IDENTIFICATION OF NEW HUMAN CYP2C19 ALLELES (CYP2C19-ASTERISK-6 AND CYP2C19-ASTERISK-2B) IN A CAUCASIAN POOR METABOLIZER OF MEPHENYTOIN

A genetic polymorphism in the metabolism of the anticonvulsant drug S- mephenytoin has been attributed to defective CYP2C19 alleles. This gen etic 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 m utations in CYP2C19 in a single Swiss Caucasian PM outlier (JOB I)whos e apparent genotype (CYP2C19*1/CYP2C19*2) did not agree with his PM ph enotype. These mutations consisted of a single base pair mutation (G(3 95)A) in exon 3 resulting in an Arg(132)-->Gln coding change and a (G( 276)C) mutation in exon 2 resulting in a coding change Glu(92)-->Asp. However, the G(276)C mutation and the G(395)A mutation resided on sepa rate alleles. Genotyping tests of a family study of JOB1 showed that t he exon 2 change occurred on the CYP2C19*2 allele, which also containe d the known splice mutation in exon 5 (this variant is termed CYP2C19* 2B to distinguish it from the original splice variant now termed CYP2C 19*2A). The exon 3 mutation resided on a separate allele (termed CYP2C 19*6). In all other respects this allele was identical to one of two w ild-type alleles, CYP2C19*1B. The incidence of CYP2C19*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 were CYP2C19*2B(15%) and 85% were CYP2C19*2A. The Arg,,,Gln mu tation was produced by site-directed mutatgenesis and the recombinant protein expressed in a bacterial cDNA expression system. Recombinant C YP2C19 6 had negligible catalytic activity toward S-mephenytoin compar ed with CYP2C19 1B, which is consistent with the conclusion that CYP2C 19*6 represents a PM allele. Thus, the new CYP2C19*6 allele contribute s to the PM phenotype in Caucasians.