INTERRACIAL DIFFERENCES IN CYTOCHROME P450 MEDIATED METABOLISM

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The U.S. population is becoming more ethnically and racially diverse. At the same time, globalization of drug development and the international marketing of new therapeutic agents have increased significantly. As a result, drugs are now regularly administered to populations that are distinctly different from those in whom they were originally evaluated. The working hypothesis of this Project is that racial differences in drug metabolism, especially those mediated by cytochrome P450 (CYP) enzymes, is an important determinant of interindividual variability in drug responsiveness. This will be tested with respect to 4 different CYP isoforms using appropriate in vivo probes that measure their activity in individual subjects of different racial origin. CYP3A is of interest because it is the predominant CYP enzyme in human liver and is also localized in the intestinal epithelium. Accordingly, it is an important determinant of first-pass metabolism and the bioavailability of orally administered drugs. Also, CYP3A's broad substrate specificity results in it being involved in the metabolism of a very large number of drugs and also some environmental procarcinogens. Midazolam will be used as the in vivo probe for CYP3A using a protocol that permits estimation of the separate contributions of its hepatic and intestinal activities. Similar studies will also be undertaken using chlorzoxazone as an in vivo probe for CYP2E1; this isoform is importantly involved in the activation of many dietary and environmental procarcinogens. The purpose of these studies is to compare the enzymes' activities in Caucasians, African-Americans, Mexican-Americans, Japanese and Asia- Indians. In the case of CYP2E1, where an inter-racial difference has already been demonstrated, studies will also be undertaken to determine the mechanism(s) of the substantially lower level of activity present in Japanese compared to Caucasians. Investigations will also focus on two enzymes with genetic polymorphisms (CYP2D6 and CYP2C19), in order to determine in extensive metabolizers the relationship between different genotypes and catalytic activity (phenotype) for the prototypic substrates; debrisoquine and mephenytoin, respectively. Because these studies will be performed in both Caucasians and Southeast Asians, it will be possible to test the hypothesis that inter-racial differences are also present in these gene products.