Alcohol: Direct and Indirect Effects in Drug Metabolism

描述（由申请人提供）：慢性酒精滥用导致一系列健康问题，每年造成数千人死亡，每年的医疗费用高达数十亿美元。酒精的生物效应与摄入的剂量、获得的血液和组织浓度、组织暴露于高浓度酒精的持续时间以及酒精摄入的频率有关。当然，还有其他变量，如性别，年龄，遗传倾向，潜在的健康影响等，然而，组织酒精浓度和暴露时间是迄今为止与酒精相关的健康影响最重要的方面，并且与酒精的代谢有关。酒精代谢是酒精作用的基础，尽管代谢酒精的酶已经知道多年，但它们的调节机制还不清楚。肝脏I类酒精脱氢酶（ADH）是主要的酒精代谢酶，负责将多达95%的酒精转化为毒性代谢物乙醛，并且是酒精最终从体内清除的第一步。直到最近，人们还认为酒精浓度高时，酒精不能向肝脏发出信号，使其合成更多的ADH。我们使用酒精性肝病（ALD）的胃内啮齿动物模型来研究酒精浓度变高时I类ADH的分子调节，例如在酗酒者中发生的情况，并发现酒精确实可以导致肝脏产生足够多的I类ADH，以将酒精浓度降低到毒性较低的浓度。这些发现对以下领域具有深远的影响：1）中枢神经系统（酒精依赖和耐受性）; 2）肝脏（ALD，酒精诱导的糖尿病和肥胖症）。此外，我们提出了一个合理的机制，这一重要的过程。这一更新的主要焦点是在慢性乙醇摄入过程中编码I类ADH的基因的调节。我们的总体工作假设是，慢性乙醇摄入导致增加生产（表达）的I类ADH通过干扰激素系统，最终调节大鼠I类ADH生产通过细胞内信号（称为信号转导途径），通常用于激素（特别是胰岛素）调节基因的行动。我们将采用一系列的体外（细胞培养，分子生物学和生物化学）和体内（含乙醇饮食的大鼠胃内输注）程序，我们已经在我们的实验室标准化研究酒精代谢。

DESCRIPTION (provided by applicant): Chronic alcohol abuse leads to a series of health problems that cost thousands of lives annually and accounts for billions of dollars each year in medical expenditures. The biological effects of alcohol are related to the dose consumed, the blood and tissue concentrations obtained, the duration that tissues are exposed to high ethanol concentrations, and the frequency of alcohol intake. There are, of course, other variables such as; gender, age, genetic predisposition, underlying health effects, etc. However, the tissue alcohol concentrations and duration of exposure are by far the most important aspects of alcohol-related health effects and are in good part related to the metabolism of alcohol. Alcohol metabolism is fundamental to alcohol's actions and although the enzymes that metabolize alcohol have been known for years, the mechanisms by which they are regulated are not well understood. Hepatic Class I Alcohol Dehydrogenase (ADH) is the principal alcohol-metabolizing enzyme and is responsible for as much as 95%of alcohol conversion to the toxic metabolite acetaldehyde and is the first step in the eventual clearance of alcohol from the body. Until recently, it was thought that alcohol could not signal the liver to synthesize more ADH when alcohol concentrations became high. We have used the intragastric rodent model of alcoholic liver disease (ALD) to study the molecular regulation of Class I ADH during times when alcohol concentrations become high, such as would occur in alcoholics, and found that alcohol can indeed cause the liver to produce sufficiently more Class I ADH to drive alcohol concentrations down to less toxic concentrations. These findings have far reaching implications for such areas as; 1) the central nervous system (alcohol dependence & tolerance); and 2) the liver (ALD, alcohol-induced diabetes and obesity). Furthermore, we have proposed a plausible mechanism underlying this important process. The major focus of this renewal is regulation of the gene encoding Class I ADH during chronic ethanol intake. Our overall working hypothesis is that chronic ethanol intake causes increased production (expression) of Class I ADH by disrupting hormonal systems that ultimately regulate rat Class I ADH production via intracellular signals (called signal transduction pathways) that are commonly used by hormones (especially insulin) to regulate gene actions. We will employ a series of in vitro (cell culture, molecular biological and biochemical) and in vivo (intragastric infusions of ethanol-containing diets to rats) procedures that we have standardized in our lab to study alcohol metabolism.