ETHANOL INDUCTION OF UDP-GLUCURONYLTRANSFERASE

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Alcohol has been shown to affect the metabolism of drugs in the body in two major ways: 1) descreasing the metabolism when the drug is given simultaneously with alcohol, thereby potentiating the action of the drug; and 2) increasing the metabolism when larger doses of ethanol are ingested (as in alcoholics) over lengthy time periods prior to taking the drug, thereby decreasing the efficacy of the drug due to faster metabolism. It is the second of these two effects that we will study in this work. The usually accepted reason for the increased metabolism of drugs observed in alcoholics is the induction of the cytochrome P-450 monooxygenase enzymes. However, another important metabolism enzyme, UDP-glucuronyltransferase (GT), may also be induced by ethanol. The extent of GT induction by ethanol, and the effect of this phenomenon on drug metabolism in animals and man has not been substantially addressed. We have demonstrated that GT activity with p-nitrophenol as substrate is substantially induced in rabbit hepatic microsomes. This research will extend the previous work by addressing two major questions: 1) does ethanol induce a unique isozyme of GT in rabbits, and what are the physical and catalytic properties of this isozyme; and 2) what are the specific in vivo pharmacokinetic changes in drug disposition associated with ethanol induction of GT activity? We will answer the first question with the purification of the GT isozyme from rabbit hepatic microsomes from animals pretreated with ethanol. We will characterize the ethanol-induced GT isozyme by comparison with other purified siozymes in respect to gel electrophoretic mobility (molecular weight), amino acid composition, catalytic specificity for several substrates, and catalytic efficiency (Km and Vmax). The second question will be answered by determining in rabbit the changes after alcohol consumption in pharmacokinetic parameters (plasma clearance, half-life, AUC, etc.) of several drugs (oxazepam, lorazepam, diazepam, and phenytoin) that are primarily excreted via glucuronide conjugation. This work will thus establish not only the specific biochemical basis for GT induction by ethanol, but also correlate the induction phenomenon to the clinical situation. Our research will increase our knowledge of the effects of alcoholism on the metabolism of drugs, and therefore on the therapeutic use of these drugs with alcoholics.