Alcohol and Acetaminophen Hepatotoxicity

描述（由申请人提供）：我们研究的总体目标是 描述了酒精饮料消费的机制 增加APAP肝毒性的风险。CYP2E1被认为是 酒精介导的APAP肝毒性增加。然而我们的研究表明 CYP3A也有作用。我们最近发现，酒精也诱导 CYP1A2，另一种产生APAP活性代谢物的CYP1A2。在 这项建议，使用基因敲除小鼠，我们将研究CYP2E1的作用， CYP3A和CYP1A2在酒精介导的APAP肝毒性中的作用 广泛使用的化学品咖啡因和茶碱增强了 CYP3A，因此有可能增加酒精介导的APAP 如果与APAP同时食用，则会产生肝毒性。因此重要的 以确定这些甲基黄嘌呤是否是额外的风险因素， 酒精介导的APAP肝毒性。在这份提案中，我们还将 研究咖啡因和茶碱对酒精介导的APAP的影响 啮齿类动物肝毒性。 假设 我们推测CYP3A可能在APAP的增强中起主要作用 酒精肝毒性。一个企业的实际贡献 酒精介导的APAP肝毒性将取决于 以及在暴露于APAP时其在肝脏中的活性， APAP的剂量 本提案的具体目标是： 1.探讨细胞色素P450 3A、2E1和1A2在APAP中的相对作用 乙醇和异戊醇预处理引起的肝毒性，使用乙醇 和报告基因敲除小鼠。 2.研究增加CYP3A活性的甲基黄嘌呤的作用 但降低CYP1A2，对酒精介导的APAP肝毒性在野生型和 CYP1A2敲除小鼠。

DESCRIPTION (provided by applicant): The overall goals of our research are to characterize the mechanism by which consumption of alcoholic beverages increases the risk of APAP hepatotoxicity. CYP2E1 is considered responsible for alcohol-mediated increases in APAP hepatotoxicity. However, our work suggests that CYP3A also has a role. We have recently found that alcohols also induce CYP1A2, another form of CYP that produces the reactive metabolite of APAP. In this proposal, using knockout mice, we will investigate the roles of CYP2E1, CYP3A and CYP1A2 in alcohol-mediated APAP hepatotoxicity. The widely consumed chemicals caffeine and theophylline enhance the activity of CYP3A, and thus have the potential to augment alcohol-mediated APAP hepatotoxicity if consumed simultaneously with APAP. Therefore it is important to ascertain whether these methylxanthines are additional risk factors in alcohol-mediated APAP hepatotoxicity. In this proposal, we will also investigate the effects of caffeine and theophylline on alcohol-mediated APAP hepatotoxicity in rodents. HYPOTHESES We hypothesize that CYP3A can have a major role in the enhancement of APAP hepatotoxicity by alcohols. The actual contribution of a CYP in alcohol-mediated APAP hepatotoxicity will depend on the relative amount of that CYP as well as its activity in the liver at the time of exposure to APAP and the dose of APAP. The SPECIFIC AIMS of this proposal are: 1. To investigate the relative roles of CYPs 3A, 2E1 and 1A2 in APAP hepatotoxicity caused by pretreatment with ethanol and isopentanol, using CYP and reporter gene knockout mice. 2. To investigate the effect of methylxanthines, which increase CYP3A activity but decrease CYP1A2, on alcohol-mediated APAP hepatotoxicity in wild-type and CYP1A2 knockout mice.