AN ADDITIONAL DEFECTIVE ALLELE, CYP2C19-ASTERISK-5, CONTRIBUTES TO THE S-MEPHENYTOIN POOR METABOLIZER PHENOTYPE IN CAUCASIANS

The metabolism of the anticonvulsant drug mephenytoin exhibits a genet ic polymorphism in humans. This polymorphism exhibits marked racial he terogeneity, with the poor metabolizer PM phenotype representing 13-23 % of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C192 and CYP2C19*3) have been describ ed, which account for more than 99% of Oriental poor metabolizer allel es but only approximately 87% of Caucasian poor metabolizer alleles. T herefore, additional defects presumably contribute to the poor metabol izer in Causasians. Recent studies have found a third mutation CYP2C19 4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C195A) (C-99,A(991),Ile(331);C12 97T,Arg(433)-->Trp) resulting in an Arg(433) to Trp substitution in th e heme-binding region has been reported in a single Chinese poor metab oliser outlier belonging to the Bai ethnic group. The present study id entifies a second variant allele CYP2C195B (C-99-->T; A(991)-->G, Ile (331)-->Val; C-1297-->T, Arg(433)-->Trp in one of 37 Caucasian poor me tabolizers. The frequency of the CYP2C195 alleles is low in Chinese ( approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese po or metabolizers and 92% in Caucasian poor metabolizers genotyped in ou r laboratory. The Arg(433) to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C195A toward S-meph enytoin and tolbutamide, which is consistent with the conclusion that CYP2C195 represents poor metabolizer alleles. Pharmacogenetics 8: 129 -135 (C) 1998 Lippincott-Raven Publishers.