ANTIOXIDANT INTERACTIONS OF SELENIUM AND VITAMINS

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The goal of this project is to define a role for selenium in preventing oxidant damage, both in vitro and in vivo. Selenium, by as yet unknown mechanisms, has long been known to "spare" vitamin E from oxidative loss in animal dietary studies. Vitamin E, or alpha-tocopherol, is the primary chain-breaking antioxidant in lipoproteins and cell membranes that must be recycled from its oxidized form. Recycling of alpha- tocopherol is thought to be mediated, at least in part, by vitamin C, or ascorbic acid. This project will test hypotheses that the selenoenzyme thioredoxin reductase and other selenoproteins are crucial in recycling ascorbic acid, in preserving alpha-tocopherol and in preventing lipid peroxidative damage in cells and in animals. Accelerated lipid peroxidation has been associated with several human diseases, including atherosclerosis, inflammatory conditions, and Alzheimer's disease. There are three specific aims. Studies in the first aim will examine the mechanisms by which thioredoxin reductase regenerates ascorbic acid from its oxidized forms, and will establish the extent to which such recycling occurs in cultured human hepatoma cells (HepG2). A novel role for low molecular weight selenoproteins to enhance the ability of thioredoxin reductase to recycle ascorbate will be examined, and there are plans to purify and characterize one or more of these proteins from rat liver. Studies in the second aim will test the hypothesis that thioredoxin reductase both spares alpha-tocopherol and prevents lipid peroxidation by reducing lipid hydroperoxides in lipid bilayers. The relative contributions of thioredoxin reductase and the glutathione peroxidases to such protection will be assessed using the differential sensitivity of these enzymes to selenium deficiency in HepG2 cells. In the third aim, a dietary model of combined nutrient deficiency in guinea pigs will be established to examine the extent to which selenium can prevent oxidative loss of both ascorbate and alpha-tocopherol. Like humans, guinea pigs cannot synthesize ascorbic acid. Thus, use of ascorbate-deficient animals will provide the means to test in vivo whether selenium preserves ascorbate, and whether this contributes to selenium-dependent sparing of alpha-tocopherol and to prevention of lipid peroxidation.