Genetic analysis of the S-mephenytoin polymorphism in a Chinese population.
The 4'-hydroxylation of S-mephenytoin exhibits a polymorphism in humans, with the poor metabolizer phenotype exhibiting a lower frequency in white (3% to 5%) than in Oriental populations (13% to 23%). Two mutations in CYP2C19 (CYP2C19m1 and CYP2C19m2) have recently been described that account for approximately 85% of white and 100% of Japanese poor metabolizers. This study examines whether these mutations account for the poor metabolizer phenotype in the Chinese population. The metabolism of S-mephenytoin exhibited a bimodal distribution in 244 unrelated Chinese subjects, although the distribution of the two phenotypes overlapped. In 75 selected Chinese subjects, CYP2C19 genotype analysis predicted the phenotype with 100% accuracy. The frequency of the poor metabolizer phenotype was approximately 11% (95% confidence interval 7% to 15%). The frequency of the CYP2C19m1 allele was 0.289, whereas that of CYP2C19m2 was 0.044. Homozygous extensive metabolizers had slightly lower ratios of S/R-mephenytoin compared with heterozygous extensive metabolizers, showing a gene-dosage effect. These data show the advantages of genotype analysis in investigations of the mephenytoin phenotype in Oriental subjects.
de Morais
S M
SM
Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park 27709, USA.
Goldstein
J A
JA
Xie
H G
HG
Huang
S L
SL
Lu
Y Q
YQ
Xia
H
H
Xiao
Z S
ZS
Ile
N
N
Zhou
H H
HH
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D002648:Child; D002681:China; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D010641:Phenotype; D011110:Polymorphism, Genetic; D013237:Stereoisomerism
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin