Vitamin E: Weighing the Tocopherols

This section is compiled by Frank M. Painter, D.C.
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From The January 1999 Issue of Nutrition Science News

By Stephanie Briggs, Ph.D.

Next to vitamin C, vitamin E is probably the most well-known vitamin. In an informal survey I conducted among acquaintances, adults could tell me that alpha-tocopherol is vitamin E and that it is an antioxidant. Many people were aware of claims that vitamin E supplementation slows aging, improves immunity, protects against cancer and heart disease, and is generally good for health. But not many people knew if they got enough. Not even doctors are clear if vitamin E supplements are necessary to prevent deficiency.

Vitamin E deficiency manifests itself differently in different species. Vitamin E-deficient male rats, for instance, become infertile; female rats resorb their fetuses; some rats also develop liver necrosis; chickens develop exudative diathesis, a condition of leaky capillaries; lambs, cattle and horses develop white muscle disease, a kind of muscular dystrophy; giraffes become unable to swallow.

For a long time, it was thought that humans did not become vitamin E deficient. The human conditions that resembled the vitamin E-deficiency conditions seen in animals were not curable with vitamin E. For instance, human muscular dystrophy is not caused by vitamin E deficiency and is not cured by vitamin E supplementation. And it wouldn't be ethical to conduct human experiments with long-term vitamin E-deficient diets just to see what would happen. So it was presumed that humans must get enough vitamin E in their diets to prevent vitamin E-deficiency syndrome.

Now we know that is not true. While rare, vitamin E deficiency occasionally occurs in humans--generally in association with a fat absorption problem or a lipoprotein deficiency. If the vitamin deficiency is not recognized and treated, the consequences can be permanently debilitating. Most problematic is discerning a deficiency.

A major reason for this difficulty is that vitamin E is not a single molecular entity. A class of structurally related, fat-soluble compounds, known collectively as tocopherols, are the most potent and well-known forms of vitamin E. Alpha-tocopherol (alpha-T) and gamma-tocopherol (gamma-T) are the two most common tocopherols in food. But most supplemental forms of vitamin E are alpha-T.

Because both forms are fat-soluble, their proper absorption requires the presence of bile, which is secreted by the liver, stored in the gallbladder and released into the intestine when fat is present. Tocopherols are stored in body fat, and considerable reserves of vitamin E may accumulate there. When dietary intake of vitamin E is insufficient, the needs for vitamin E are met by its release from fat stores. If fat malabsorption develops in adulthood, it may be many years before vitamin E deficiency manifests because of the amount stored in fat.

Vitamin E deficiency in humans is a progressive syndrome of neural degeneration involving reduced reflexes, decreased sensation, weakness, ataxia (failure of muscular coordination) and visual abnormalities. If this syndrome is not treated soon enough with vitamin E, the debilitation is irreversible.

The neural degeneration related to human vitamin E deficiency is the result of an extreme situation--exhaustion of vitamin E stores and no new vitamin E. However, there may be other conditions that occur when vitamin E in the body is not so low as to cause neural degeneration but perhaps lower than optimal in a particular tissue.

Deficiency vs. Insufficiency

This issue of what is a deficiency and what is an insufficiency in relation to optimal function is important. The idea that there is an RDA for everyone does not take into account two things: First, optimal is different from adequate, and second, biochemical individuality exists; that is, differences in both our genes and in environmental factors can affect the nutrient amounts we each require.

There are many examples of optimal intake being different from adequate:

  • Coronary heart disease risk is lower among those whose vitamin E intake is higher than among those with lower intake. [1]

  • In a large study of male smokers 50 to 69 years old, prostate cancer incidence was significantly lower in those who took supplementary vitamin E (50 mg/day for five to eight years) than in those who took beta-carotene or placebo. [2]

  • In a two-year study of patients in early stages of Alzheimer's disease, those treated with very large doses of alpha-T (1,000 IU twice daily) required significantly less supervision than those who received placebo. Also, institutionalization was significantly delayed in the alpha-T group. [3]

Along the lines of biochemical individuality, a compound's vitamin E activity has historically been determined by the amount of it necessary to overcome deficiency conditions. In the laboratory where the rat is the most typical model, alpha-T has shown the greatest vitamin E activity--that is, alpha-T enabled rats to overcome infertility and liver necrosis caused by deficiency. Thus, by virtue of its unparalleled potency in preventing and overcoming overt vitamin E deficiency symptoms in the rat, alpha-T has become synonymous with vitamin E. However, the superiority of alpha-T in its ability to overcome particular conditions in the rat does not mean that alpha-T is the best form of vitamin E for all purposes. Using another standard, we might find that gamma-T is better.

For instance, while gamma-T has only one-tenth the vitamin E activity of alpha-T in the rat model, [4] recent evidence indicates that gamma-T is better at neutralizing certain reactive molecules that are generated in vivo and can cause oxidative damage. [5] For example, molecules generated by large scavenger cells, or phagocytes, during inflammation can form a powerful oxidant, peroxynitrite, that readily reacts with lipids, amino acids and DNA. Gamma-T traps and inactivates peroxynitrite, thus protecting those vulnerable molecules. Although alpha-T also inhibits lipid peroxidation by peroxynitrite, it operates by a different mechanism and inhibits lipid peroxidation to a lesser degree.

This is an important model to consider because smokers are exposed to great amounts of nitric oxide, a molecule that can react with a superoxide radical to form peroxynitrite when mixed with inhaled smoke. Plasma levels of gamma-T increase rapidly when long-term smokers give up smoking. [6] This suggests that their gamma-T was being used by something associated with smoking--probably the nitric oxide.

Remember the story of beta-carotene: Researchers measured plasma levels of nutrients in relation to cancer and showed that groups with higher beta-carotene had less lung cancer. But in studies in which beta-carotene was given to smokers, there was a higher lung cancer incidence among those who took beta-carotene than among those who did not. [2 ] The most accepted explanation for this at present is that a diet--not supplements--high in beta-carotene protects against lung cancer, but that beta-carotene is not the protective agent. One candidate to consider is nitric oxide-consuming gamma-T.

Get It From the Diet

A diet of gamma-T--not supplements of alpha-T--has been shown in some studies to have greater effects in general. In one study, vitamin E offered protection from heart disease when it came from the diet (gamma-T) but not when it came from supplements (alpha-T). [7] Certain types of margarine, nuts and seeds, which are excellent sources of gamma-T, showed the best protection. [8]

Why might supplementary vitamin E be less effective than dietary vitamin E? The answer may lie in the way the body processes the two forms.

Gamma-T is present in much higher quantities in the American diet than is alpha-T, probably because of the frequent use of soybean oil, corn oil and canola oil in margarine and baked goods (see box, page 20). Yet alpha-T is five or so times higher in plasma than gamma-T. This apparent anomaly is probably due to a molecule in the liver that preferentially incorporates alpha-T into plasma lipoproteins. [9] Gamma-T initially enters the blood along with alpha-T in association with fat. While in circulation, some of the alpha-T and gamma-T is taken up by tissues such as adipose (fat) and muscle; the rest eventually reaches the liver, where the resident alpha-T-binding protein repackages alpha-T into very-low-density lipoproteins (VLDL) and returns it to circulation. Again a part of the plasma, alpha-T is also distributed to high- and low-density lipoproteins (HDL and LDL). Gamma-T, on the other hand, is excreted by the liver in bile and not returned to circulation.

The apparent "preservation program" for alpha-T suggests the importance of alpha-T to the organism. The absence of such a preservation plan for gamma-T, however, may not be a sign of unimportance but merely of its greater abundance in the diet.

So does that mean we need more of one or the other? We don't really know. It has been observed that plasma levels of gamma-T decline with intake of alpha-T supplements [10] --the majority of supplements on the market. The mechanism of this reduction is unknown, although it is not competition for intestinal absorption. [10] Hence, a prudent approach to vitamin E supplementation for a healthy person may be to take mixed tocopherols. Since alpha-T is stored and also preserved in plasma, supplementing only every other day allows the body more access to dietary components with which the presence of high alpha-T may interfere.

In general, the RDA for vitamin E seems low relative to amounts in commercially available supplements. The RDA is 10 international units (IU) for adult men and 8 IU for women. Requirements increase as consumption of polyunsaturated fatty acids increases. Supplements, meanwhile, are typically 200 IU or higher. However, there seems to be little risk of toxicity with high doses; for example the 2,000 IU per day used in the Alzheimer's study was tolerated and was apparently beneficial.

The process of deciding how much, what kind--or whether--to supplement with vitamin E has some resemblance to jury deliberations in a criminal trial: Some information necessary to making a wise decision is missing. While a preponderance of evidence suggests vitamin E is useful, the current state of information on vitamin E leaves questions about what to supplement and at what level, if at all.

Stephanie Briggs, Ph.D., is a nutritional biochemist with more than 20 years experience in laboratory research. She is also a freelance writer.


1. Rimm EB, et al. N Engl J Med 1993;328:1450-6.

2. The alpha-tocopherol, beta-carotene cancer prevention study group. N Engl J Med 1994;330:1029-35.

3. Sano M, et al. N Engl J Med 1997;336:1216-22.

4. Bieri JG, Evarts RP. J Nutr 1974;104:850-7.

5. Christen S, et al. Proc Natl Acad Sci USA 1997;94:3217-22.

6. Brown AJ. J Nutr Biochem 1996;7:29-39.

7. Rapola JM, et al. Lancet 1997;49:1715-20.

8. Kushi LH, et al. N Engl J Med 1996;334:1156-62.

9. Kayden HJ, Traber MG. J Lipid Res 1993;34:343-58.

10. Dieber-Rotheneder M, et al. J Lipid Res 1991;32:1325-32

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