ALCOHOL: DIRECT AND INDIRECT EFFECTS ON DRUG METABOLISM

人类慢性酒精中毒或慢性实验

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.