Abstract
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.
Footnotes
-
Send reprint requests to: Joyce Blaisdell (C3–01), NIEHS, P.O. Box 12233, Room C324, 111 Alexander Drive, Research Triangle Park, NC 27709. E-mail: Blaisde1{at}NIEHS.NIH.GOV
-
↵1 This work was supported in part (S.M., C.B., P.D.) by the Swiss Cancer League, Switzerland (FOR063); League against Cancer of Fribourg, Switzerland (FOR381.88); Cancer Research, Switzerland (AKT617); and Fund for Clinical Research against Cancer, Gustave-Roussy Institute, Villejuif, France (88D28).
- Abbreviations:
- PM
- poor metabolizer
- EM
- extensive metabolizer
- PCR
- polymerase chain reaction
- HI
- hydroxylation index
- CYP
- cytochrome P450
- RFLP
- restriction fragment length polymorphism
- Received February 13, 1998.
- Accepted May 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|