Genetic Polymorphisms of Human Cytochrome P450: Relevance to Drug Metabolism

Abstract

The human cytochrome P450 (CYP) enzymes play critical roles in the metabolism of numerous exogenous and endogenous molecules. All genes encoding P450 in families 1-3 are polymorphic,particularly CYP2C9,CYP2C19,CYP2D6 and CYP3A5. Polymorphic P450s are involved in the metabolism of more than 50% of clinical drugs. Genetic variation in the CYP genes is he main cause for individual variation in drug response. Over the past several years,Alleles are responsible for the variable enzymatic activity of P450 and the variable expression of CYP genes,have been identified. The phenotype can be determined by genotyping the functional variants or tag variants of the CYP genes. This helps doctors to choose ppropriate medication for patients to enhance the curative effect and to reduce the side effect,especially when drugs with narrow therapeutic index are involved. Knowledge of genetic variants of the CYP genes is necessary for both drug therapy and drug development. With a high degree of multiplexing,microarrays offer promise for simultaneously enotyping a large number of genetic variants of CYP genes,and thus provide technical basis for realizing personalized medicine. However,DNA preparation is the bottleneck for developing microarrays for genotyping genetic variants of the CYP genes. Extensive application of predictive CYP microarrays in clinical practice will be made in the near uture. Key words: Cytochrome P450 ; Polymorphism ; Drug metabolism; Microarray