Experiments will be conducted to determine the biochemical basis for the protection from oxidant drug toxicity by dietary Se. Se-deficient chicks and rats will be used as the animal models; nitrofurantoin will be used as the oxidant drug.
Specific aims will include determination of a) whether dietary Se affects nitrofurantoin metabolism and tissue distribution, b) the mode of death in acute nitrofurantoin intoxication c) whether nitrofurantoin exposure promotes sub-cellular oxidations of lipids, protein sulfhydryls and non-protein factors (GSH, ascorbic acid, pyridine nucleotides, Se), d) the relationship of Se-dependent glutathione peroxidase to protection against nitrofurantoin toxicity by dietary Se, e) the effect of chronic exposure to nitrofurantoin in Se metabolism and dietary requirement, f) whether Se interacts with vitamin E to protect the rat from acute nitrofurantoin toxicity, g) whether high levels of vitamin E or other antioxidants can also reduce nitrofurantoin toxicity in the presence/absence of Se, and h) the extent to which the protective effect of dietary Se includes other oxidant drugs. Standard biochemical methods will be employed in these studies. The results will elucidate the nature of the interaction of dietary Se and oxidant drugs, such as nitrofurantoin, which undergo reductive activation initially to form free radical intermediates ultimately posing oxidative stress to the cell. Because Se deficiency is a practical problem in human health in several parts of the world, and because drugs such as the 5-nitrofurans and others that produce oxidant stress are widely used in human therapeutics, these interactions have practical significance relative to reducing the toxicities of such compounds.
| Mercurio, S D; Combs Jr, G F (1987) Mercaptans decrease selenium-dependent glutathione peroxidase activity in the chick. J Nutr 117:880-5 |
| Mercurio, S D; Combs Jr, G F (1986) Selenium-dependent glutathione peroxidase inhibitors increase toxicity of prooxidant compounds in chicks. J Nutr 116:1726-34 |
| Mercurio, S D; Combs Jr, G F (1986) Synthetic seleno-organic compound with glutathione peroxidase-like activity in the chick. Biochem Pharmacol 35:4505-9 |
| Mercurio, S D; Combs Jr, G F (1985) Drug-induced changes in selenium-dependent glutathione peroxidase activity in the chick. J Nutr 115:1459-70 |
