DESCRIPTION: This is a proposal to investigate the mechanisms by which alpha-lipoic acid prevents changes in cellular redox balance and oxidative damage during oxidative stress. Lipoic acid displays antioxidant effects in vitro and protects against oxidative damage in animal models in vivo. The hypothesis to be tested is that lipoic acid maintains cellular redox balance by acting directly as an antioxidant, by regenerating other cellular antioxidants, and by raising cellular glutathione levels. The first specific aim is to determine how lipoic acid is reduced to the more potent cellular antioxidant dihydrolipoic acid. Studies with cultured cells, subcellular fractions, and purified enzymes are proposed. The second aim is to determine the effective concentrations of lipoic acid in vivo. Analyses of lipoic acid and dihydrolipoic acid biokinetics and tissue concentrations are proposed. The third aim is to determine how lipoic acid interacts with other cellular antioxidants. This will be addressed by antioxidant turnover studies in vivo. The fourth aim will employ cell culture studies to determine how lipoic acid increases cellular glutathione. The fifth aim will employ cell culture studies to determine how lipoic acid influences redox sensitive signal transduction pathways. It is proposed that this information will be useful in the study of diseases where glutathione levels are depressed, such as AIDS.