TY - JOUR T1 - Identification of New Human <em>CYP2C19</em> Alleles (<em>CYP2C19*6</em> and <em>CYP2C19*2B</em>) in a Caucasian Poor Metabolizer of Mephenytoin JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1490 LP - 1495 VL - 286 IS - 3 AU - Gordon C. Ibeanu AU - Joyce A. Goldstein AU - Urs Meyer AU - Simone Benhamou AU - Christine Bouchardy AU - Pierre Dayer AU - Burhan I. Ghanayem AU - Joyce Blaisdell Y1 - 1998/09/01 UR - http://jpet.aspetjournals.org/content/286/3/1490.abstract N2 - A genetic polymorphism in the metabolism of the anticonvulsant drugS-mephenytoin has been attributed to defectiveCYP2C19 alleles. This genetic polymorphism displays large interracial differences with the poor metabolizer (PM) phenotype representing 2–5% of Caucasian and 13–23% of Oriental populations. In the present study, we identified two new mutations inCYP2C19 in a single Swiss Caucasian PM outlier (JOB 1) whose apparent genotype (CYP2C19*1/CYP2C19*2) did not agree with his PM phenotype. These mutations consisted of a single base pair mutation (G395A) in exon 3 resulting in an Arg132→Gln coding change and a (G276C) mutation in exon 2 resulting in a coding change Glu92→Asp. However, the G276C mutation and the G395A mutation resided on separate alleles. Genotyping tests of a family study of JOB1 showed that the exon 2 change occurred on the CYP2C19*2 allele, which also contained the known splice mutation in exon 5 (this variant is termedCYP2C19*2B to distinguish it from the original splice variant now termed CYP2C19*2A). The exon 3 mutation resided on a separate allele (termed CYP2C19*6). In all other respects this allele was identical to one of two wild-type alleles, CYP2C19*1B. The incidence ofCYP2C19*6 in a European Caucasian population phenotyped for mephenytoin metabolism was 0/344 (99% confidence limits of 0 to 0.9%). Seven of 46 Caucasian CYP2C19*2 alleles wereCYP2C19*2B(15%) and 85% wereCYP2C19*2A. The Arg132Gln mutation was produced by site-directed mutatgenesis and the recombinant protein expressed in a bacterial cDNA expression system. Recombinant CYP2C19 6 had negligible catalytic activity toward S-mephenytoin compared with CYP2C19 1B, which is consistent with the conclusion thatCYP2C19*6 represents a PM allele. Thus, the newCYP2C19*6 allele contributes to the PM phenotype in Caucasians. The American Society for Pharmacology and Experimental Therapeutics ER -