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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Nutrition Study Section (NTN)
Program Officer
Finkelstein, David B
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Hill, Kristina E; Motley, Amy K; May, James M et al. (2009) Combined selenium and vitamin C deficiency causes cell death in guinea pig skeletal muscle. Nutr Res 29:213-9
May, James M; Li, Liying; Qu, Zhi-Chao et al. (2007) Mitochondrial recycling of ascorbic acid as a mechanism for regenerating cellular ascorbate. Biofactors 30:35-48
Burk, Raymond F; Christensen, Joani M; Maguire, Mark J et al. (2006) A combined deficiency of vitamins E and C causes severe central nervous system damage in guinea pigs. J Nutr 136:1576-81
Huang, Junjun; May, James M (2003) Ascorbic acid spares alpha-tocopherol and prevents lipid peroxidation in cultured H4IIE liver cells. Mol Cell Biochem 247:171-6
Hill, Kristina E; Montine, Thomas J; Motley, Amy K et al. (2003) Combined deficiency of vitamins E and C causes paralysis and death in guinea pigs. Am J Clin Nutr 77:1484-8
Jones, Wright; Li, Xia; Qu, Zhi-chao et al. (2002) Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med 33:83-93
Li, Xia; Cobb, Charles E; May, James M (2002) Mitochondrial recycling of ascorbic acid from dehydroascorbic acid: dependence on the electron transport chain. Arch Biochem Biophys 403:103-10
May, James M; Morrow, Jason D; Burk, Raymond F (2002) Thioredoxin reductase reduces lipid hydroperoxides and spares alpha-tocopherol. Biochem Biophys Res Commun 292:45-9
Li, X; Hill, K E; Burk, R F et al. (2001) Selenium spares ascorbate and alpha-tocopherol in cultured liver cell lines under oxidant stress. FEBS Lett 508:489-92
Li, X; Cobb, C E; Hill, K E et al. (2001) Mitochondrial uptake and recycling of ascorbic acid. Arch Biochem Biophys 387:143-53

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