Alcohol and Acetaminophen Hepatotoxicity

描述(由申请人提供)：我们研究的总体目标是 描述酒精饮料的消费机制 增加APAP肝毒性的风险。CYP2E1被认为对 酒精介导的APAP肝毒性增加。然而，我们的工作表明 CYP3A也有一定的作用。我们最近发现酒精也能诱导 CYP1A2，另一种形式的CYP，产生APAP的反应性代谢物。在……里面 这项建议，使用基因敲除的小鼠，我们将研究CYP2E1的作用， 细胞色素P450 3A和细胞色素P1A2在酒精介导的APAP肝毒性中的作用 广泛使用的化学物质咖啡因和茶碱可增强 CyP3A，因此有可能增强酒精介导的APAP 如果与APAP同时食用，则会产生肝脏毒性。因此，它是重要的 以确定这些甲基黄嘌呤是否是 酒精介导的APAP肝毒性。在这项提案中，我们还将 咖啡因和茶碱对酒精介导的急性胰腺炎的影响 对啮齿动物的肝脏毒性。 假设 我们推测，CyP3A在APAP的增强中可能起主要作用 酒精对肝脏的毒性。CYP的实际贡献在 酒精介导的APAP肝毒性将取决于其相对含量 以及在暴露于APAP时其在肝脏中的活性 APAP的剂量。 这项建议的具体目标是： 1.探讨细胞周期蛋白3A、2E1和1A2在APAP中的相关作用 用CYP研究乙醇和异戊醇预处理引起的肝毒性 和记者基因敲除小鼠。 2.研究甲基黄嘌呤对细胞色素P3A活性的影响 但降低乙醇介导的APAP肝毒性的野生型和 CYP1A2基因敲除小鼠。

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.