated the presence of an oxidative insult. Glutathione-S-transferase (GST) activity, however, did not differ from control values for any dose or at any time point in cerebral and hepatic tissues. Pretreatment of rats with allopurinol (100 mg/kg, ip) or Vitamin E (100 mg/kg per day, ig, for 3 days and a dose of 40 mg/kg on the 4th day) provided significant protection against the elevation of TBARS levels in cerebral and hepatic tissues, induced by single high dose of oral cypermethrin administration within 4 h. Thus, the results suggest that cypermethrin exposure of rats results in free radical-mediated tissue damage, as indicated by elevated cerebral and hepatic lipid peroxidation, which was prevented by allopurinol and Vitamin E.

Alpha-tocopherol succinate inhibits growth of gastric cancer cells in vitro.

Rose AT, McFadden DW Department of Surgery, UCLA Medical Center, Los Angeles, California, USA.

J Surg Res 2001 Jan;95(1):19-22

BACKGROUND: Vitamin E in the form of alpha-tocopherol succinate (ATS) has been shown to inhibit growth of several cancer cell lines in vitro, including pancreas, breast, and prostate. No data exist on the effect of ATS on gastric cancer cell viability. METHODS: A gastric cancer cell line in suspension form, KATO-III, was plated in 96-well plates at 30,000 cells per well with 100 microl RPMI media. The cells were allowed to incubate for 24 h and were then treated with ATS at doses of 25, 50, or 100 microg/ml. The ATS was dissolved in 1% EtOH solution and control cells received an identical solution of EtOH without ATS. Treated cells were incubated for 24, 48, or 72 h. At the completion of the treatment period, MTT assay was performed to determine cell viability. Statistical analysis was performed using Student's t test. RESULTS: All doses of ATS resulted in inhibition of growth of the KATO-III cells. Both 100 and 50 microg/cc doses inhibited growth at all time points (P<0.005), with 48- and 72-h treatments more effective than 24-h treatment. At 24 and 48 h, 100 microg/cc was more effective at inhibition of growth than 50 microg/ml (P<0.005), but by 72 h the effects of the doses were equivalent; 25 microg/ml inhibited cell growth only at 48 and 72 h. At all time points, 50 and 100 microg/ml doses were more effective at inhibiting cell growth than 25 microg/ml. Conclusions. ATS inhibits gastric carcinoma cell growth in vitro in a dose- and time-dependent fashion. In vivo studies are indicated to further evaluate the potential benefit of this antioxidant against gastric cancer.

Fanconi anemia lymphocytes: effect of DL-alpha-tocopherol (Vitamin E) on chromatid breaks and on G2 repair efficiency.

Pincheira J, Bravo M, Santos MJ, de la Torre C, Lopez-Saez JF Programa de Genetica Humana, y Facultad de Medicina, Universidad de Chile, Casilla 70061, Santiago 7, Chile.

Mutat Res 2001 Jan 5;461(4):265-71

The high frequency of chromosomal breaks in Fanconi anemia (FA) lymphocytes has been related to the increased oxidative damage shown by these cells. The effect of 100 microM DL-alpha-tocopherol (Vitamin E) on the level of chromosomal damage in mitosis was studied in lymphocytes from five FA patients and from age matched controls, both under basal conditions and when G2 repair was prevented by 2.5 mM caffeine (G2 unrepaired damage). In addition, the effect of this antioxidant on G2 duration and the efficiency of G2 repair was also evaluated in the sample. alpha-tocopherol (AT) decreased the frequency of chromosomal damage (under basal and inhibited G2 repair conditions) and the duration of G2 in FA cells. This antioxidant protective effect, expressed as the decrease in chromatid breaks, was greater in FA cells (50.8%) than in controls (25%). The efficiency of the G2 repair process (G2 R rate) defined as the ratio between the percentage of chromatid breaks repaired in G2 and the duration of this cell cycle phase was lesser in FA cells (10.6) than in controls (22.6). AT treatment slightly increased this G2 R rate, both in FA cells and controls. These results suggest that an increased oxidative damage and a lower G2 repair rate may be simultaneously involved in the high frequency of chromatid damage detected in FA cells.

alpha -Tocopherol Transfer Protein Is Important for the Normal Development of Placental Labyrinthine Trophoblasts in Mice.

Jishage Ki K, Arita M, Igarashi K, Iwata T, Watanabe M, Ogawa M, Ueda O, Kamada N, Inoue K, Arai H, Suzuki H Pharmaceutical Technology Laboratory, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513 Japan and the Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan.

J Biol Chem 2001 Jan 19;276(3):1669-1672

alpha-tocopherol transfer protein (alpha-TTP), a cytosolic protein that specifically binds alpha-tocopherol, is known as a product of the causative gene in patients with ataxia that is associated with vitamin E deficiency. Targeted disruption of the alpha-TTP gene revealed that alpha-tocopherol concentration in the circulation was regulated by alpha-TTP expression levels. Male alpha-TTP(-/-) mice were fertile; however, placentas of pregnant alpha-TTP(-/-) females were severely impaired with marked reduction of labyrinthine trophoblasts, and the embryos died at mid-gestation even when fertilized eggs of alpha-TTP(+/+) mice were transferred into alpha-TTP(-/-) recipients. The use of excess alpha-tocopherol or a synthetic antioxidant (BO-653) dietary supplement by alpha-TTP(-/-) females prevented placental failure and allowed full-term pregnancies. In alpha-TTP(+/+) animals, alpha-TTP gene expression was observed in the uterus, and its level transiently increased after implantation (4.5 days postcoitum). Our results suggest that oxidative stress in the labyrinth region of the placenta is protected by vitamin E during development and that in addition to the hepatic alpha-TTP, which governs plasma alpha-tocopherol level, the uterine alpha-TTP may also play an important role in supplying this vitamin.