HEPATIC METABOLISM OF ALCOHOL BY GSH TRANSFERASES

你研究的目的是描述一部新奇而激动人心的作品 酒精在肝脏中的代谢途径与致癌物质相关 失活。在过去八年中，校长的实验室 研究人员已经确定了器官中非氧化酒精代谢的特征。 通常因酗酒而受伤，但通常缺乏氧化 酒精的代谢。基于这些发现，他描述了 纯化至均一的催化两种脂肪酸乙酯合成酶 由乙醇生成脂肪酸乙酯的过程。主要的合成酶 最近从人的心脏及其氨基酸中提纯到均一 序列显示它与肝脏之间有显著的同源性 谷胱甘肽S转移酶。后一种系统负责 对多种药物和致癌物解毒，但人们从来不知道 来代谢酒精。我们的研究显示在初步数据中 部分证明，事实上，主要的脂肪酸乙酯 合酶是第一个纯化到均一的酸性谷胱甘肽转移酶。 它还可以催化与多种谷胱甘肽形成偶联物 毒品。此外，肝脏中的谷胱甘肽转移酶可以催化这种形成。 脂肪酸乙酯和GSTs底物抑制FAEE 合成酶。因此，在这份新的R01拨款申请中，校长 研究人员建议表征在体内的重要性 生化和~(13)C核磁共振在肝脏非氧化代谢研究中的应用 实验。随后，肝脏中GSH转移酶的同工酶 将酒精代谢成脂肪酸乙酯的能力将是 已确认身份。脂肪酸乙酯合成酶的潜在调节作用 常食药物/致癌物的活性或谷胱甘肽转移酶活性 由转移酶系统代谢的将被表征。这个 乙醇喂养对兔体内转移酶的诱导作用 特色化的。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，可能受到环境或遗传因素的调节。 由于通过转移酶来灭活致癌物是公认的 对它们的转化方法，研究具有重要的意义。 酒精滥用与肿瘤之间的临床关联 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.