ALCOHOL-INDUCED LIVER DAMAGE: ROLE OF XANTHINE OXIDASE

该项目的长期目标是提供信息，以便 协助制定治疗和/或预防疟疾的战略 乙醇所致的肝毒性。它寻求通过以下方式实现这一目标 研究乙醇可能通过其潜在机制发挥其作用 肝脏毒性作用。这项研究将集中在阐明 急、慢性乙醇处理对肝脏黄嘌呤的影响 大鼠的脱氢酶/氧化酶系统。这两个潜在的转换 黄嘌呤脱氢酶为氧化物型的酶 乙醇诱导的底物次黄嘌呤的积累 肝脏缺氧可通过产生显著的肝损伤 剧毒的超氧阴离子自由基。如果是这样，则抑制 黄嘌呤氧化酶类药物别嘌醇可减轻肝毒性 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导致转化 黄嘌呤脱氢酶为黄嘌呤氧化酶，以及黄嘌呤脱氢酶的积累 在体内的次黄嘌呤，从而触发高度的 有毒的超氧阴离子自由基。2.确定酒精的影响是否 肝脏黄嘌呤脱氢酶/氧化酶系统的治疗 对酒精处理的动物肝脏易感性负责 缺氧造成的损伤。3.确定黄嘌呤的抑制作用 药物别嘌醇的氧化酶可减轻乙醇所致的肝毒性 在经历短暂低氧的大鼠中。

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.