ETHANOL INDUCTION OF UDP-GLUCURONYLTRANSFERASE

点击翻译按钮获取中文摘要

APPLICANT'S ABSTRACT: Chronic alcohol consumption changes the therapeutic efficacies and pharmacokinetics of a number of drugs. Usually, these changes are manifest as increased metabolism of the drugs leading to shorter half-lives, increased clearance, and decreased plasma concentrations. These changes can lead to inadequate therapeutic doses. Such effects may primarily be observed in the clinical treatment of alcoholics, but may be important in the effects of moderate alcohol consumption on drug efficacies. Glucuronidation of many of these drugs is the major or only route of elimination, and induction of UDP-glucuronosyltransferase isozymes could lead to significant increases in the clearance of the drugs. Chronic alcohol exposure induces the production of a unique UDP-glucuronosyltransferase (GT) isozyme in rabbit hepatic microsomes, and this biochemical effect is manifest in the increased clearance, via glucuronidation, of morphine and oxazepam in the animals. The major goal of this research is to determine the precise molecular events and dose requirements that control this induction process in rabbits, and to demonstrate that these processes also occur in man. Realization of this goal will be accomplished through the following methods: 1) the production and use of antibodies to the rabbit ethanol-induced GT in immunoblots and immunoprecipitation studies with ethanol-induced rabbit microsomes and purified isozymes to determine the time course and dose requirements for induction; 2) preparation and sequencing of rabbit hepatic cDNA clones of the DNA coding for the ethanol-induced GT and use of cDNA probes to screen rabbit and human mRNA levels to determine the molecular events that are responsible for production of the isozyme; and 3) purification and characterization of the ethanol-induced GT protein(s) and cDNAs from human liver tissue. The long-term objectives of this research are to establish the existence of ethanol-induced UDP-glucuronosyltransferase isozymes in experimental animals and humans, characterize the isozymes and provide information about the molecular events that are responsible for their production, and relate these biochemical events to the treatment of humans, after chronic exposure to ethanol, with drugs that are metabolized by these GT isozymes. These studies represent a multifaceted approach on the biochemical, molecular biological, and clinical levels that will provide significant new information about the effects of chronic alcohol consumption on an important human drug metabolism enzyme.