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OtherDRUG METABOLISM AND DISPOSITION

A New Genetic Defect in Human CYP2C19: Mutation of the Initiation Codon Is Responsible for Poor Metabolism of S-Mephenytoin

Ronald J. Ferguson, Sonia M.F. De Morais, Simone Benhamou, Christine Bouchardy, Joyce Blaisdell, Gordon Ibeanu, Grant R. Wilkinson, Troy C. Sarich, James M. Wright, Pierre Dayer and Joyce A. Goldstein
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 356-361;
Ronald J. Ferguson
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Sonia M.F. De Morais
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Simone Benhamou
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Christine Bouchardy
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Joyce Blaisdell
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Gordon Ibeanu
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Grant R. Wilkinson
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Troy C. Sarich
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James M. Wright
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Pierre Dayer
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Joyce A. Goldstein
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Abstract

The 4′-hydroxylation of the S-enantiomer of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism shows marked interracial heterogeneity, with the poor metabolizer (PM) phenotype representing 2 to 5% of Caucasian and 13 to 23% of Asian populations. Two defective CYP2C19alleles, CYP2C19*2 and CYP2C19*3, have been described which account for ∼87% of Caucasian and >99% of Oriental PM alleles. The present study identifies a new allele (CYP2C19*4) in Caucasian PMs which contains an A → G mutation in the initiation codon. A new polymerase chain reaction-restriction fragment length polymorphism genotyping test was developed, and the incidence of this allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. One of nine putative PMs was heterozygous forCYP2C19*2/CYP2C19*4, which suggests thatCYP2C19*4 represents a defective allele. Six of the seven remaining putative PMs available for genotyping were explained byCYP2C19*2. The frequency of the CYP2C19*4 allele in Caucasians was 0.6%. An additional Caucasian PM from a separate study was also heterozygous for CYP2C19*2 andCYP2C19*4. To verify that CYP2C19*4 represented a defective CYP2C19 allele, the initiation codon of the normal CYP2C19*1 cDNA was mutated to a GTG, and both cDNAs were expressed in yeast. Recombinant CYP2C19 protein was detected by Western blot analysis of colonies transformed with CYP2C19*1 cDNA, but not in those transformed with CYP2C19*4 cDNA. The two cDNAs were also used in an in vitro coupled transcription/translation assay. CYP2C19 protein was translated only from the CYP2C19*1 allele. These data indicate that CYP2C19*4 represents a new PM allele.

Footnotes

  • Send reprint requests to: Dr. Joyce Goldstein, NIEHS, PO Box 12233, Research Triangle Park, NC 27709.

  • ↵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), by USPHS grants GM31304 (G.R.W.); and by Program Project Grant 32165, National Institutes of Health (T.C.S., J.M.W.).

  • ↵2 Current affiliation: University of Florida Shands Cancer Center, Health Science Center, PO Box 100286, Gainesville, FL 32610-0286.

  • ↵3 Current affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.

  • ↵4 The present paper uses a nomenclature for theCYP2C19 alleles based on the recommendations of Dalyet al. (1996). We denote the wild-type allele reported byRomkes et al. (1991) as CYP2C19*1A. A second wild-type allele (C99T, A991 G, Ile331 Val) (Richardson et al., 1997; S.M.F. de Morais, J. Blaisdell and J. A. Goldstein, unpublished data) is designated CYP2C19*1B. The mutant alleles previously reported by our laboratory (deMorais et al., 1994a, b) are designated as follows: CYP2C19m1 is designatedCYP2C19*2, CYP2C19m2 is designatedCYP2C19*3 and CYP2C19m3 is designatedCYP2C19*4.

  • Abbreviations:
    PM
    poor metabolizer
    EM
    extensive metabolizer
    PCR
    polymerase chain reaction
    HI
    hydroxylation index
    CYP
    cytochrome P450
    RFLP
    restriction fragment length polymorphism
    • Received March 25, 1997.
    • Accepted August 21, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherDRUG METABOLISM AND DISPOSITION

A New Genetic Defect in Human CYP2C19: Mutation of the Initiation Codon Is Responsible for Poor Metabolism of S-Mephenytoin

Ronald J. Ferguson, Sonia M.F. De Morais, Simone Benhamou, Christine Bouchardy, Joyce Blaisdell, Gordon Ibeanu, Grant R. Wilkinson, Troy C. Sarich, James M. Wright, Pierre Dayer and Joyce A. Goldstein
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 356-361;

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OtherDRUG METABOLISM AND DISPOSITION

A New Genetic Defect in Human CYP2C19: Mutation of the Initiation Codon Is Responsible for Poor Metabolism of S-Mephenytoin

Ronald J. Ferguson, Sonia M.F. De Morais, Simone Benhamou, Christine Bouchardy, Joyce Blaisdell, Gordon Ibeanu, Grant R. Wilkinson, Troy C. Sarich, James M. Wright, Pierre Dayer and Joyce A. Goldstein
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 356-361;
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