Clinical relevance of genetic polymorphisms in the human CYP2C9 gene

Cytochrome P450 (CYP) 2C9 hydroxylates about 16% of drugs in current clinical use. Of special interest are those with a narrow therapeutic index, such as S-warfarin, tolbutamide and phenytoin, where impairment in CYP2C9 metabolic activity might cause difficulties in dose adjustment as well as toxicity. Single-nucleotide polymorphisms (SNP) in the CYP2C9 gene have increasingly been recognized as determinants of the metabolic phenotype that underlies interindividual and ethnic differences. Apart from the wild-type protein CYP2C9*1 at least five allelic variants produce allozymes with reduced or deficient metabolic activity. Among white populations only CYP2C9*2 and CYP2C9*3 variants are of significance, with allelic frequencies of 0.08-0.14 and 0.04-0.16, respectively. In contrast, in Africans (African-Americans and Ethiopians) and Asians both variants are much less frequent (0.005-0.04), and CYP2C9*2 has not yet been detected in Asians. CYP2C9*4 has been exclusively identified in Japanese patients, and CYP2C9*5 and *6 were only found among African-Americans with a low allelic frequency of 0.017 and 0.006, respectively. Furthermore in Japanese a CYP2C9 promotor variant of four linked SNPs was correlated with reduced intrinsic clearance of phenytoin in vitro. Subjects who are carriers of one or more variant alleles may be at risk for adverse drug reactions/toxicities when prescribed drugs extensively metabolized by CYP2C9.