Genetic polymorphism of drug metabolizing enzymes: new mutations in CYP2D6 and CYP2A6 genes in Japanese

Abstract

Interindividual variation of drug effects in humans can be attributed to many factors. Among the factors, the rate of drug metabolism has been regarded as the most important one. A genetic defect of enzymes involved in drug metabolism, particularly cytochrome P450 (CYP), has been believed to be one of the important causal factors of adverse drug reactions. There are multiple gene mutations for CYP causing the poor metabolizer phenotype. The occurrence of genetic polymorphism has been seen in genes for CYP1A1, CYP2A6, CYP2C9, CYP2D19, CYP2D6, CYP2E1 and CYP3A5. Among them, the molecular mechanisms of genetic polymorphisms of CYP2D6 (debrisoquine/sparteine type) and CYP2A6 (coumarin type) in Japanese have been the focus of investigations. Only 20-30% of the Japanese population that shows the CYP2D6 poor metabolizer phenotype can be diagnosed by gene analysis. By other means, we found two new mutations, CYP2D6/J9 and CYP2D6/C8, in Japanese. With regard to CYP2A6, we discovered SM-12502, a new probe drug in addition to coumarin, that is currently under development; this drug is mainly metabolized by CYP2A6. Using this drug as a probe, we found poor metabolizers and analyzed the genes for CYP2A6. We found a new mutation (CYP2A6 whole deletion) responsible for the poor metabolizer phenotype. These results should contribute to the selection of an effective drug prescription and a reduced incidence of adverse effects.