ALCOHOL DIRECT AND INDIRECT EFFECTS ON DRUG METABOLISM

酗酒是美国的一个主要健康问题，造成数十亿美元的损失。 每年的医疗支出为8美元。酒精性肝病 (ALD)是24-65岁成年男性的第四大死因 居住在城市地区的适龄儿童。一个日益令人担忧的问题是有证据表明 酒精滥用的增加和女性ALD发病率的增加，甚至 尽管他们平均来说比男性喝得少。生化机制 酒精引起的肝毒性的发展基础是 在世界各地的实验室进行了深入的研究，包括我们的实验室。 有证据表明，它本身不是乙醇，而是 乙醇的代谢，这是启动的关键因素 肝病病机。在社交饮酒条件下， 微粒体乙醇氧化系统(Meos)是一个相对较小的系统。 以乙醇代谢率表示的代谢途径。这个 MEOS的主要成分是细胞色素P450 CYP 2E1 代谢酒精，但酒精刺激产生额外的CYP 2e1(通过一种称为归纳的过程)。这种酶的诱导是 重要的是因为CyP2E1被认为负责启动 组织损伤导致ALD。因此，即使CYP 2E1可能是一个未成年人 乙醇代谢物在社会饮酒者中，它可能在酒精性酒精性痴呆中起主要作用。 我们开发了一种大鼠模型，在该模型中，乙醇被灌胃作为 全肠内营养(TEN)系统的一部分，用于研究乙醇 细胞色素P450 2E1的代谢与调控。在酒精的十种模式中 如果以恒定的速度注入，血液中的酒精浓度(BAC)就会发生 作为从峰值起平均周期为6天的大“脉冲” 一个脉冲到下一个脉冲的峰值。这些周期似乎是 酒精循环代谢的结果。我们已经证明了乙醇 通过一个复杂的两步诱导过程来调节细胞色素P450 2E1。第一步 由后平移机构在循环的低BAC处发生 过程，而第二步涉及提高转录速度 CyP2E1基因，只发生在高BAC的周期中。在这次更新中， 研究的具体目标是：1)循环BAC的形成机制 Ten模型，并确定CyP2E1在这一过程中的可能作用 过程；2)营养/乙醇相互作用；以及3)乙醇代谢 女性。两步诱导法的分子机制 乙醇生成的CyP2E1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为我们提供对 细胞色素P450 2E1在乙醇代谢和酒精性肝损伤中的作用 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.