POLYMORPHIC DRUG OXIDATION--THE HUMAN AND RAT DEBRISOQUINE 4-HYDROXYLASE GENES

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Individual subjects vary considerably in their abilities to metabolize drugs. In addition, genetic influences are thought to govern individual susceptibility to chemically-induced cancers. The mixed function monooxygenase system is composed of multiple forms of P450s that are the principle enzymes associated with drug and carcinogen metabolism. These enzymes can serve to detoxify and hasten the elimination of foreign agents or they can activate inert chemicals to harmful electrophilic metabolites that damage DNA and initiate the carcinogenic process. We have begun to study polymorphic drug oxidation in humans by establishing the mechanism of the debrisoquine 4-hydroxylase polymorphism. This polymorphism effects from 5% to 10% of the North American and European Caucasian population. These individuals, referred to as poor metabolizers, or PMs, cannot metabolize debrisoquine and many other related drugs, while the rest of the population, called extensive metabolizers, or EMs, rapidly hydroxylate this drug resulting in the inactivation of its therapeutic form. To examine the mechanism of this defect we have isolated the rat P450 that metabolizes debrisoquine, designated IIDI, and prepared a specific antibody that reacts with both the rat and human IIDI protein. We also isolated the human IIDI genes. By analysis of lymphocyte DNA we are able to phenotype PMs using Southern blots and the IIDI cDNA. The human IIDI locus contains three related genes and is located on the long arm of chromosome 22.