[Genetic polymorphism in human drug metabolism].
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 contrast, 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 mechanisms of both types of polymorphism and structural relationships of CYP2D6 and CYP2C9 substrates are shown. Relationships between specific phenotypes and cancer risks or disease are also discussed.
Yamazoe
Y
Y
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Nagata
K
K
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008862:Microsomes, Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System