The Biological Activity
The study of vitamin E, the major fat-soluble antioxidant vitamin, has been a major focus of my research for the past 10 years of my nearly 20 years in the field of nutrition. I began my career in nutrition studying cholesterol metabolism. Then at New York University Medical Center, I spent several years investigating the role of macrophages (scavenging cells in the immune system) in atherosclerosis. My experience in lipoprotein metabolism was pivotal for our subsequent studies on vitamin E.
Initially, I began to study vitamin E not for its antioxidant activity, but to establish the manner by which vitamin E is transported from our food to the tissues in our bodies. Cell culture and animal models, but especially studies in humans were used to elucidate these delivery mechanisms. These studies demonstrated that the biological activity of vitamin E is dependent upon the alphalpha-tocopherol transfer protein in the liver.
Both of these esters are broken down in the gastrointestinal tract, resulting in absorption of alpha-tocopherol. Synthetic vitamin E (all-rac-alpha-tocopherol; also known incorrectly as dl-alpha-tocopherol) and its different stereoisomers have lower activity than the naturally occurring form. Although vitamin E is an important antioxidant, its biological activity largely depends on regulatory processes and not on its inherent antioxidant activity. This is most clearly shown by comparing natural with synthetic vitamin E. Both have identical antioxidant activities, yet the natural vitamin E has at least one and one-half times the biological activity of the synthetic form.
What determines the biological activity of vitamin E? Possibilities include absorption, transport, delivery to tissues, metabolism, and excretion. The absorption of vitamin E is the obvious step where differences in biological activity might occur--if a vitamin E homologue is not absorbed, it cannot have very high metabolic activity. However, our studies in rats clearly demonstrated that alpha-tocopherol and gamma-tocopherol do not compete during absorption. Furthermore, we demonstrated that chylomicrons (triglyceride-rich lipoprotein particles) isolated from the plasma of humans following a meal containing doses of vitamin E (both natural and synthetic isomers of alpha-tocopherol or gamma-tocopherol) contained equal concentrations of the various forms administered. Absorption did not appear to play a role in the efficacy of the particular form of vitamin E. To completely rule out the role of absorption as a factor in the determination of plasma concentrations of vitamin E, we infused a lipid emulsion containing gamma-tocopherol into the subjects' blood. This raised the plasma gamma-tocopherol concentrations as high as alpha-tocopherol (usually they are only about 20% of alpha-tocopherol concentrations). When the infusion stopped, plasma gamma-tocopherol concentrations began to decrease, and 24 hours later, gamma-tocopherol concentrations had returned to their pre-infusion levels. This observation led us to conclude that plasma concentrations were not dependent on absorption but rather upon a metabolic process.
This result brings us to the concept of vitamin E transport and metabolism. Children with cholestatic liver disease become vitamin E deficient as a result of fat malabsorption-previously, the occurrence of human vitamin E deficiency had not been observed. For the first time, these reports documented that in humans, vitamin E deficiency causes neurological abnormalities. Ron Sokol and his colleagues at the University of Colorado Health Sciences Center in Denver were then able to identify patients with neurological abnormalities and extremely low plasma vitamin E levels, but with no other abnormalities. These patients had no other known disorder that would cause vitamin E deficiency. We measured the patients' plasma, nerve, and fat tissue vitamin E concentrations and found that they were very low or absent. Surprisingly, one patient with "Familial Isolated Vitamin E Deficiency," who had been supplemented with vitamin E, had fat tissue concentrations in the normal range. These patients also had an unusual response to vitamin E supplementation. Supplements raised their plasma concentrations to normal, but when supplementation ended, plasma concentrations fell to undetectable levels within days. These two clues and the observations on absorption led me to think that the liver plays a major role in the regulation of plasma and tissue alpha-tocopherol concentrations. We tested this experimentally and found that, indeed, the liver is central to the regulation of plasma vitamin E concentrations because it is the organ in which the alpha-tocopherol transfer protein preferentially incorporates alpha-tocopherol into lipoproteins that are circulated in blood. The patients in this study have a defect in the gene for the alpha-tocopherol transfer protein.
The role of excretion and metabolism in the regulation of plasma vitamin E is not well understood. Certainly the studies carried out by Don Reed's group at Oregon State University on the mechanism by which vitamin E is excreted in bile have added critical new information in this area. But questions remain.
In epidemiological and intervention studies, vitamin E supplements were associated with decreased risk of heart disease. In two particularly compelling studies published by Harvard researchers in The New England Journal of Medicine in 1993, daily vitamin E intakes of 100 IU or more were associated with a significantly reduced risk of heart disease in both men and women. The results were about the same for daily doses between 100-600 IU, although only very slight benefits were observed for daily intakes under 100 IU. The most protective dosage was between 100-249 IU/day. Most experts agree that these levels of vitamin E intake are safe. Additionally, the CHAOS study in England (published in Lancet in 1996) demonstrated that vitamin E supplements prevented second heart attacks. The exact mechanisms by which vitamin E is protective against heart disease remain unknown, but may be related to the inhibition of low-density lipoprotein oxidation (see Frei's article in the Fall/Winter 1997 Newsletter), anti-inflammatory effects, or the inhibition of platelet aggregation. Many studies have suggested other roles for vitamin E in cancer prevention and immune enhancement. For us to fully develop these health benefits, we need to understand the role that vitamin E plays at the molecular level. Based on this knowledge, new recommendations about the optimal intake of vitamin E will emerge. Basic studies on the function of vitamin E, using cell cultures as well as whole organisms, including humans, are needed to answer many questions, including:
My laboratory at LPI will carry out research to answer these and other questions, which will contribute to the breadth of knowledge about the compounds we refer to simply as vitamin E, but which actually represent a complex set of biochemicals.
Last updated May, 1998
For general information on vitamin E and health, see the Linus Pauling Institute's Micronutrient Information Center.
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