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Vol. 284, Issue 1, 356-361, 1998
National Institute of Environmental Health Sciences, Research
Triangle Park, North Carolina (R.J.F., S.M.F.d.M., J.B., G.I., J.A.G.),
INSERM U351, Villejuif, France (S.B.),
Geneva Cancer Registry, Geneva,
Switzerland (C.B.),
Department of Pharmacology, Vanderbilt University
School of Medicine, Nashville, Tennessee (G.R.W.),
Department of
Pharmacology and Therapeutics, The University of British Columbia,
Vancouver, B.C., Canada (J.M.W.), and
Geneva University Hospital,
Geneva, Switzerland (P.D.)
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 CYP2C19
alleles, 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 for
CYP2C19*2/CYP2C19*4, which suggests that
CYP2C19*4 represents a defective allele. Six of the seven
remaining putative PMs available for genotyping were explained by
CYP2C19*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 and CYP2C19*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.
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