HEPATIC METABOLISM OF ALCOHOL BY GSH TRANSFERASES

这些研究的目的是描述一个新颖而令人兴奋的 酒精在肝脏中的代谢途径及其与致癌物的关系 失活 在过去的八年里，校长的实验室 研究者描述了器官中的非氧化性酒精代谢 通常会因酗酒而受伤，但通常缺乏氧化 酒精代谢。 根据这些发现，他描述了和 纯化至均一的两种脂肪酸乙酯脱氢酶， 由乙醇形成脂肪酸乙酯。 主要合成酶 最近从人心脏中纯化到均一， 序列揭示了它与肝细胞癌之间的高度同源性。 谷胱甘肽S-转移酶。 后一种系统负责 解毒多种药物和致癌物质，但它从来没有被称为 代谢酒精 我们的研究在初步数据中提出 部分表明，事实上，主要的脂肪酸乙酯 合成酶是第一个被纯化至均一的酸性GSH转移酶 并且它还可以催化GSH与多种 毒品 此外，来自肝脏的GSH转移酶可以催化 脂肪酸乙酯和底物的GST抑制FAEE 合成酶 因此，在新的R 01赠款申请中，校长 研究者建议描述以下方面的体内重要性： 通过生化和13 C NMR测定肝脏中的非氧化代谢 实验 随后，肝脏中GSH转移酶的同工酶 能够将酒精代谢成脂肪酸乙酯， 鉴定 脂肪酸乙酯合成酶的潜在调控 活性或GSH转移酶活性，通过通常摄入的药物/致癌物 将表征由转移酶系统代谢的蛋白质。 的 通过在兔子中喂食乙醇诱导转移酶将是 表征了 因此，拟议研究的目标反映了 谷胱甘肽转移酶作为酒精代谢系统的特性 在肝脏中，这可能受到环境或遗传因素的调节。 由于转移酶对致癌物的灭活是公认的 研究其转化的方法，对长期的 酒精滥用和肿瘤之间的临床联系 发展

The purpose of thee studies is to characterize a novel and exciting metabolic pathway for alcohol present in liver and related to carcinogen inactivation. Over the past eight years, the laboratory of the Principal Investigator has characterized nonoxidative alcohol metabolism in organs that are commonly injured by alcohol abuse, but often lack oxidative metabolism of alcohol. Based on these findings, he has described and purified to homogeneity two fatty acid ethyl ester synthases that catalyze the formation of fatty acid ethyl esters from ethanol. The major synthase was recently purified to homogeneity from human heart and its amino acid sequence reveals a remarkable degree of homology between it and hepatic glutathione S-transferase. This latter system is responsible for detoxifying a variety of drugs and carcinogens, but it has never been known to metabolize alcohol. Our studies presented in the Preliminary data section demonstrate that, in fact, the major fatty acid ethyl ester synthase is the first acidic GSH transferase to be purified to homogeneity and it can also catalyze the formation of GSH conjugates with a variety of drugs. In addition, GSH transferases from liver can catalyze the formation of fatty acid ethyl esters and substrates of the GSTs inhibit FAEE synthase. In this new R01 grant application, therefore, the Principal Investigator proposes to characterize the in vivo importance of nonoxidative metabolism in the liver by both biochemical and 13C NMR experiments. Subsequently, isoenzymes of the GSH transferases in liver capable of metabolizing alcohol into fatty acid ethyl esters will be identified. The potential modulation of fatty acid ethyl ester synthase activity or GSH transferase activity by commonly ingested drugs/carcinogens metabolized by the transferase system will be characterized. The inducibility of the transferases by ethanol feeding in the rabbit will be characterized. The goal of the proposed studies, therefore, reflects characterization of the GSH transferase as an alcohol-metabolizing system in liver which may be modulated by either environment or genetic factors. Since carcinogen inactivation by the transferases is a well recognized method of their transformation, studies bear importantly on the long- appreciated clinical association between alcohol abuse and tumor development.