ALCOHOL: DIRECT AND INDIRECT EFFECTS ON DRUG METABOLISM

申请者摘要：人类慢性酒精中毒或慢性实验性 酒精对大鼠的治疗会导致多种内分泌疾病， 新陈代谢和生理异常，如性和生殖 衰竭和肝功能不全。尽管有大量的数据 关于酒精对药物代谢的某些方面的影响，我们的 酒精性肝病发病机制的总体认识 变化是表面上的。目前提案的总体目标是 区分酒精对肝脏代谢的直接影响和 是内分泌或内分泌变化的次要或协同作用 营养系统。有很多证据表明， 乙醇对P-450j(IIE1)的诱导是一种直接的翻译后反应 蛋白质的稳定性。然而，人们看到的营养不足 对酗酒的男性也可能在诱导这一过程中发挥协同作用 和其他细胞色素P-450同工酶。在……里面 此外，乙醇对小鼠的激素有抑制作用。 下丘脑-垂体-性腺轴，导致低雄激素化和 人和大鼠的高雌激素。因为荷尔蒙似乎有一种 肝细胞色素P-450表达的重要调节作用 同工酶、酒精滥用、内分泌功能和 药物代谢需要研究。这项提案的重点是5个 主要方面：1)乙醇对肝脏的直接影响 微粒体单加氧酶系统(HMO)；2)间接肝脏效应 因营养或内分泌状态改变而继发的酒精；3) 乙醇引起药物代谢改变的体内外相关性研究 4)慢性乙醇与其他诱导剂的相互作用 微粒体单加氧酶系统；以及5)一种 乙醇诱导的新细胞色素P-450同工酶。也有很多酗酒者 作为社交酒精使用者，正在服用多种药物，并暴露于 到饮食和环境中的一系列外来生物。 尽管除了酒精之外，许多化合物都能引起HMO，但很少有化合物 研究已经解决了乙醇消费可能会如何改变的问题 P-450j以外的细胞色素P-450的诱导。结果来自我们的 研究应该提供有价值的分子和荷尔蒙信息 关于酒精引起的肝脏代谢改变的机制和 提供合理的临床依据；1)减少有毒药物的相互作用 2)优化康复期间的营养支持 死于酗酒。

APPLICANT'S ABSTRACT: Chronic alcoholism in humans or chronic experimental alcohol treatment in rats results in a multitude of endocrinologic, metabolic and physiologic abnormalities such as sexual and reproductive failure and hepatic dysfunction. Although there is a wealth of data available on alcohol's effects on some aspects of drug metabolism, our overall understanding of the mechanisms underlying alcohol-related hepatic changes is superficial. The overall goal of the current proposal is to distinguish the direct effects of ethanol on liver metabolism from those that are secondary to or synergistic with changes in endocrine or nutritional systems. There is much evidence to indicate that part of the induction of P-450j (IIE1) by ethanol is a direct post-tranlational stabilization of the protein. However, the nutritional deficiencies seen in alcoholic men may also play a synergistic role in the induction of this and other cytochrome P-450 isozymes after chronic ethanol abuse. In addition, ethanol has inhibitory effects on the hormones of the hypothalamic-pituitary-gonadal axis, resulting in hypoandrogenization and hyperestrogenization in men and rats. Since hormones appear to have an important regulatory role in the expression of liver cytochrome P-450 isozymes, the interaction between ethanol abuse, endocrine function and drug metabolism requires investigation. The focus of this proposal is on 5 principal areas: 1) the direct effects of ethanol on the hepatic microsomal monooxygenase system (HMO); 2) the indirect hepatic effects of ethanol secondary to alterations in nutritional or endocrine status; 3) the in vitro/in vivo correlation of ethanol induced changes in drug metabolism and activation; 4) the interaction of chronic ethanol with other inducers of the microsomal monooxygenase system; and 5) the characterization of a new ethanol induced cytochrome P-450 isozyme. Many alcohol abusers as well as social alcohol users, are taking multiple medications, and are exposed to a wide range of xenobiotics in the diet and in the environment. Although many compounds are known to induce HMO in addition to alcohol, few studies have addressed the question of how ethanol consumption might alter induction of cytochrome P-450 forms other than P-450j. Results from our studies should provide valuable molecular and hormonal information regarding the mechanisms or ethanol induced changes in liver metabolism and provide a rational clinical basis for; 1) reducing toxic drug interactions in alcohol users, and 2) optimizing nutritional support during recovery from alcoholism.