Genetic polymorphism in human drug metabolism

Abstract

During the last decade, the influences of genetic factors on individual drug metabolizing capacity in humans have been characterized in fairly great detail at the molecular level. Debrisoquine/sparteine and mephenytoin polymorphisms are now known to be derived from defects in the human liver of specific forms of microsomal CYP (P450 or previously termed cytochrome P-450), CYP2D6 and CYP2C9 (2C18), respectively. In these polymorphisms, clear ethnic differences are observed in the incidence of poor metabolizers (PM). Although debrisoquine PM is detected in high incidence (5-10%) in Caucasians, little was found in Japanese. In con trast, mephenytoin PM is detected in higher percentages in Japanese (15 -25%) than in Caucasians (3-7%). In this mini-review, current understanding of the molecular mechanism of both types of polymorphism and structural relationships of CYP2D6 and CYP2C9 substrates are shown. Relationships between specific pheno types and cancer risks or disease are also discussed. © 1993, The Japanese Pharmacological Society. All rights reserved.