ETHANOL INDUCTION OF UDP-GLUCURONYLTRANSFERASE

UDP-葡萄糖醛酸转移酶的乙醇诱导

• 批准号: 3109705
• 负责人: Garold S Yost
• 金额: $ 10.42万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1987-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3109705
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; benzodiazepines; diazepam; drug metabolism; enzyme induction /repression; enzyme structure; enzyme substrate; ethanol; gel electrophoresis; glucuronides; glucuronosyltransferase; isozymes; oxazepam; phenytoin; psychotropic drugs

Alcohol has been shown to affect the metabolism of drugs in the body in two major ways: 1) descreasing the metabolism when the drug is given simultaneously with alcohol, thereby potentiating the action of the drug; and 2) increasing the metabolism when larger doses of ethanol are ingested (as in alcoholics) over lengthy time periods prior to taking the drug, thereby decreasing the efficacy of the drug due to faster metabolism. It is the second of these two effects that we will study in this work. The usually accepted reason for the increased metabolism of drugs observed in alcoholics is the induction of the cytochrome P-450 monooxygenase enzymes. However, another important metabolism enzyme, UDP-glucuronyltransferase (GT), may also be induced by ethanol. The extent of GT induction by ethanol, and the effect of this phenomenon on drug metabolism in animals and man has not been substantially addressed. We have demonstrated that GT activity with p-nitrophenol as substrate is substantially induced in rabbit hepatic microsomes. This research will extend the previous work by addressing two major questions: 1) does ethanol induce a unique isozyme of GT in rabbits, and what are the physical and catalytic properties of this isozyme; and 2) what are the specific in vivo pharmacokinetic changes in drug disposition associated with ethanol induction of GT activity? We will answer the first question with the purification of the GT isozyme from rabbit hepatic microsomes from animals pretreated with ethanol. We will characterize the ethanol-induced GT isozyme by comparison with other purified siozymes in respect to gel electrophoretic mobility (molecular weight), amino acid composition, catalytic specificity for several substrates, and catalytic efficiency (Km and Vmax). The second question will be answered by determining in rabbit the changes after alcohol consumption in pharmacokinetic parameters (plasma clearance, half-life, AUC, etc.) of several drugs (oxazepam, lorazepam, diazepam, and phenytoin) that are primarily excreted via glucuronide conjugation. This work will thus establish not only the specific biochemical basis for GT induction by ethanol, but also correlate the induction phenomenon to the clinical situation. Our research will increase our knowledge of the effects of alcoholism on the metabolism of drugs, and therefore on the therapeutic use of these drugs with alcoholics.

酒精已被证明会影响体内药物的代谢， 主要途径：1）给药时降低代谢 同时与酒精，从而增强药物的作用; 以及2）当摄入较大剂量的乙醇时， (as在酗酒者中）在服用药物之前的长时间内， 从而由于更快的代谢而降低药物的功效。 它 是我们在本书中要研究的两个效应中的第二个。 的 通常被接受的原因，增加药物代谢观察到的， 酒精是诱导细胞色素P-450单加氧酶。 然而，另一种重要的代谢酶UDP-葡萄糖醛酸转移酶， (GT)乙醇也可以诱导。 GT诱导的程度 乙醇，以及这种现象对动物药物代谢的影响 和人的问题还没有得到实质性的解决。 我们已经证明，以对硝基苯酚为底物的GT活性是 在兔肝微粒体中基本上诱导。 这项研究将 通过解决两个主要问题扩展了以前的工作：1） 乙醇诱导家兔产生一种独特的GT同工酶， 这种同工酶的催化特性; 2）什么是具体的， 与乙醇相关的药物处置的体内药代动力学变化 诱导GT活性？ 我们将用GT同工酶的纯化来回答第一个问题 来自乙醇预处理动物的兔肝微粒体。 我们 将通过与其他同工酶的比较来表征乙醇诱导的GT同工酶。 纯化的siozyme在凝胶电泳迁移率方面（分子 重量），氨基酸组成，催化特异性的几个 底物和催化效率（Km和Vmax）。 第二个问题 将通过测定家兔在酒精作用后的变化来回答 消耗的药代动力学参数（血浆清除率，半衰期， AUC等）几种药物（奥沙西泮、劳拉西泮、地西泮和苯妥英） 主要通过葡糖苷酸结合排泄。 因此，这项工作不仅将建立特定的生物化学基础， 乙醇诱导GT，但也将诱导现象与 临床情况。 我们的研究将增加我们对 酒精中毒对药物代谢的影响，因此对 这些药物对酗酒者的治疗作用。