Alcohol: Direct and Indirect Effects in Drug Metabolism

描述(申请人提供)：长期酗酒导致一系列健康问题，每年导致数千人丧生，每年的医疗支出高达数十亿美元。酒精的生物效应与消耗的剂量、获得的血液和组织浓度、组织暴露在高浓度酒精中的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与酒精有关的健康影响的最重要方面，在很大程度上与酒精的新陈代谢有关。酒精代谢是酒精活动的基础，尽管人们多年来已经知道了代谢酒精的酶，但对它们的调节机制还不是很清楚。肝脏I类酒精脱氢酶(ADH)是酒精代谢的主要酶，负责高达95%的酒精转化为有毒代谢物乙醛，是酒精最终从体内清除的第一步。直到最近，人们还认为当酒精浓度变高时，酒精不能向肝脏发出信号，让其合成更多的ADH。我们使用了酒精性肝病(ALD)的胃内啮齿动物模型来研究酒精浓度变高时I类ADH的分子调控，发现酒精确实可以导致肝脏产生足够多的I类ADH，从而将酒精浓度降低到较低的毒性浓度。这些发现对以下领域有深远的影响：1)中枢神经系统(酒精依赖和耐受)；2)肝脏(ALD、酒精引起的糖尿病和肥胖)。此外，我们还提出了这一重要进程背后可能存在的机制。这一更新的主要焦点是在慢性乙醇摄入过程中编码第I类ADH的基因的调节。我们的总体工作假设是，长期摄入乙醇会扰乱荷尔蒙系统，最终通过细胞内信号(称为信号转导途径)调节大鼠I类ADH的产生，而激素(尤其是胰岛素)通常使用这些信号来调节基因活动，从而导致I类ADH的产生(表达)增加。我们将采用我们实验室标准化的一系列体外(细胞培养、分子生物学和生化)和体内(向大鼠灌胃含乙醇饮食)程序来研究酒精代谢。

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.