Vitamin E and human health: rationale for determining recommended intake levels.

The recent literature provides strong evidence that vitamin E intakes much higher than the current recommendations can contribute to and/or improve human health. In fact, the available data indicate that at higher-than-current recommended intake levels, vitamin E affects several functions related to human health. For example, Vitamin E is required to protect polyunsaturated fatty acids (PUFAs) against auto-oxidation. The amount of vitamin E needed to protect PUFAs against oxidative damage is at least 0.4-0.8 mg vitamin E per gram PUFAs and may be in excess of 1.5 mg/g when diets contain higher-than-average levels of long-chain PUFAs. Based upon studies of vitamin E kinetics and metabolism, a daily vitamin E intake of 135-150 IU is suggested. Important functions such as protection against oxidative damage, immune response, and the propensity of platelets to adhere to the vessel wall are related to vitamin E intakes. Vitamin E intake of 40 IU/d was the least amount demonstrated to inhibit low-density lipoprotein oxidation; a dose-dependent effect was seen up to 800 IU/d. Vitamin E intakes of at least 60 IU/d enhanced immune responses and intakes of 200 IU-400 IU/d decreased platelet adhesion to the vessel wall. Based upon the effects of modulating these functions, it is hypothesized that vitamin E plays a pivotal role in the prevention of cardiovascular diseases. Indeed, many observational studies have reported vitamin E to reduce the risk of cardiovascular disease. Recent intervention studies corroborate these findings. Of equal importance, there is a solid body of literature that demonstrates that these and much higher vitamin E intakes are safe.

Critical assessment of the epidemiological data concerning the impact of antioxidant nutrients on cancer and cardiovascular disease.

Epidemiological studies strongly suggest that high intakes of foods rich in beta carotene, as well as those rich in vitamin E or vitamin C, reduce the risk of some but not all cancers and cardiovascular disease. It is difficult to determine whether these antioxidant nutrients per se are the sole protective agents or whether other factors associated with foods containing them contribute to the foods' protective effects. With respect to vitamin E, a number of studies where dietary and supplementary vitamin E were clearly differentiated, a reduced risk of certain cancers or cardiovascular disease from supplemental vitamin E but not from dietary vitamin E was demonstrated. This provides strong presumptive evidence that high intakes of vitamin E per se provide a health benefit. Only a few intervention studies with specific nutrients are available and results are inconsistent.

Human adipose alpha-tocopherol and gamma-tocopherol kinetics during and after 1 y of alpha-tocopherol supplementation.

Alpha-tocopherol and gamma-tocopherol were monitored in human adipose by using needle biopsies in four subjects during a 1-y supplementation trial with 800 mg all-rac-alpha-tocopherol/d, and for 1 additional year after cessation of supplement. Some increase in adipose alpha-tocopherol (per milligram adipose cholesterol) and a more consistent decrease in gamma-tocopherol were observed during the supplementation period. The alpha-tocopherol/gamma-tocopherol ratio rose consistently during supplementation and fell only gradually after the supplement was stopped. We estimate that > or = 2 y are required for the alpha-tocopherol/gamma-tocopherol ratio to reach a new steady state after a change in alpha-tocopherol intake. In a cross-sectional measurement in five subjects who reported long-term use of alpha-tocopherol supplements (> or = 250 mg/d), and in five other subjects who reported no supplement use, the adipose alpha-tocopherol/gamma-tocopherol ratio clearly discriminated between the two groups (P < 0.002). This ratio may be of value in ranking individuals according to long-term alpha-tocopherol intake.

Use and safety of elevated dosages of vitamin E in adults.

Subjects with a variety of enteropathies, hemolytic anemias, acute respiratory distress syndrome, hepatitis, Gaucher's disease as well as those on TPN and hemodialysis, often have low ("deficient") blood levels of vitamin E. A deficiency of vitamin E can be manifested by accelerated red blood cell destruction and neuromuscular deficit. Supplementation of these patients may be advisable. Neurological dysfunction has been observed in adults with prolonged vitamin E deficiency resulting from lipid malabsorption. Long-term treatment with high doses of vitamin E results in improvement. Administration of 800 IU/day of vitamin E to subjects with G6PD deficiency, sickle-cell anemia and beta-thalassemia has resulted in improvement of hematological parameters. Supplementation with 300 IU/day for 3-6 months has resulted in improved walking distances and improved blood flow in patients with intermittent claudication. In a limited number of controlled studies, 300-600 IU/day resulted in improvement in premenstrual syndrome, tardive dyskinesia and also arthritis. Epidemiological studies suggest that high levels of serum vitamin E are associated with lower risk of certain cancers, cardiovascular disease and infections. In some cases the high levels are difficult to obtain by diet alone. High levels of vitamin E are contraindicated in subjects who are receiving vitamin K antagonists as anticoagulant therapy. Except for this interaction with vitamin K, there are no specific side effects associated with high doses of vitamin E. Thus, there are various reasons for supplementations with vitamin E and, with the exception noted, the risk of such supplementation is very low.

Safety of oral intake of vitamin E.

A review of the literature concerning the safety of oral intake of vitamin E indicated that the toxicity of vitamin E is low. Vitamin E supplementation has resulted in inconsistent effects in serum lipid and lipoprotein levels. Animal studies showed that vitamin E is not mutagenic, carcinogenic, or teratogenic. In human studies with double-blind protocols and in large population studies, oral vitamin E supplementation resulted in few side effects even at doses as high as 3200 mg/d (3200 IU/d).

Biopsy method for human adipose with vitamin E and lipid measurements.

An adaptation of the needle biopsy procedure of Beynen and Katan for human adipose tissue, which yields 2-10 mg adipose samples, is described and evaluated. Micromethods are presented for the analysis of alpha-tocopherol, cholesterol and fatty acids in each adipose specimen. The needle biopsy procedure, which uses a Vacutainer to create suction, is compared with a punch biopsy method. The needle biopsy is rapid (6 samples/hr), simple and unobjectionable to the subjects, and provides samples with reproducible ratios of cholesterol and alpha-tocopherol. Unlike the punch biopsy, the needle biopsy reliably obtains specimens with a lipid composition typical of adipocytes. The needle biopsy method is adaptable to nutritional studies of tocopherol and fatty acid metabolism in adipose, and to studies of hazardous compounds stored in adipose. The linoleic acid content of adipose from residents of the West Coast was found to be considerably higher than values reported earlier. The adipose fatty acid data indicate an increase in human adipose linoleate when compared with earlier reports and suggest a trend toward increasing linoleic acid in the American diet.

Free radical tissue damage: protective role of antioxidant nutrients.

Highly reactive molecules called free radicals can cause tissue damage by reacting with polyunsaturated fatty acids in cellular membranes, nucleotides in DNA, and critical sulfhydryl bonds in proteins. Free radicals can originate endogenously from normal metabolic reactions or exogenously as components of tobacco smoke and air pollutants and indirectly through the metabolism of certain solvents, drugs, and pesticides as well as through exposure to radiation. There is some evidence that free radical damage contributes to the etiology of many chronic health problems such as emphysema, cardiovascular and inflammatory diseases, cataracts, and cancer. Defenses against free radical damage include tocopherol (vitamin E), ascorbic acid (vitamin C), beta-carotene, glutathione, uric acid, bilirubin, and several metalloenzymes including glutathione peroxidase (selenium), catalase (iron), and superoxide dismutase (copper, zinc, manganese) and proteins such as ceruloplasmin (copper). The extent of tissue damage is the result of the balance between the free radicals generated and the antioxidant protective defense system. Several dietary micronutrients contribute greatly to the protective system. Based on the growing interest in free radical biology and the lack of effective therapies for many of the chronic diseases, the usefulness of essential, safe nutrients in protecting against the adverse effects of oxidative injury warrants further study.

Dietary vitamin E requirement for optimum immune responses in the rat.

Supplementation of diets with vitamin E has been shown to enhance immune responses in numerous animal models. However, these experiments have not investigated the dietary requirement of vitamin E for optimal T- and B-lymphocyte mitogen responses and compared this directly with the requirement for growth, maintenance of spleen-body weight ratios, platelet count as well as prevention of myopathy and red blood cell lysis. We have found that male weanling rats maintain normal rate of growth and spleen-body weight ratio when fed purified diets containing 7.5 mg/kg vitamin E. A level of 15 mg/kg was adequate to prevent myopathy, and 50 mg/kg was necessary for the prevention of red blood cell hemolysis. The dietary requirement for optimum T- and B-lymphocyte responses to mitogens was greater than 50 mg/kg and was significantly correlated with plasma vitamin E levels over a range of 0.04-18 micrograms/ml. Thus, the requirement for this index of immune system activity was higher than for the other functional parameters of vitamin E adequacy measured. Therefore, the immune system responds to changes in dietary vitamin E well before there are signs of frank vitamin deficiency.

Comparison of plasma alpha and gamma tocopherol levels following chronic oral administration of either all-rac-alpha-tocopheryl acetate or RRR-alpha-tocopheryl acetate in normal adult male subjects.

Vitamin E was administered orally (400 IU twice a day) to adult male humans for 28 days as either dl-alpha-tocopheryl acetate (all-rac-alpha-tocopheryl acetate) or d-alpha-tocopheryl acetate (RRR-alpha-tocopheryl acetate). Plasma alpha-tocopherol rose rapidly and fell at the same rate following cessation of supplementation with both forms of vitamin E. No significant differences in plasma alpha- or gamma-tocopherol levels were found between the two forms of vitamin E following their administration. The results confirm the currently accepted biopotencies of 1.0 IU/mg and 1.36 IU/mg, respectively for the two forms of vitamin E. Supplementation with either form of alpha-tocopheryl acetate resulted in depressing plasma gamma-tocopherol to less than 1/3 of initial levels; also the gamma/alpha ratio was depressed to less than 1/7 of the initial value. The study suggests that the gamma/alpha vitamin E ratio might also serve as a sensitive index of alpha-tocopherol ingestion.

Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans.

In a cross-sectional survey of 86 elderly persons, it was observed that subjects with elevated plasma alpha-tocopherol levels had depressed plasma gamma-tocopherol. Tocopherols were measured by both reverse-phase and normal-phase high performance liquid chromatography (HPLC). When eight human volunteers (age range 30-60) were given 1200 IU of all-rac-alpha-tocopherol daily for 8 wk, plasma gamma-tocopherol and beta-tocopherol decreased in all subjects. After supplementation, gamma-tocopherol values were typically 30-50% of initial values, and alpha-tocopherol values were typically 200-400% of initial values. These results suggest that intestinal uptake and/or plasma transport make more efficient use of alpha-tocopherol than of gamma- or beta-tocopherol. Moreover, the results indicate that the ratio of gamma- to alpha-tocopherol in plasma would be a more satisfactory index to measure compliance in trials involving supplementation with alpha-tocopherol.

Clinical uses of vitamin E.

Early administration of vitamin E to low birth weight (less than 1500 g) infants results in alleviation of the symptoms of retinopathy of prematurity and a lowered incidence of intraventricular hemorrhage. If vitamin E is given to children with cholestatic liver disease (orally or parenterally) before 3 years of age, neurological symptoms such as areflexia, ataxia, and sensory neuropathy are prevented or reversed. Restitution of neurological function is more limited in children ages 5-17 years even after prolonged therapy. Vitamin E is also useful in prevention of neuropathy and retinopathy associated with abetalipoproteinemia and cystic fibrosis. Blood levels of tocopherol are often low in subjects with hemolytic anemias. Administration of vitamin E to G-6-P-D-deficient subjects increased hemoglobin levels, and decreased the number of irreversibly sickled cells in sickle-cell anemia subjects. Most trials have indicated that administration of vitamin E for 6 months or more to subjects with intermittent claudication results in longer walking distance and improved blood flow. Vitamin E reduces platelet aggregation, platelet adhesion to collagen, and platelet thromboxane production. Prostacyclin production is generally enhanced. The significance of these effects to thrombotic diseases. Epidemiological studies have indicated that subjects with higher blood levels of vitamin E have lower risk of death from ischemic heart disease and cancer, a lower risk of breast cancer, and a lower incidence of infections.

Kinetic characteristics of beta-carotene uptake and depletion in rat tissue.

Rats were fed a semi-purified diet supplemented with 0, 0.002, 0.02 and 0.2% beta-carotene (BC) for 21 weeks, followed by a 5-week depletion period. At various time points liver, adrenal, ovary, lung, heart, kidney, plasma, skin, brain and muscle were analyzed for BC content. The results indicated a dose-response effect between ingested BC and BC tissue content. The tissue saturation levels of BC, and time to reach saturation were determined in animals fed 0.2% BC diets. The half-life for BC was also determined. There was no apparent relationship among tissue content, rate of uptake and rate of depletion of BC. Each tissue studied was different. The absence of BC in fat suggests to us that BC distribution is not simply a matter of deposition into lipid depots. There was a wide range in tissue levels of BC; liver had the greatest value with 50 micrograms/g tissue, and muscle had the lowest value with 0.03 micrograms/g tissue. Plasma was saturated within 3 days, whereas liver, adrenal and ovary had not yet reached saturation at 147 days. The half-life varied from less than 3 days for plasma to 18 days for muscle.

Interaction of dietary vitamin C and vitamin E on guinea pig immune responses to mitogens.

Guinea pigs were fed semipurified diets with 0.2 g/kg vitamin C and either 0, 30 or 200 mg/kg all-rac-alpha-tocopheryl acetate or 10 mg/kg vitamin C and either 0, 30 or 200 mg/kg all-rac-alpha-tocopheryl acetate for 4 weeks. Animals were killed, and blastogenic responses of splenocytes to T- and B-cell mitogens were measured. Both T- and B-cell responses were significantly depressed in vitamin E-deficient guinea pigs when compared to responses from guinea pigs fed diets containing vitamin E. The two dietary levels of vitamin C examined did not affect the magnitude of these responses. The higher dietary vitamin C, however, increased the vitamin E content of the lung at all levels of vitamin E intake.

Strain differences in testes degeneration, myopathy, and the lymphocyte mitogen response in vitamin E-deficient rats.

The differences in sensitivity to vitamin E deficiency were examined in two genetically related inbred strains of rat, the spontaneously hypertensive rat and its genetic ancestor, the Wistar-Kyoto rat, as well as in the outbred Sprague-Dawley strain. The three strains showed differences in growth rate, myopathy, testes degeneration, and immunological responses in response to vitamin E deficiency with the spontaneously hypertensive rat showing the greatest sensitivity to the deficiency.

Effect of dietary level of Vitamin E on the immune system of the spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rat.

Spontaneously hypertensive rats (SHR) had depressed splenic mitogen responses as well as lower splenic vitamin E when compared to normotensive Wistar Kyoto strain (WKY) rats fed a stock diet. Both strains had depressed T- and B-cell splenic mitogen responses after 17 weeks on a semipurified, vitamin E-deficient diet when compared to animals fed either stock or dl-alpha-tocopheryl acetate-supplemented semipurified diet. In addition, SHR fed the vitamin E-supplemented diet had enhanced thymocyte rosetting compared to those fed the vitamin E-deficient diet. In contrast, the dietary vitamin E level did not affect the thymocyte rosetting in WKY rats.

Differences in vitamin E levels in tissues of the spontaneously hypertensive and Wistar-Kyoto rats.

Tissue vitamin E levels were significantly lower in spontaneously hypertensive rats (SHR) than in the normotensive, genetically related Wistar/Kyoto (W/K). This difference was also observed when animals were given identical oral doses of vitamin E. The possible relationship of lower vitamin E tissue levels to lower immune responses in the SHR is discussed.