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Vitamin E ameliorates renal injury in an experimental model of immunoglobulin A nephropathy.

Trachtman H; Chan JC; Chan W; Valderrama E; Brandt R; Wakely P; Futterweit S; Maesaka J; Ma C
Department of Pediatrics (Division of Nephrology), Schneider Children's Hospital, New Hyde Park New York 11040, USA.
Pediatr Res (UNITED STATES) Oct 1996, 40 (4) p620-6

IgA nephropathy is one of the most common forms of glomerular disease. Nearly 25% of affected patients progress to end-stage renal disease over a 20-25-y follow-up period. IgA-containing immune complexes stimulate oxygen-free radical production by mesangial cells in vitro. The excessive oxidant stress may mediate glomerular injury in this disorder. Therefore, we studied whether dietary supplementation with the antioxidant agent, vitamin E, attenuates renal disease in an experimental model of incipient IgA nephropathy with mild kidney inflammation. IgA nephropathy was induced in male Lewis rats by oral immunization with 0.1% bovine gamma-globulin (BGG)-containing drinking water for 8 wk. At the completion of this period, animals received BGG, 1 mg/dose i.v., on three successive days. Experimental rats (n = 10) received a specially formulated diet containing 100 IU of vitamin E/kg of chow, whereas control animals (n = 10) were fed chow containing 30 IU of vitamin/kg of chow. The BGG immunization regimen induced mesangial IgA deposition in all rats. Vitamin E supplementation resulted in a nearly 5-fold increase in the serum vitamin E concentration. Vitamin E-treated rats gained more weight and had a lower incidence of hematuria, 20% versus 80% (p < 0.03). Moreover, proteinuria was decreased by 50%, and reduced renal plasma flow was restored to normal, compared with untreated rats with IgA nephropathy. Glomerular hypertrophy occurred in animals with IgA nephropathy, but less so in those receiving vitamin E supplementation. Renal cortical malondialdehyde content was reduced from 1.55 +/- 0.10 to 1.22 +/- 0.09 nmol/mg of protein (p < 0.01) in rats fed the vitamin E-enriched diet. Finsforming growth factor-beta 1 gene expression was reduced by 34% in rats with IgA nephropathy receiving vitamin E treatment (p < 0.05). We conclude that experimental IgA nephropathy is associated with increased renal oxidant injury. Dietary treatment with the antioxidant agent, vitamin E, attenuated renal functional and structural changes in this experimental glomerulopathy. These studies support the importance of clinical trials for the evaluation of the efficacy of antioxidant therapy in patients with IgA nephropathy.

Demonstration of organotropic effects of chemopreventive agents in multiorgan carcinogenesis models.

Tsuda H; Iwahori Y; Asamoto M; Baba-Toriyama H; Hori T; Kim DJ; Uehara N; Iigo M; Takasuka N; Murakoshi M; Nishino H; Kakizoe T; Araki E; Yazawa K
National Cancer Center Research Institute, National Cancer Center Hospital, Tokyo, Japan.
IARC Sci Publ (FRANCE) 1996, (139) p143-50

Organotropic chemopreventive effects of three (pro)vitamins and three unsaturated fatty acids were examined using mouse and rat multiorgan carcinogenesis models. For the study of (pro)vitamins, male and female B6C3F1 mice were treated with N,N-diethylnitrosamine (DEN) and N-methyl-N-nitrosourea (MNU) during the first 11 weeks, then from weeks 12 to 32 they received alpha-carotene (0.4 mg/mouse), beta-carotene (0.4 mg/mouse) or alpha-tocopherol (40 mg/mouse) three times a week by gavage; control mice received vehicle alone. In male mice, alpha-carotene significantly reduced liver weights, representing a reduced tumour mass (P < 0.001), and alpha-carotene, beta-carotene and alpha-tocopherol significantly reduced the numbers of liver tumours (adenomas a0.01) as compared with control mice, the effects being greatest with alpha-carotene. In female mice, alpha-carotene significantly decreased the number of liver tumours (P < 0.001). In the lung, alpha-carotene and alpha-tocopherol reduced the area of lesions (hyperplasias and adenomas combined) only in males (P < 0.05). For the study of unsaturated fatty acids, F344 male rats were treated with DEN, MNU, N-butyl-N-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and N,N-bis(2-hydroxy)propylnitrosamine during the first 5 weeks, then from weeks 6 to 36 they were given docosahexaenoic acid (C22:6), eicosapentaenoic acid (C20:5) or linoleic acid (C18:2) at 1.0 g/rat, three times a week by gavage; control rats were treated with oleic acid (C18:1) using the same protocol. All animals were fed a low linoleic acid and calorie-adjusted basal diet during fatty acid administration. Docosahexaenoic acid and linoleic acid reduced tumours in the large and small intestines, respectively. However, they did not influence the yield of preneoplastic liver, lung, kidney, forestomach and urinary bladder lesions. The data thus provide evidence for organotropic effects of carotenoids and unsaturated fatty acids on carcinogenesis.

What dose of vitamin E is required to reduce susceptibility of LDL to oxidation?

Simons LA; Von Konigsmark M; Balasubramaniam S
University of New South Wales Lipid Research Department, St Vincent's Hospital, Sydney, NSW.
Aust N Z J Med (AUSTRALIA) Aug 1996, 26 (4) p496-503

BACKGROUND: Oxidation modification of low density lipoprotein (LDL) may play a role in the pathogenesis of atherosclerosis. Ingestion of vitamin E in high dosage has been shown to reduce the susceptibility of LDL to copper-induced oxidation, as assessed ex vivo. AIM: To determine a minimum dose of supplementary vitamin E which will significantly reduce the susceptibility of LDL to oxidation. METHODS: A single centre, double-blind, parallel placebo-controlled trial. Healthy volunteers (total n = 42) were randomised to receive placebo, 500, 1000 or 1500 IU/day of vitamin E (D-alpha-tocopherol) for a period of six weeks. Primary outcomes were change in lag time or oxidation rate to copper-induced LDL oxidation. Secondary outcomes were changes in plasma vitamin E levels and clinical tolerance. RESULTS: Lag time to LDL oxidation was significantly prolonged and oxidation rate significantly slowed at all dose levels of vitamin E, indicating a threshold effect from 500 IU/day. Compared to placebo, the median prolongation in lag time on 500 IU/day was 26%, on 1000 IU/day 24% and on 1500 IU/day 35%. The corresponding slowing in oxidation rates was 14%, 19% and 25% respectively. The per cent change in plasma vitamin E concentration was highly correlated with the change in lag time (r = 0.61, p < 0.001) and oxidation rate (r = 0.55, p < 0.001). Vitamin E was generally well tolerated. CONCLUSIONS: Vitamin E in a dose of 500 IU/day will significantly reduce the susceptibility of LDL to oxidation. Whether or not this treatment will consistently reduce the future incidence of coronary artery disease will only be answered by further clinical trials.

Inhibition of steroid-induced cataract in rat eyes by administration of vitamin-E ophthalmic solution.

Kojima M; Shui YB; Murano H; Sasaki K
Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan.
Ophthalmic Res (SWITZERLAND) 1996, 28 Suppl 2 p64-71

The efficacy of a vitamin-E (VE) ophthalmic solution was evaluated on a newly developed rat steroid-induced cataract model. Brown Norway rats irradiated with 2 Gy X-ray, right eyes only, were divided into 5 groups: the control group; 2 steroid (1 mg/kg/day)-treated groups with topic (Top) and systemic (Sys) administration, and 2 VE-treated groups, 1 with the same treatment as the Top group with the addition of 5% VE twice a day (Top + VE) and 1 with the same treatment as the Sys group with 5% VE twice a day (SYS + VE). The lens changes were documented with a Scheimpflug camera and changes in light scattering were evaluated quantitatively. The VE-treated groups (Top + VE and Sys + VE) showed a significant inhibition of the increase in the opaque area compared with each of the non-VE-treated groups. The VE ophthalmic solution was strong enough to prevent steroid-induced cataract in rats.

Anticataract action of vitamin E: its estimation using an in vitro steroid cataract model.

Ohta Y; Okada H; Majima Y; Ishiguro I
Department of Biochemistry, School of Medicine, Fujita Health University, Aichi, Japan.
Ophthalmic Res (SWITZERLAND) 1996, 28 Suppl 2 p16-25

The aim of this study was to estimate the anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a decrease in vitamin E content and an increase in water content in addition to further increases in LPO content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane function.

Study design and baseline characteristics of the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E: SECURE.

Lonn EM; Yusuf S; Doris CI; Sabine MJ; Dzavik V; Hutchison K; Riley WA; Tucker J; Pogue J; Taylor W
Division of Cardiology and Preventive Cardiology, Hamilton Civic Hospitals Research Center, McMaster University, Ontario, Canada.
Am J Cardiol (UNITED STATES) Oct 15 1996, 78 (8) p914-9

Atherosclerotic cardiovascular disease remains a major cause of mortality and morbidity in most developed countries. Experimental and clinical evidence suggests that angiotensin-converting enzyme inhibitors and vitamin E therapy may retard the atherosclerotic process; however, definitive proof in humans is lacking. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) is designed to assess the effects of ramipril--an angiotensin-converting enzyme inhibitor, at 2 doses: 2.5 mg daily (which has little effect oure) and 10 mg daily--and the antioxidant vitamin E, 400 IU daily, on atherosclerosis progression in 732 patients using a factorial 3 x 2 study design. High-risk patients with a documented history of significant cardiovascular disease or with diabetes and additional risk factors were enrolled and will be followed for 4 years. The extent and progression of atherosclerosis are assessed noninvasively by B-mode carotid ultrasonography. The SECURE trial is a substudy of the larger Heart Outcomes Prevention Evaluation (HOPE) study of 9,541 high-risk patients evaluating the effects of ramipril and vitamin E on major cardiovascular events (cardiovascular death, myocardial infarction, and stroke). The 2 studies are complementary. Whereas HOPE is expected to provide information on major clinical outcomes, SECURE will shed light on the mechanisms by which these effects may be mediated.

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance

Albanes D; Heinonen OP; Taylor PR; Virtamo J; Edwards BK; Rautalahti M; Hartman AM; Palmgren J; Freedman LS; Haapakoski J; Barrett MJ; Pietinen P; Malila N; Tala E; Liippo K; Salomaa ER; Tangrea JA; Teppo L; Askin FB; Taskinen E; Erozan Y; Greenwald P; Huttunen JK
Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, MD 20892-7326, USA.
J Natl Cancer Inst (UNITED STATES) Nov 6 1996, 88 (21) p1560-70

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carot lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Vitamin E in humans: demand and delivery.

Traber MG; Sies H
Department of Molecular and Cell Biology, University of California, Berkeley 94720, USA.
Annu Rev Nutr (UNITED STATES) 1996, 16 p321-47

How much vitamin E is enough? An established use of supplemental vitamin E in humans is in the prevention and therapy of deficiency symptoms. The cause of vitamin E deficiency, characterized by peripheral neuropathy and ataxia, is usually malabsorption-a result of fat malabsorption or genetic abnormalities in lipoprotein metabolism. Genetic abnormalities in the hepatic alpha-tocopherol transfer protein also cause vitamin E deficiency-defects in this protein cause an impairment in plasma vitamin E transport. Impaired delivery of vitamin E to tissues, thereby, results in deficiency symptoms. Also discussed is the use of supplemental vitamin E in chronic diseases such as ischemic heart disease, atherosclerosis, diabetes, cataracts, Parkinson's disease, Alzheimer's disease, and impared immune function, as well as in subjects receiving total parenterol nutrition. In healthy individuals, a daily intake of about 15-30 mg of alpha-tocopherol is recommended to obtain "optimal plasma alpha-tocopherol concentrations" (30 microM or greater). (158 Refs.)

Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits.

Wiseman SA; Mathot JN; de Fouw NJ; Tijburg LB
Unilever Research Laboratory, Vlaardingen, The Netherlands.
Atherosclerosis (IRELAND) Feb 1996, 120 (1-2) p15-23

Consumption of a range of dietary antioxidants may be beneficial in protecting low density lipoprotein (LDL) against oxidative modification, as studies have demonstrated that antioxidants other than vitamin E may also function against oxidation of LDL in vitro. In the present study, the effect of polyphenol antioxidants on the susceptibility of LDL to copper-mediated oxidation was investigated after feeding semi-purified diets to 3 groups of New Zealand white (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic acid. Dietary fatty acid compositions were identical. Oils with different polyphenol contents were used to provide the dietary source of oleic acid-refined olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil. Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in the extra virgin olive oil. Vitamin E was equalised in all diets. LDL oxidizability in vitro was determined by continuously monitoring the copper-induced formation of conjugated dienes after 6 weeks of experimental diet feeding. The lag phase before demonstrable oxidation occurred was significantly increased in the high polyphenol, extra virgin olive oil group (P < 0.05) when compared with combined results from the low polyphenol group (refined olive oil and Trisun), even thoug vitamin E concentration in the high polyphenol group was significantly lower. The rate of conjugated diene formation was not influenced by the presence of dietary polyphenols. Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.

The effect of modest vitamin E supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients.

Jain SK; McVie R; Jaramillo JJ; Palmer M; Smith T; Meachum ZD; Little RL
Department of Pediatrics, Louisiana State University Medical Center, Shreveport 71130, USA.
Lipids (UNITED STATES) Mar 1996, 31 Suppl pS87-90

Among many factors, elevated lipids and lipid peroxide levels in blood are major risk factors in the development of cardiovascular disease in diabetic patients. This study has examined whether oral supplementation of vitamin E, an antioxidant, has any effect on blood of diabetic patients. Thirty-five diabetics(D) were supplemented with DL-alpha-tocopherol (E) capsule (orally, 100 IU/d) or placebo (P) for three months in double-blind clinical trials. Plasma E was analyzed by HPLC and LP by the thiobarbituric acid-reactivity; serum lipids by auto-analyzer. Data were analyzed using paired t-test and Wilcoxon Signed Rank Test. Vitamin E supplementation significantly lowered LP and lipid levels in diabetic patients; there were no differences in these parameters after P supplementation. There were no differences in the duration of diabetes and ages of D between P- and E- supplemented groups. This study suggests that vitamin E supplementation significantly lowers blood LP and lipid levels in diabetic patients.

Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation.

Keaney JF Jr; Guo Y; Cunningham D; Shwaery GT; Xu A; Vita JA
Evans Memorial Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118, USA.
J Clin Invest (UNITED STATES) Jul 15 1996, 98 (2) p386-94

Excess vascular oxidative stress has been linked to impaired endlemia. alpha-Tocopherol (AT) preserves endothelial function in hypercholesterolemia although the mechanism(s) for this protective effect is (are) not known. We examined the tissue-specific effects of AT on oxidized LDL (ox-LDL)-mediated endothelial dysfunction in male New Zealand White rabbits. Animals consumed chow deficient in (< 10 IU/kg) or supplemented with (1,000 IU/kg) AT for 28 d. Exposure of thoracic aortae from AT-deficient animals to ox-LDL (0-500 microg/ml) for 4 h produced dose-dependent inhibition of acetylcholine-mediated relaxation (P < 0.05) while vessels derived from animals consuming AT were resistant to ox-LDL-mediated endothelial dysfunction. Animals consuming AT demonstrated a 100-fold increase in vascular AT content and this was strongly correlated with vessel resistance to endothelial dysfunction from ox-LDL (R = 0.67; P = 0.0014). These results were not explained by an effect of AT on ox-LDL-mediated cytotoxicity by LDH assay or scanning electron microscopy. Vascular incorporation of AT did produce resistance to endothelial dysfunction from protein kinase C stimulation, an event that has been implicated in the vascular response to ox-LDL. Human aortic endothelial cells loaded with AT also demonstrated resistance to protein kinase C stimulation by both phorbol ester and ox-LDL. Thus, these data indicate that enrichment of vascular tissue with AT protects the vascular endothelium from ox-LDL-mediated dysfunction, at least in part, through the inhibition of protein kinase C stimulation. These findings suggest one potential mechanism for the observed beneficial effect of AT in preventing the clinical expression of coronary artery disease that is distinct from the antioxidant protection of LDL.

Oxidatively modified LDL and atherosclerosis: an evolving plausible scenario.

Jialal I; Fuller CJ
Center for Human Nutrition, University of Texas--Southwestern Medical Center, Dallas 75235-9052, USA.
Crit Rev Food Sci Nutr (UNITED STATES) Apr 1996, 36 (4) p341-55

Much evidence has accumulated that implicates the oxidative modification of low-density lipoprotein (LDL) in the early stages of atherogenesis. The , they have nutrients alpha-tocopherol, ascorbic acid, and betacarotene been shown to increase the resistance of LDL to oxidation when given to animals and humans. Because plasma levels of these nutrients can be increased by dietary supplementation with minimal side effects, they may show promise in the prevention of coronary artery disease. (115 Refs.)

The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium.

Devaraj S; Li D; Jialal I
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9052, USA.
J Clin Invest (UNITED STATES) Aug 1 1996, 98 (3) p756-63

Low levels of alpha tocopherol are related to a higher incidence of cardiovascular disease and increased intake appears to afford protection against cardiovascular disease. In addition to decreasing LDL oxidation, alpha tocopherol may exert intracellular effects on cells crucial in atherogenesis, such as monocytes. Hence, the aim of this study was to test the effect of alpha tocopherol supplementation on monocyte function relevant to atherogenesis. Monocyte function was assessed in 21 healthy subjects at baseline, after 8 wk of supplementation with d-alpha tocopherol (1,200 IU/d) and after a 6-wk washout phase. The release of reactive oxygen species (superoxide anion, hydrogen peroxide), lipid oxidation, release of the potentially atherogenic cytokine, interleukin 1 beta, and monocyte-endothelial adhesion were studied in the resting state and after activation of the monocytes with lipopolysaccharide at 0, 8, and 14 wk. There was a 2.5-fold increase in plasma lipid-standardized and monocyte alpha tocopherol levels in the supplemented phase. After alpha tocopherol supplementation, there were significant decreases in release of reactive oxygen species, lipid oxidation, IL-1 beta secretion, and monocyte-endothelial cell adhesion, both in resting and activated cells compared with baseline and washout phases. Studies with the protein kinase C inhibitor, Calphostin C, suggest that the inhibition of reactive oxygen species release and lipid oxidation is due to an inhibition of protein kinase C activity by alpha tocopherol. Thus, this study provides novel evidence for an intracellular effect of alpha tocopherol in monocytes that is antiatherogenic.

[Can vitamin E prevent development of coronary heart disease?]

Nguyen KN; Landmark K
Institutt for farmakoterapi, Universitetet i Oslo.
Tidsskr Nor Laegeforen (NORWAY) Mar 30 1996, 116 (9) p1109-13

Oxidation of low-density lipoprotein (LDL) probably plays an important part in atherosclerosis. Vitamin E (alpha-tocopherol) is a potent antioxidant carried in LDL. It increases the resistance of LDL to oxidation, thereby, among other things, inhibiting foam cell formation and proliferation of smooth muscle cells. Some animal experiments have indicated that vitamin E retards the development of atherosclerotic lesions. Observational studies (case-control and cohort) have shown that long-term treatment with vitamin E is associated with lower incidence of coronary heart disease introlled trial gave a nonsignificant reduction in mortality from ischemic heart disease. Although vitamin E seems to reduce the risk of coronary heart disease, randomised trials of adequate size are necessary in both secondary and primary prevention in order to test this. Such trials are in progress. (61 Refs.)

Long-term oral vitamin E supplementation in cystic fibrosis patients: RRR-alpha-tocopherol compared with all-rac-alpha-tocopheryl acetate preparations.

Winklhofer-Roob BM; van't Hof MA; Shmerling DH
Division of Gastroenterology and Nutrition, Department of Pediatrics, University of Zurich, Switzerland.
Am J Clin Nutr (UNITED STATES) May 1996, 63 (5) p722-8

To investigate the efficacy of three different vitamin E preparations for optimizing vitamin E status in cystic fibrosis (CF patients long-term, 29 patients (aged 0.7-29.8 y) were randomly assigned to receive 400 IU of either RRR-alpha-tocopherol (A: 268 mg, n = 10) or all rac-alpha-tocopheryl acetate as a fat-soluble (B: 400 mg, n = 10) or water-miscible preparation (C: 400 mg, n = 9) and were followed for 6 wk. In the whole study group, plasma alpha-tocopherol concentrations increased from baseline (10.5 ±- 4.6 micromol/L) to 3 wk (25.7 ± 6.5 micromol/L; P < 0.001), but not further between 3 and 6 wk; concentrations at 3 and 6 wk did not differ from those of age-matched control subjects (23.6 ± 3.9 micromol/L). There was no significant difference in the increase from baseline to 6 wk among preparations A (17.75 ± 8.43 micromol/L), B (14.0 ± 9.4 micromol/L), and C (15.5 ± 7.1 micromol/L). Because of differences in body weight, the dose administered ranged from 5.5 to 47.4 IU x kg-1 x d-1; it correlated positively with the increase in plasma alpha-tocopherol concentrations (P < 0.001). There was no significant difference in the increase in plasma alpha-tocopherol concentrations between patients with CF-associated liver disease (n = 8) who received 10.2 ± 3.8 IU x kg-1 x d-1 and those without liver disease taking comparable doses. We conclude that CF patients can be efficiently supplemented with 400 IU/d of any one of the three vitamin E preparations and plasma values of healthy control subjects can be achieved.

The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. The HOPE study investigators.

Can J Cardiol (CANADA) Feb 1996, 12 (2) p127-37

OBJECTIVE: To describe the design of the HOPE (Heart Outcomes Prevention Evaluation) study. DESIGN: Description of the key design features of HOPE, a large, simple randomized trial of two widely applicable treatments--ramipril, an angiotensin-converting enzyme inhibitor; and vitamin E, a naturally occurring antioxidant vitamin--in the prevention of myocardial infarction, stroke or cardiovascular death. SETTING: Two-hundred and sixty-seven hospitals, physician offices and clinics in Canada, the United States, Mexico, Europe and South America. PATIENTS: Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infarction and stroke were recruited over 18 months. INTERVENTIONS: A 2X2 factorial design with ramipril and vitamin E with follow-up for up to four years. CONCLUSIONS: HOPE will be one of the largest trials of two new interventions to prevent myocardial infarction, stroke or cardiovascular death in high risk patients. The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice. Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease, inclusion of a substantial proportion of patients with diabetes (36%) and women (27%), and detailed substudies to provide data on mechanisms of benefit.

Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial.

Rapola JM; Virtamo J; Haukka JK; Heinonen OP; Albanes D; Taylor PR; Huttunen JK
National Public Health Institute, Helsinki, Finland.
JAMA (UNITED STATES) Mar 6 1996, 275 (9) p693-8

OBJECTIVE: To examine the effect of supplementation with vitamin E (alpha tocopherol), beta carotene, or both on the incidence of angina pectoris in men without known previous coronary heart disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING AND PARTICIPANTS: Participants in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study (N=29133) were male smokers aged 50 through 69 years who were living in southern and western Finland. Of these men, 22269 were considered free of coronary heart disease at baseline and were followed up for the incidence of angina pectoris. INTERVENTION: Participants were randomized to receive 50 mg/d of alpha tocopherol, 20 mg/d of beta carotene, both, or placebo in a 2x2 design. OUTCOME MEASURES: An incident case was defined as the first occurrence of typical angina pectoris identified in administering the annually repeated World Health Organization (Rose) Chest Pain Questionnaire. RESULTS: During a median follow-up time of 4.7 years (96427 person-years), 1983 new cases of angina pectoris were detected. Comparing alpha tocopherol-supplemented subjects with non-alpha tocopherol-supplement ed subjects showed a relative risk (RR) of angina pectoris incidence of 0.91 (95% confidence interval[CI], 0.83 to 0.99; P=.04). The RR for incidence of angina pectoris for the beta carotene- supplemented subjects compared with those not receiving beta carotene was 1.06 (95% CI, 0.97 to 1.16; P=.19). Compared with those receiving placebo, the RRs for incidence of angina pectoris were 0.97 (95% CI, 0.85 to 1.10) and 0.96 (95% CI, 0.85 to 1.09) in the alpha tocopherol and alpha tocopherol plus beta carotene groups, respectively, and 1.13 (95% CI, 1.00 to 1.27) in the beta carotene group (P=.06). Baseline dietary intakes and serum levels of alpha tocopherol and beta carotene did not predict incidence of angina pectoris. CONCLUSIONS: Supplementation with alpha tocopherol was associated with only a minor decrease in the incidence of angina pectoris. Beta carotene had no preventive effect and was associated with a slight increase of angina.

Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits.

Wiseman SA; Mathot JN; de Fouw NJ; Tijburg LB
Unilever Research Laboratory, Vlaardingen, The Netherlands.
Atherosclerosis (IRELAND) Feb 1996, 120 (1-2) p15-23

Consumption of a range of dietary antioxidants may be beneficial in protecting low density lipoprotein (LDL) against oxidative modification, as studies have demonstrated that antioxidants other than vitamin E may also function against oxidation of LDL in vitro. In the present study, the effect of polyphenol antioxidants on the susceptibility of LDL to copper-mediated oxidation was investigated after feeding semi-purified diets to 3 groups of New Zealand white (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic acid. Dietary fatty acid compositions were identical. Oils with different polyphenol contents were used to provide the dietary source of oleic acid-refined olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil. Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in the extra virgin olive oil. Vitamin E was equalised in all diets. LDL oxidizability in vitro was determined by continuously monitoring the copper-induced formation of conjugated dienes after 6 weeks of experimental diet feeding. Thecreased in the high polyphenol, extra virgin olive oil group (P < 0.05) when compared with combined results from the low polyphenol group (refined olive oil and Trisun), even though the LDL vitamin E concentration in the high polyphenol group was significantly lower. The rate of conjugated diene formation was not influenced by the presence of dietary polyphenols. Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.

In vitro oxidation of vitamin E, vitamin C, thiols and cholesterol in rat brain mitochondria incubated with free radicals

USA Neurochemistry International (United Kingdom), 1995, 26/5 (527-535)

The kinetics of oxidation of endogenous antioxidants such as vitamins C and E and thiols as well as membrane cholesterol in isolated rat brain mitochondria were studied. Oxidation was induced by incubating the mitochondria at 37degreeC with the free radical generators 2,2' azobis (2'-amidinopropane) dihydrochloride (ABAPH) and 2,2' azobis (2,4-dimethyl) valeronitrile (ABDVN) which undergo thermal decomposition to yield free radicals. An approximate order for the in vitro ease of oxidation was. ascorbate << alpha-tocopherol < sulfhydryls << cholesterol. However, small amounts of ascorbate were present in the mitochondria when alpha-tocopherol and sulfhydryl compounds were getting oxidized. This observation is different from those with more homogeneous biological substrates like blood plasma or serum. The order of oxidation of the various compounds is a function of not only the redox potentials but also the (a) concentrations of the oxidized and reduced species, (b) compartmentation of the compounds and (c) enzymatic and nonenzymatic systems for the repair or regeneration of the individual antioxidants. Even though ascorbate levels are quite low within mitochondria this nutrient may play a major role as a first line of defense against oxidative stress. The lipid-soluble ABDVN was much more potent in oxidizing membrane alpha-tocopherol and thiols than the water-soluble ABAPH. With both free radical generators the rate of oxidation of the antioxidants consisted of two phases. The initial phase, that is more rapid, may represent a pool of antioxidant that is involved in immediate antioxidant protection of the organelle with the slower compartment being responsible for replenishing the faster pool whenever needed. The observation that one antioxidant (e.g. vitamin E) is oxidized prior to the total depletion of a more easily oxidized compound (vitamin C) suggests that antioxidants of different structures and redox potentials can function simultaneously in biological systems. Many degenerative brain diseases such as Parkinson's disease have been associated with oxidative damage. Therefore, it is possible that novel synthetic antioxidants may find therapeutic use in these conditions by providing additional antioxidant protection and/or enhancing the activities of endogenous antioxidants.

Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa. Parkinson Study Group.

Ann Neurol. 1996 Jan. 39(1). P 37-45

The Deprenyl and Tocopherol Antioxidant Therapy of Parkinsonism (DATATOP) trial was designed to test outcomes from treatment with 10 mg of deprenyl and/or 2,000 mg of tocopherol/day in 800 untreated patients with Parkinson's disease. The need of subjects for symptomatic treatment with levodopa and the conversion of all subjects to open-label deprenyl made it possible to study the long-term effect of early deprenyl and tocopherol treatment on the later development of levodopa-associated side effects. The rate of developing these side effects did not differ among the original treatment groups (early versus late deprenyl and tocopherol versus nontocopherol). About 50% of subjects developed "wearing off," 30% dyskinesias, and 25% "freezing" in each group. At the end of the study, the groups were similarly disabled on the Hoehn-Yahr, Schwab-England, and Unified Parkinson's Disease Rating scales and took similar amounts of levodopa. Young subjects were more likely to develop wearing off, women to develop dyskinesias, and older subjects with rapidly progressive disease to develop freezing. We conclude that prior treatment with deprenyl or tocopherol did not reduce the occurrence of subsequent levodopa-associated adverse effects in this population.

[Diabetes mellitus--a free radical-associated disease. Results of adjuvant antioxidant supplementation]

Z Gesamte Inn Med (GERMANY) May 1993, 48 (5)

Our investigations carried out in patients with diabetes mellitus revealed oxidative stress loads. The study presented here was to clarify whether a therapy with antioxidants can contribute to an improvement of prognosis. 80 patients affected with a long term diabetic late syndrome were randomised and arranged to 4 groups of n = 20 each. In contrast to a control group these patients received 600 mg of alpha lipoic acid or 100 micrograms of selenium (sodium selenite) daily or 1200 IE of D-alpha-tocopherol respectively for a time of 3 months. In comparison with the control group all groups treated in an antioxidative way showed significantly diminished serum concentrations of thiobarbituric acid reactive substances and of urinary albumin excretion rates. The symptoms of distal symmetric neuropathy measured according to the thermo- and vibration sensitivity also improved in a highly significant manner. The results prove that oxidative stress plays a promoting role in developing of long term diabetic late complications and that a therapy with adjuvant antioxidants may lead to a regression of diabetic late complications.

NUTRITION -- Miscellanea; HEALTH -- Miscellanea

Better Nutrition for Today's Living, Sep94, Vol. 56 Issue 9, p8, 1p, 1c

Answers questions related to nutrition and health. Topical application of vitamin E to broken nails; Nutritional aspects of psoriasis; Regimen for administering the herb echinacea; Nutritional aspects of acne rosacea; Reusing once-heated oil. (no abstract)

Alpha-tocopherol and hydroperoxide content in breast adipose tissue from patients with breast tumors.

Int J Cancer (UNITED STATES) Jul 17 1996, 67 (2) p170-5

The study of the relationship between dietary intake of vitamin E and the risk of breast cancer has not yielded definite conclusions with respect to causality, possibly due to methodological issues inherent to nutritional epidemiology. To avoid the pitfalls of dietary recalls, alpha-tocopherol content of adipose tissue was used as a biochemical indicator of long-term dietary intake of vitamin E. alpha-tocopherol and hydroperoxides were measured in breast adipose tissue obtained at the time of diagnosis from 70 patients with early breast cancer. Thirty women with non-malignant breast tumors served as control. Lipid peroxidation was monitored by quantifying conjugated dienes spectrophotometrically and by assaying hydroperoxides with an iodometric method; alpha-tocopherol was measured by HPLC associated with fluorescence detection. Mean alpha-tocopherol value in breast adipose tissue was significantly lower in breast cancer patients than in control patients, whereas the hydroperoxide content was significantly higher in cancer patients than in controls. The alpha-tocopherol concentration in adipose tissue was not correlated with the clinical status of the patients with respect to age, menopausal status or body mass index. We conclude from this pilot study that breast cancer is associated with a low content of alpha-tocopherol in breast adipose tissue, and with an altered lipid oxidation pattern, which might be related to a low antioxidant status.

Assessment of selenium and vitamin E deficiencies in dairy herds and clinical disease in calves.

Vet Rec (ENGLAND) Oct 19 1996, 139 (16) p391-4

Because of the very low concentrations of selenium in the dry matter of grass, grass silage, hay and maize silage Slovenian dairy herds need to be supplemented with selenium. Selenium in the form of mineral and feed mixtures maintained adequate mean (sd) blood serum selenium concentrations of 43.9 (27.6) to 65.3 (18.5) micrograms/litre in lactating cows, but in late lactation and in the dry period when only mineral mixtures were used, about 60 per cent of the cows had marginal serum selenium concentrations, mainly because of the low intake of the mineral supplement. In 18 herds which were either unsupplemented or irregularly supplemented with selenium, the mean (sd) concentrations in blood serum were 13.7 (5.5) micrograms/litre and 17.4 (9.2) micrograms/litre, respectively, for selenium and 2.98 (2.72) mg/litre and 1.62 (1.73) mg/litre for vitamin E, indicating that under extensive farming conditions in Slovenia the lack of both micronutrients may be responsible for nutritional muscular dystrophy in calves. Among 37 clinical cases, cardiorespiratory signs predominated in 25 of the calves and skeletal myopathy was dominant in 12. A very low mean serum selenium concentration [9.7 (7.2) micrograms/litre] and typically high activities of aspartate aminotransferase (AST) [1125 (373) U/litre] and creatine kinase (CK) [9169 (3681) U/litre) were observed for the myocardial form of the disease, and 2797 (550) U/litre and 22,650 (13,500) U/litre were observed for the skeletal form of the disease. A highly significant (P < 0.0001) difference in the selenium concentration of liver dry matter between the regularly supplemented [402 (207) micrograms/kg] and irregularly supplemented [173 (69) micrograms/kg] herds was observed. If a minimum value of 300 micrograms/kg of liver dry matter is accepted as the criterion for the determination of adequate selenium status, 93 per cent of the samples from the irregularly supplemented herds were selenium deficient. A similar proportion was estimated to be selenium deficient when the criterion was taken to be 30 micrograms selenium/litre of blood serum.

Wheat kernel ingestion protects from progression of muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy.

Pediatr Res (UNITED STATES) Sep 1996, 40 (3) p444-9

A simple, reproducible test was used to quantify muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy. The effect of bedding on wheat kernels and of dietary supplementation of alpha-tocopherol on the progression of muscle weakness was investigated in mdx mice. When measured during the first 200 d of life, mdx mice developed muscle weakness, irrespective of bedding and diet. When kept on wood shavings and fed a conventional rodent diet, mdx mice showed progressive muscle weakness over the consecutive 200 d, and eventually showed a significant weight loss during the next 200-d observation period. Progression of muscle weakness and weight loss were almost completely prevented in mdx mice that were kept on wheat kernel bedding. In contrast, only incomplete maintenance of muscle strength and body weight was observed in mdx mice kept on wood shavings and fed the alpha-tocopherol-supplemented diet. It is concluded from these experiments that a component of wheat kernels other than alpha-tocopherol is essential to prevent the progression of muscle weakness in mdx mice.

Aortic and iliac artery thrombosis in calves: nine cases (1974-1993).

J Am Vet Med Assoc (UNITED STATES) Jul 1 1996, 209 (1) p130-6

OBJECTIVE--To identify common clinical and diagnostic features of calves with aortic or iliac artery thrombosis that might aid in antemortem diagnosis of this condition. DESIGN--Retrospective case series. ANIMALS--9 calves < or = 6 months old in which aortic or iliac artery thrombosis was confirmed at necropsy. RESULTS--All calves had an acute onset of paresis or flaccid paralysis of 1 or both hind limbs. Affected limbs were hypothermic and had diminished spinal reflexes and diminished pulse pressures. Diagnosis was definitively established in 2 calves by use of angiography. All 9 calves died or were euthanatized. CLINICAL IMPLICATIONS--This condition is rare and could be mistaken for more common diseases of young cattle, such as traumatic injury of the axial or appendicular skeleton, vertebral osteomyelitis, nutritional muscular dystrophy associated with vitamin E or selenium deficiency, injury to the sciatic or femoral nerves, or clostridial myositis.

[Efficiency of ubiquinone and p-oxybenzoic acid in prevention of E-hypovitaminosis-induced development of muscular dystrophy]

Ukr Biokhim Zh (USSR) Sep-Oct 1981, 53 (5) p73-9

It is shown that E-hypovitaminosis-induced muscular dystrophy in rabbits is accompanied by a sharp decrease in the body mass, an increase in the urine creatine-index, a decrease in the vitamin E and ubiquinone contents in the liver and skeletal muscle tissues. In the myocardium mitochondria a decrease in the vitamin E content and an increase in the ubiquinone content are observed. The activity of NADH-cytochrome c-, NADH-ubiquinone- and succinate-ubiquinone-reductase also varies in mitochondria of the studied tissues. In myocardium organellas a direct dependence is found between the content of ubiquinone, NADH- and succinate-ubiquinone-reductase activity and an inverse one-between its content and the activity of the NADH-cytochrome c-reductase system. It is established that p-oxybenzoic acid as well as vitamin E prevents development of muscular dystrophy and causes changes analogous in direction in the activity of the ubiquinone-dependent enzymic systems of mitochondria. Ubiquinone-9 is less efficient in preventing the development of muscular dystrophy.

Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group


OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. DESIGN--The multicenter Eye Disease Case-Control Study. SETTING--Five ophthalmology centers in the United States. PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of vitamin C, particularly from foods. CONCLUSION--Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship.

Antioxidant status and neovascular age-related macular degeneration

ARCH. OPHTHALMOL. (USA), 1993, 111/1 (104-109)

We evaluated the hypothesis that higher serum levels of micronutrients with antioxidant capabilities may be associated with a decreased risk of neovascular age-related macular degeneration by comparing serum levels of carotenoids, vitamins C and E, and selenium in 421 patients with neovascular age-related macular degeneration and 615 controls. Subjects were classified by blood level of the micronutrient (low, medium, and high). Persons with carotenoid levels in the medium and high groups, compared with those in the low group, had markedly reduced risks of neovascular age-related macular degeneration, with levels of risk reduced to one half and one third, respectively. Although no statistically significant protective effect was found for vitamin C or E or selenium individually, an antioxidant index that combined all four micronutrient measurements showed statistically significant reductions of risk with increasing levels of the index. Although these results suggest that higher blood levels of micronutrients with antioxidant potential, in particular, carotenoids, may be associated with a decreased risk of the most visually disabling form of age-related macular degeneration, it would be premature to translate these findings into nutritional recommendations.

Radial distribution of tocopherols in rhesus monkey retina and retinal pigment epithelium-choroid.

Invest Ophthalmol Vis Sci (UNITED STATES) Jan 1996, 37 (1) p61-76

PURPOSE. To map vitamin E as a function of distance from the foveal center in the primate retina and retinal pigment epithelium (RPE)-choroid. METHODS. Eyecups from rhesus monkeys were dissected with circular trephines so that the innermost disc, centered on the fovea, was in the center of a series of concentric rings. Two different types of dissection were performed. For one type, the authors used circular trephines with diameters of 1, 4, 8, and 10 mm (1,4-D), whereas for the other type the diameters were 2, 5, 8, and sometimes 10 mm (2,5-D). When possible, the neural retina was separated from the RPE-choroid. Tissues were analyzed for vitamin E, retinyl palmitate, and protein. RESULTS. Surface area, volume, and protein were used as indexes of the amount of tissue analyzed. Distributions of vitamin E in neural retina were dependent on the tissue metric used and type of dissection performed. However, regardless of the tissue metric used, the central 1-mm disc of the 1,4-D was, on average, higher in vitamin E content than was the central 2-mm disc of the 2,5-D. This was particularly true when volume was the tissue metric. From the average values of vitamin E in a series of concentric discs, a composite plot of the vitamin E concentration in the neural retina was generated that took into consideration both types of dissection. That plot displayed a local maximum in the fovea and then precipitously declined to a minimum in the region between 0.5 and 1.0 mm eccentricity (near the foveal crest); at greater eccentricities, the vitamin E concentration rose to a value similar to that in the fovea, i.e., the composite plot indicated that vitamin E has a V-shaped distribution in the central neural retina. Vitamin E distribution in the RPE-choroid, with surface area as the tissue metric, also was measured. For this tissue, the foveal region displayed a local maximum. CONCLUSIONS. By combining the results of two different types of dissection, the authors found that in the neural retina, vitamin E displayed a minimum near the foveal crest. This minimum correlated //anatomically with the site at which areolar (geographic) atrophy frequently occurs in retinal pigment epithelial cells in the human disease, age-related macular degeneration.

Antioxidant defenses in metal-induced liver damage

Seminars in Liver Disease (USA), 1996, 16/1 (39-46)

Recent investigations have begun to define more clearly the cellular and molecular roles of oxidant stress in mediating the liver injury and fibrosis of metal storage diseases. Because of a variety of perturbations in antioxidant homeostasis in iron and copper overload, restoring the antioxidant balance to normal, or even exceeding normal levels of selected antioxidants, may provide additional protection against liver injury and prevent the progression to fibrosis and cirrhosis. Inasmuch as GSH levels appear to be elevated in livers of experimentally iron-overloaded animals, attempts to increase this antioxidant should perhaps be limited to copper overload conditions in which hepatic GSH is low. Vitamin C (ascorbate) supplementation should probably be avoided in all metal overload states because of its potentiation of radical generation by transition metals. The safety of beta-carotene in alocholic liver disease has been questioned. Therefore, until more is known about its toxicity in metal overload, beta- carotene may not be an ideal antioxidant for clinical trials. Vitamin E and related compounds, therefore, appear to be the most reasonable antioxidants to test in metal overload states at this time. In the near future, the results of controlled clinical trials of the use of antioxidants in these and other liver disorders will hopefully provide clearer guidelines for their safety and possible use.

Effects of hepatic stimulator substance, herbal medicine, selenium/vitamin E, and ciprofloxacin on cirrhosis in the rat

Gastroenterology (USA), 1996, 110/4 (1150-1155)

Background and Aims: Cirrhosis is a potentially lethal condition for which there is no proven effective therapy. The aim of this study was to compare the effects of hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin treatment on biochemical and histological features of fibrosis in rats with carbon tetrachloride (CCl4)/ethanol-induced cirrhosis. Methods: One hundred twenty adult Wistar rats were divided into six study groups (20 rats/group): healthy controls, CCl4/ethanol-injured rats left untreated, and CCl4/ethanol-injured rats treated for 4 weeks with either hepatic stimulator substance, traditional Chinese herbal medicine, a combination of selenium plus vitamin E, or ciprofloxacin. After the 4-week treatment, rats were killed and the following parameters of hepatic fibrosis were determined: hepatic hydroxyproline and proline levels, serum hyaluronic acid concentrations, and histological staining of hepatic tissue. Results: Hepatic fibrosis was significantly improved in all four treated groups compared with the untreated CCl4/ethanol-injured controls. Improvements were most striking in the groups treated with traditional Chinese herbal medicine and ciprofloxacin. Conclusions: The data indicate that hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin significantly decrease the amount of hepatic fibrosis caused by CCl4/ethanol injury in rats.

Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents

Ann Med Interne (Paris). 1994. 145(6). P 405-8

Mucositis represents one of the most frequent complications during chemotherapy or radiotherapy. Few studies have showed effective prevention against mucositis in this setting. In this randomized study, we tested the efficacy of vitamin E in the treatment of chemotherapy-induced mucositis. Twenty patients with malignant haemopathies were included; 19 patients were evaluable for the prevention of mucositis. Ten patients were treated with induction therapy for acute myelogenous leukaemia and 9 were treated with intensive therapy followed by autologous bone marrow transplantations. The severity of mucositis was evaluated according to World Health Organization classification. Our results showed that vitamin E may be of therapeutical value in the prevention of mucositis especially during induction therapy for acute myelogenous leukaemia.

Induction of renal damage in rats by a diet deficient in antioxidants

Nutrition Research (USA), 1996, 16/9 (1607-1612)

Male albino rats, age 28 days, were fed a diet containing both vitamin E (10 g/kg) and selenium (5 mg/kg) or a diet lacking these antioxidants. Animals were examined for renal function after 4, 8, 12 and 16 wk on the respective diets. After 8 wk, animals on the deficient diet weighed less than controls (15%, p&lt0.01), and this became more pronounced by 16 weeks (25%, p&lt0.01). Expressed on a body weight basis, kidney wet weights did not differ between the two groups of animals. Urine volume increased in the animals fed the deficient diet at 8 weeks (66%, p&lt0.01) and this was maintained at 16 weeks (35%, p&lt0.01). Similar increases were observed for the rates of excretion of urinary total protein (77% elevation at 16 wk, p&lt0.01) and urinary acid phosphatase (51% elevation, p&lt0.01). At 16 wk, the specific activity of renal acid phosphatase in the animals given the deficient diet was reduced in cortex (57%, p&lt0.01) and medulla (20%, p&lt0.01), but not in papilla. These data indicate that dietary antioxidant deficiency causes progressive and pronounced renal damage.

Vitamin E supplementation and in vivo immune response in healthy elderly subjects: A randomized controlled trial

Journal of the American Medical Association (USA), 1997, 277/17 (1380-1386)

Objective. - To determine whether long-term supplementation with vitamin E enhances in vivo, clinically relevant measures of cell-mediated immunity in healthy elderly subjects. Design. - Randomized, double-blind, placebo- controlled intervention study. Setting and Participants. - A total of 88 free-living, healthy subjects at least 65 years of age. Intervention. - Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days. Main Outcome Measures. - Delayed- type hypersensitivity skin response (DTH); antibody response to hepatitis B, tetanus and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin were assessed before and after supplementation. Results. - Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3- fold, respectively), 60-mg/d (41% and 3-told, respectively), and 800-mg/d (49% and 2.5-fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (&gt48.4 micromol/L (2.08 mg/dL)) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed. Conclusions. - Our results indicate that a level of vitamin E greater than currently recommended enhances certain clinically relevant in vivo indexes of T-cell-mediated function in healthy elderly persons. No adverse effects were observed with vitamin E supplementation.

Viamin E supplementation induces an early recovery of cellular immunity decreased following X-ray irradiation

Nutrition Research (USA), 1996, 16/4 (645-656)

We have previously reported that vitamin E has an ability to enhance T cell differentiation in rat thymus. The aim of this study is to investigate whether T cell differentiation enhanced by vitamin E supplementation is effective in decreasing cellular immunity after X-ray irradiation in rats. Male Fisher rats, 4-weeks old, were fed control (50 mg vitamin E/kg diet) or high vitamin E diet (585 mg vitamin E/kg diet) for 4 weeks and then irradiated X-ray. On 2, 5 and 9 days after X-ray irradiation, rats were killed under anesthesia and their cellular immune functions were assayed. Vitamin E supplementation did not result in decreased thymic weights or change in the numbers of thymocytes and peripheral blood lymphocytes (PBL) following X-ray irradiation. In addition, proliferation of PBL with T cell mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), also decreased in both control and high vitamin E groups following X-ray irradiation. On the contrary, proliferation of bone marrow cells (BMC) was maintained much the same as pretreatment of X-ray irradiation in high vitamin E group even after X-ray irradiation compared to a significant decrease in the control group. The proliferation of thymocytes with PHA or ConA also showed an early recovery in high vitamin E, which was associated with not the production of interleukin 2 (IL2), T cell growth factors, but early recovery in the proportion of CD4+CD8+ T cells in thymocyte. These results suggest that vitamin E supplementation accelerates the recovery of the X-ray irradiation- induced decrease in cellular immunity. The signs of accelerated recovery were enhanced T cell differentiation in thymus and the maintenance of bone marrow cell (BMC) proliferation during X-ray irradiation.

Food uses and health effects of corn oil.

J Am Coll Nutr (UNITED STATES) Oct 1990, 9 (5) p438-70

This review of corn oil provides a scientific assessment of the current knowledge of its contribution to the American diet. Refined corn oil is composed of 99% triacylglycerols with polyunsaturated fatty acid (PUFA) 59%, monounsaturated fatty acid 24%, and saturated fatty acid (SFA) 13%. The PUFA is linoleic acid (C18:2n-6) primarily, with a small amount of linolenic acid (C18:3n-3) giving a n-6/n-3 ratio of 83. Corn oil contains a significant amount of ubiquinone and high amounts of alpha- and gamma-tocopherols (vitamin E) that protect it from oxidative rancidity. It has good sensory qualities for use as a salad and cooking oil. Corn oil is highly digestible and provides energy and essential fatty acids (EFA). Linoleic acid is a dietary essential that is necessary for integrity of the skin, cell membranes, the immune system, and for synthesis of icosanoids. Icosanoids are necessary for reproductive, cardiovascular, renal, and gastrointestinal functions and resistance to disease. Corn oil is a highly effective food oil for lowering serum cholesterol. Because of its low content of SFAs which raises cholesterol and its high content of PUFAs which lowers cholesterol, consumption of corn oil can replace SFAs with PUFAs, and the combination is more effective in lowering cholesterol than simple reduction of SFA. PUFA primarily lowers low-density-lipoprotein cholesterol (LDL-C) which is atherogenic. Research shows that PUFA has little effect on high-density-lipoprotein cholesterol (HDL-C) which is protective against atherosclerosis. PUFA generally improves the ratio of LDL-C to HDL-C. Studies in animals show that PUFA is required for the growth of cancers; the amount required is considered to be greater than that which satisfies the EFA requirement of the host. At this time there is no indication from epidemiological studies that PUFA intake is associated with increased risk of breast or colon cancer, which have been suggested to be promoted by high-fat diets in humans. Recommendations for minimum PUFA intake to prevent gross EFA deficiency are about 3% of energy (en%). Recommendations for prevention of heart disease are 8-10 en%. Consumption of PUFA in the United States is 5-7 en%. The use of corn oil to contribute to a PUFA intake of 10 en% in the diet would be beneficial to heart health. No single source of salad or cooking oil provides an optimum fatty acid (FA) composition. Many questions remain to be answered about the relation of FA composition of the diet to various physiological functions and disease processes. (277 Refs.)

Vitamin E supplementation normalizes immune dysfunction in murine AIDS induced by LP-BM5 retrovirus infection

Nutrition Research (USA), 1996, 16/10 (1709-1720)

It is known that murine AIDS, induced by i.p. injection of LP-BM5 retrovirus, is functionally similar to human AIDS. In this study, we tried to examine the effect of vitamin E (dl-alpha-tocopheryl acetate) supplementation on the decrease of cellular immune functions following the development of murine AIDS. Female C57BL/6 mice, 4 weeks old, were infected with LP-BM5 retrovirus and then fed control (50 IU/kg diet) or high vitamin E (500 or 2500 IU/kg diet) diets for 10 weeks. The spleen weight and number of splenocytes were largely increased following the development of murine AIDS. On the contrary, vitamin E supplementation suppressed the enlargement of spleen and the increased number of splenocytes following retrovirus infection. The decrease of NK activity shown in mice infected with LP-BM5 retrovirus was also partly improved by high vitamin E diet. Proliferation of splenic T lymphocytes, showing the marked decrease following murine AIDS, was significantly restored by higher vitamin E (2500 IU/kg diet) diet compared to control group, which was still lower in comparison with that of uninfected control group. Furthermore, vitamin E supplementation increased production of interferon-gamma (IFN-gamma) and suppressed production of tumor necrosis factor-alpha (TNF-alpha) from splenocytes. In addition, high vitamin E diet also decreased the increased ratio of CD4 and CD8 single positive T cells following the development of murine AIDS, which was almost equal to the levels of uninfected control and high vitamin E groups. These results suggest that vitamin E supplementation normalizes the decrease of immune functions following the development of murine AIDS.

Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload

American Journal of Physiology - Gastrointestinal and Liver Physiology (USA), 1997, 272/1 35-1 (G116-G123)

It has been suggested that lipid peroxidation plays an important role in hepatic fibrogenesis resulting from chronic iron overload. Vitamin E is an important lipid-soluble antioxidant that has been shown to be decreased in patients with hereditary hemochromatosis and in experimental iron overload. The aim of this study was to determine the effects of vitamin E supplementation on hepatic lipid peroxidation and fibrogenesis in an animal model of chronic iron overload. Rats were fed the following diets for 4, 8, or 14 mo: standard laboratory diet (control), diet with supplemental vitamin E (200 IU/kg, control + E), diet with carbonyl iron (Fe), and diet with carbonyl iron supplemented with vitamin E (200 IU/kg, Fe + E). Iron loading resulted in significant decreases in hepatic and plasma vitamin E levels at all time points, which were overcome by vitamin E supplementation. Thiobarbituric acid-reactive substances (an index of lipid peroxidation) were increased three- to fivefold in the iron-loaded livers; supplementation with vitamin E reduced these levels by at least 50% at all time points. Hepatic hydroxyproline levels were increased twofold by iron loading. Vitamin E did not affect hydroxyproline content at 4 or 8 mo but caused an 18% reduction at 14 mo in iron-loaded livers. At 8 and 14 mo, vitamin E decreased the number of alpha-smooth muscle actin-positive stellate cells in iron-loaded livers. These results demonstrate a dissociation between lipid peroxidation and collagen production and suggest that the profibrogenic action of iron in this model is mediated through effects which cannot be completely suppressed by vitamin E.

Biological markers of oxidative stress induced by ethanol and iron overload in rat.

Int J Occup Med Environ Health (POLAND) 1994, 7 (4) p355-63

Studies on rats treated for 15 months with ethanol (10%, w/v, solution in drinking water) revealed that the stimulation of hepatic cytochrome P-450 monooxygenases activity was accompanied by enhanced microsomal malondialdehyde formation, a lipid peroxidation index and a decreased level of the antioxidant, alpha-tocopherol. The other components of the prooxidant/antioxidant system, diene conjugates and catalase, glutathione peroxidase and superoxide dismutase activities were unaffected. Oxidative stress in blood was shown by a significant decrease in the alpha-tocopherol level whereas lipid peroxidation and antioxidant enzyme activity remained unchanged. The prooxidative effect of ethanol was catalytically promoted by an iron overload (Fe-saccharate, 100 mg Fe3+/kg body wt. intraperitoneally, 2, 5 and 7 day before test) to simulate the effect of alcoholic hemochromatosis. Thus, the level of malondialdehyde and alpha-tocopherol in the serum may be recommended as biological markers of ethanol-provoked oxidative stress, which is especially useful in the evaluation of the combined effect of ethanol and other chemicals that affect the redistribution of active iron complexes.

Antioxidant status and lipid peroxidation in hereditary haemochromatosis.

Free Radic Biol Med (UNITED STATES) Mar 1994, 16 (3)

Hereditary haemochromatosis is characterised by iron overload that may lead to tissue damage. Free iron is a potent promoter of hydroxyl radical formation that can cause increased lipid peroxidation and depletion of chain-breaking antioxidants. We have therefore assessed lipid peroxidation and antioxidant status in 15 subjects with hereditary haemochromatosis and age/sex matched controls. Subjects with haemochromatosis had increased serum iron (24.8 (19.1-30.5) vs. 17.8 (16.1-19.5) mumol/l, p = 0.021) and % saturation (51.8 (42.0-61.6) vs. 38.1 (32.8-44.0), p = 0.025). Thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were increased in haemochromatosis (0.59 (0.48-0.70) vs. 0.46 (0.21-0.71) mumol/l, p = 0.045), and there were decreased levels of the chain-breaking antioxidants alpha-tocopherol (5.91 (5.17-6.60) vs. 7.24 (6.49-7.80) mumol/mmol cholesterol, p = 0.001), ascorbate (51.3 (33.7-69.0) vs. 89.1 (65.3-112.9), p = 0.013), and retinol (1.78 (1.46-2.10) vs. 2.46 (2.22-2.70) mumol/l, p = 0.001). Patients with hereditary haemochromatosis have reduced levels of antioxidant vitamins, and nutritional antioxidant supplementation may represent a novel approach to preventing tissue damage. However, the use of vitamin C may be deleterious in this setting as ascorbate can have prooxidant effects in the presence of iron overload.

Protection of rat myocardial phospholipid against peroxidative injury through superoxide-(xanthine oxidase)-dependent, iron-promoted fenton chemistry by the male contraceptive gossypol

BIOCHEM. PHARMACOL. (United Kingdom), 1988, 37/17 (3335-3342)

Metal-promoted oxygen free-radical chemistry is a cause of tissue damage in many disease states, such as myocardial ischemia. The effect of gossypol, a polyphenolic plant pigment and male contraceptive, on the peroxidation of myocardial membrane phospholipid was studied and quantitatively characterized. As a result of exposure to xanthine oxidase (superoxide)-dependent, iron-promoted Fenton chemistry, cardiac phospholipid was readily peroxidized with defined kinetics. The peroxidation could be blocked by substances which interdict at specific points in the Fenton chemistry: superoxide dismutase, alpha-tocopherol, the iron chelator desferrioxamine, and the xanthine oxidase substrate-analogs allopurinol and oxypurinol. The oxidatve-injury system displayed a characteristic antiperoxidant response to each type of inhibitor. Gossypol, at low micromolar concentrations, profoundly altered the rate and extent of myocardial phospholipid peroxidation. Gossypol was ineffective as a xanthine oxidase inhibitor and as a superoxide scavenger at concentrations that abolished myocardial lipid peroxidation. Since metal chelation was an effective means of preventing lipid peroxidation in this system only when the iron therein was completely chelated, the low anti-peroxidant IC50 for gossypol, 1.1 microM, relative to the concentration of iron (100 microM) did not support a functionally significant antiperoxidant role for gossypol as an iron chelator. Rather, it appears that, at low micromolar gossypol concentrations which approximate the peak plasma concentrations in humans, the antiperoxidant effects of gossypol against superoxide-mediated, iron-promoted lipid damage rest with the ability of gossypol to intercept lipid radical intermediates as a 'chain-breaking' aromatic phenol.

Chemoprevention of oral leukoplakia and chronic esophagitis in an area of high incidence of oral and esophageal cancer.

Ann Epidemiol. 1993 May. 3(3). P 225-34

This intervention trial carried out in Uzbekistan (former USSR) in an area with a high incidence of oral and esophageal cancer involved random allocation of 532 men, 50 to 69 years old, with oral leukoplakia and/or chronic esophagitis to one of four arms in a double-blind, two-by-two factorial design, with active arms defined by the administration of (a) riboflavin; (b) a combination of retinol, beta-carotene, and vitamin E; or (c) both. Weekly doses were 100,000 IU of retinol, 80 mg of vitamin E, and 80 mg of riboflavin. The dose of beta-carotene was 40 mg/d. Men in the trial were followed for 20 months after randomization. The aim of the trial was to determine whether treatment with these vitamins or their combination could affect the prevalence of oral leukoplakia and/or protect against progression of oral leukoplakia and esophagitis, conditions considered to be precursors of cancer of the mouth and esophagus. A significant decrease in the prevalence odds ratio (OR) of oral leukoplakia was observed after 6 months of treatment in men receiving retinol, beta-carotene, and vitamin E (OR = 0.62; 95% confidence interval (CI): 0.39 to 0.98). After 20 months of treatment, no effect of vitamin supplementation was seen when the changes in chronic esophagitis were compared in the four different treatment groups, although the risk of progression of chronic esophagitis was lower in the subjects allocated to receive retinol, beta-carotene and vitamin E (OR = 0.65; 95% CI: 0.29 to 1.48) A secondary analysis not based on the randomized design revealed a decrease in the prevalence of oral leukoplakia in men with medium (OR = 0.45; 95% CI: 0.21 to 0.96) and high (OR = 0.59; 95% CI: 0.29 to 1.20) blood concentrations of beta-carotene after 20 months of treatment. Risk of progression of chronic esophagitis was also lower in men with a high blood concentration of beta-carotene, odds ratios being 0.30 (95% CI: 0.10 to 0.89) and 0.49 (95% CI: 0.15 to 1.58) for medium and high levels, respectively. A decrease in risk, also statistically not significant, was observed for high vitamin E levels (OR = 0.39; 95% CI: 0.14 to 1.10). These results were based on levels of vitamins in blood drawn after 20 months of treatment.

The effect of hormone replacement therapy on vitamin E status in postmenopausal women.

Wen Y.; Doyle M.C.T.; Harrison R.F.; Feely J.
J. Feely, Department of Therapeutics, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8 Ireland
Maturitas (Ireland), 1997, 26/2 (121-124)

Objectives: Vitamin E (alpha-tocopherol) is the most important dietary antioxidant found in lipids and cell membranes and its intake is inversely related to the incidence of atherosclerotic cardiovascular disease. Oestrogen-containing oral contraceptives may decrease plasma vitamin E level in young women. We investigated if oestrogen-containing hormone replacement therapy (HRT) may have the same effect on vitamin E status in postmenopausal women. Methods: Eighteen healthy postmenopausal women took a combination of oestrogen/progestogen (Harmogen/Provera) therapy and another ten acted as a control group. Blood samples were taken at baseline and repeated after 3 and 6 months in both groups. Vitamin E in plasma, red cells and isolated low-density lipoprotein (LDL) was measured as alpha-tocopherol by high-performance liquid chromatography. Results: Vitamin E status showed no change in either group after 3 and 6 months in comparison to its baseline value. Conclusion: Combined oestrogen/progestogen HRT for 6 months in healthy postmenopausal women did not alter vitamin E status in vivo.