ALCOHOL-INDUCED LIVER DAMAGE: ROLE OF XANTHINE OXIDASE

该项目的长期目标是提供信息， 帮助制定治疗和/或预防 乙醇诱导的肝毒性。 它力求通过以下方式实现这一目标： 研究乙醇可能发挥其 肝毒性作用。 本研究将着重于阐明 急性和慢性乙醇处理对肝脏黄嘌呤的影响 脱氢酶/氧化酶系统。 无论是潜在的转换 黄嘌呤脱氢酶的氧化酶形式的酶和 由于乙醇诱导的底物次黄嘌呤的积累 肝脏缺氧可通过产生 剧毒超氧阴离子自由基的。 如果是， 黄嘌呤氧化酶的药物别嘌呤醇可能会减少肝毒性 乙醇的影响。 这项建议的具体目标如下： 1.确定急性或慢性乙醇治疗是否会导致转化 黄嘌呤脱氢酶的黄嘌呤氧化酶，以及积累 次黄嘌呤在体内，从而触发生产的高度 有毒的超氧阴离子自由基 2.为了确定乙醇的影响 对肝黄嘌呤脱氢酶/氧化酶系统的治疗是 导致乙醇处理动物的肝脏易感性 缺氧造成的损伤。 3.为了确定是否抑制黄嘌呤 氧化酶的药物别嘌呤醇可以减轻乙醇诱导的肝毒性 在短暂缺氧的大鼠中。

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.