ALCOHOL DIRECT AND INDIRECT EFFECTS ON DRUG METABOLISM

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Alcoholism is a major health problem in the U.S., costing billions of dollars annually in medical expenditures. Alcohol-induced liver disease (ALD) is the fourth leading cause of death among adult men 24-65 years of age residing in urban areas. A growing concern is the evidence of increasing alcohol abuse and of increased incidence of ALD in women, even though they on average drink less than males. Biochemical mechanisms underlying the development of alcohol-induced hepatotoxicity are being studied intensively in laboratories throughout the world, including ours. There is evidence to suggest that it is not ethanol per se, but the metabolism of ethanol that is the crucial factor in initiation of the hepatic pathogenesis. Under conditions of social drinking, the microsomal ethanol oxidizing system (MEOS) is a relatively minor metabolic pathway in terms of the percentage of ethanol metabolized. The principal component of MEOS is cytochrome P450 CYP 2E1 not only metabolizes alcohol, but alcohol stimulates production of additional CYP 2E1 (by a process called induction). Induction of this enzyme is important because CYP 2E1 is thought to be responsible for initiating tissue damage leading to ALD. Thus, even though CYP 2E1 may be a minor ethanol metabolizer in social drinkers, it may play a major role in ALD. We developed a rat model in which ethanol is infused intragastrically as part of a total enteral nutrition (TEN) system, to study ethanol metabolism and the regulation of CYP 2E1. In the TEN model where alcohol is infused at a constant rate, blood alcohol concentrations (BACs) occur as large "pulses" that have an average period of 6 days from the peak of one pulse to the peak of the next pulse. These cycles appear to be the result of cyclic ethanol metabolism. We have demonstrated that ethanol regulates CYP 2E1 by a complex Two-Step Induction process. Step-One occurs by post-translational mechanisms at low BACs of the cycling process, while Step-Two involves increases in transcription rate of the CYP 2E1 gene and occurs only at high BACs in the cycle. In this renewal, the specific aims re to study: 1) the mechanisms of the cyclic BACs in the TEN model and to determine the possible role of CYP 2E1 in this process; 2) nutrition/ethanol interactions; and 3) ethanol metabolism in females. The molecular mechanisms underlying the Two-Step Induction of CYP 2E1 by ethanol is a key component of all three of these aims. Knowledge gained from these studies will provide new insights into the role of CYP 2E1 in ethanol metabolism and in alcohol-induced liver disease.