GENETIC-ANALYSIS OF THE HUMAN CYTOCHROME-P450 CYP2C9 LOCUS

Cytochrome P450 CYP2C9 metabolizes a wide variety of clinically import ant drugs, including phenytoin, tolbutamide, warfarin and a large numb er of non-steroidal anti-inflammatory drugs. Previous studies have sho wn that even relatively conservative changes in the amino acid composi tion of this enzyme can affect both its activity and substrate specifi city. To date six different human CYP2C9 cDNA sequences, as well as th e highly homologous CYP2C10 sequence have been reported suggesting tha t the CYP2C9 gene is polymorphic. Only nine single base substitutions in the coding region of CYP2C9 account for the differences seen betwee n the CYP2C9 proteins. In this report we have developed polymerase cha in reaction (PCR)-based assays to distinguish all seven sequences, and have determined their allele frequencies in the Caucasian population. Of the seven sequences studied in one hundred individuals only three appeared to be CYP2C9 alleles. These alleles termed CYP2C91, CYP2C9*2 and CYP2C93 had allele frequencies of 0.79, 0.125 and 0.085 respecti vely. The CYP2C10 gene could not be found in any of the samples studie d. The assays developed here will allow the prediction of CYP2C9 pheno type, thus identifying those individuals who may exhibit different dru g for CYP2C9 substrates.