Recent advances in understanding the molecular basis of polymorphisms in genes encoding cytochrome P450 enzymes

The cytochrome P450 superfamily is known to exhibit a high degree of geneti c polymorphism and polymorphisms associated with absent or low enzyme activ ity in CYP2D6, CYP2C19 and CYP2C9 are particularly well studied. However, d espite early reports of strong disease associations for particular CYP2D6 p henotypes, these have not been confirmed in recent, more detailed studies a nd it now appears that analysis of CYPD2D6, CYP2C19 and CYP2C9 genotype is of most value in predicting metabolism of specific drugs. Polymorphisms in other cytochrome P450 genes are less well studied and appear not to be asso ciated with complete absence of enzyme activity. We have recently carried o ut studies of polymorphism in both CYP1A1 and CYP2E1. The molecular basis o f the apparent CYP1A1 'high inducibility' polymorphism was investigated by studying CYP1A1 and Ah receptor polymorphisms in a group of phenotyped indi viduals who were genotyped both for known and novel CYP1A1 and Ah receptor polymorphisms. Three novel polymorphisms in CYP1A1 (C-459T, G(-469)A and C4 151T) and one in the Ah receptor (G(1768)A; V570I) were detected by single strand conformational polymorphism analysis and DNA sequencing. Among both novel and previously known polymorphisms, only the Ah receptor G(1721)A pol ymorphism, which has an allele frequency of 0.12 in Caucasians and was dete cted previously in a Japanese population, was significantly associated with high induced CYP1A1 activity. In the case of CYP2E1, we have detected thre e polymorphisms in the promoter region (A(-316)G, T(-297)A and G(-35)T) and one in the coding sequence (G(4804)A; V179I) by screening Caucasian DNA sa mples. The significance of these alleles has been investigated but only G(- 35)T combined with T(-297)A, which has an allele frequency of 0.05, appears to be of functional significance, with an apparent 1.8-fold increase in le vels of transcriptional activity compared with the wild-type. (C) 1998 Else vier Science Ireland Ltd. All rights reserved.