ALCOHOL DIRECT AND INDIRECT EFFECTS ON DRUG METABOLISM

酗酒在美国是一个主要的健康问题，耗资数十亿 每年的医疗费用。 酒精性肝病 (ALD)是24-65岁成年男性的第四大死因 居住在城市地区的年龄。 越来越多的关注是， 酒精滥用的增加和女性ALD发病率的增加， 尽管她们的平均饮酒量比男性少。 生化机制 酒精诱导的肝毒性发展的基础正在 在世界各地的实验室里进行了深入的研究，包括我们的实验室。 有证据表明，这不是乙醇本身，而是 乙醇的代谢，这是启动的关键因素， 肝脏发病机制 在社交饮酒的情况下， 微粒体乙醇氧化系统（MEOS）是一个相对较小的 代谢途径中乙醇代谢的百分比。 的 MEOS的主要成分是细胞色素P450 β 2 E1， 代谢酒精，但酒精刺激生产额外的酒精 2 E1（通过一个称为归纳的过程）。 这种酶的诱导是 重要的是，因为E2 E1被认为是负责启动 组织损伤导致ALD。 因此，即使2 E1可能是一个小的， 在社交饮酒者中，它可能在ALD中起主要作用。 我们开发了一种大鼠模型，其中乙醇被灌胃， 全肠内营养（TEN）系统的一部分，用于研究乙醇 代谢和调节β 2 E1。 在10模型中，酒精 以恒定速率输注时，血液酒精浓度（BAC） 作为大的“脉冲”，平均周期为6天， 一个脉冲到下一个脉冲的峰值。 这些周期似乎是 循环乙醇代谢的结果。 我们已经证明乙醇 通过一个复杂的两步诱导过程来调节β 2 E1。 步骤一 通过翻译后机制在循环的低BAC下发生 过程中，而第二步涉及增加转录速率的 E12 E1基因，并且仅在周期中的高BAC处发生。 在这次更新中， 具体目的是研究：1）环化BAC的作用机制 TEN模型，并确定E2 E1在其中的可能作用。 过程; 2）营养/乙醇相互作用; 3）乙醇代谢 女性 两步诱导的分子机制 用乙醇生产2 E1是所有这三个目标的关键组成部分。 从这些研究中获得的知识将提供新的见解， β_2E_1在乙醇代谢和酒精诱导的肝脏中的作用 疾病

Alcoholism is a major health problem in the U.S., costing billions of dollars annually in medical expenditures. Alcohol-induced liver disease (ALD) is the fourth leading cause of death among adult men 24-65 years of age residing in urban areas. A growing concern is the evidence of increasing alcohol abuse and of increased incidence of ALD in women, even though they on average drink less than males. Biochemical mechanisms underlying the development of alcohol-induced hepatotoxicity are being studied intensively in laboratories throughout the world, including ours. There is evidence to suggest that it is not ethanol per se, but the metabolism of ethanol that is the crucial factor in initiation of the hepatic pathogenesis. Under conditions of social drinking, the microsomal ethanol oxidizing system (MEOS) is a relatively minor metabolic pathway in terms of the percentage of ethanol metabolized. The principal component of MEOS is cytochrome P450 CYP 2E1 not only metabolizes alcohol, but alcohol stimulates production of additional CYP 2E1 (by a process called induction). Induction of this enzyme is important because CYP 2E1 is thought to be responsible for initiating tissue damage leading to ALD. Thus, even though CYP 2E1 may be a minor ethanol metabolizer in social drinkers, it may play a major role in ALD. We developed a rat model in which ethanol is infused intragastrically as part of a total enteral nutrition (TEN) system, to study ethanol metabolism and the regulation of CYP 2E1. In the TEN model where alcohol is infused at a constant rate, blood alcohol concentrations (BACs) occur as large "pulses" that have an average period of 6 days from the peak of one pulse to the peak of the next pulse. These cycles appear to be the result of cyclic ethanol metabolism. We have demonstrated that ethanol regulates CYP 2E1 by a complex Two-Step Induction process. Step-One occurs by post-translational mechanisms at low BACs of the cycling process, while Step-Two involves increases in transcription rate of the CYP 2E1 gene and occurs only at high BACs in the cycle. In this renewal, the specific aims re to study: 1) the mechanisms of the cyclic BACs in the TEN model and to determine the possible role of CYP 2E1 in this process; 2) nutrition/ethanol interactions; and 3) ethanol metabolism in females. The molecular mechanisms underlying the Two-Step Induction of CYP 2E1 by ethanol is a key component of all three of these aims. Knowledge gained from these studies will provide new insights into the role of CYP 2E1 in ethanol metabolism and in alcohol-induced liver disease.