The long term objective of this project is to supply information which will aid in the development of strategies for treatment and/or prophylaxis of ethanol-induced hepatotoxicity. It seeks to accomplish this objective by investigating a potential mechanism through which ethanol might exert its hepatotoxic effects. This research will focus on the elucidation of the effects of acute and chronic ethanol treatment on the hepatic xanthine dehydrogenase/oxidase system in rats. Both the potential conversion of xanthine dehydrogenase to the oxidase form of the enzyme and the accumulation of the substrate hypoxanthine as a result of ethanol-induced liver hypoxia could contribute markedly to liver damage through production of the highly toxic superoxide anion radical. If so, inhibition of xanthine oxidase by the drug allopurinol might diminish the hepatotoxic effects of ethanol.
The specific aims of this proposal are as follows: 1. To determine if acute or chronic ethanol treatment causes the conversion of xanthine dehydrogenase to xanthine oxidase, as well as the accumulation of hypoxanthine in vivo, thereby triggering the production of the highly toxic superoxide anion radical. 2. To determine if effects of ethanol treatment on the hepatic xanthine dehydrogenase/oxidase system are responsible for the predisposition of ethanol treated animals to liver damage resulting from hypoxia. 3. To determine if inhibition of xanthine oxidase by the drug allopurinol can diminish ethanol-induced hepatotoxicity in rats subjected to brief hypoxia.