CYP2C19 genotyping and associated mephenytoin hydroxylation polymorphism in a Canadian Inuit population.
The CYP2C19-associated oxidation polymorphism of mephenytoin was investigated in an Inuit population living in the high Arctic of Canada. Results were obtained for 152 subjects, of whom 90 were unrelated to first degree relatives. Phenotyping was based on the capillary gas chromatographic determination of the S/R enantiomeric ratio in overnight urine collected after a dose of 100 mg (R,S)-mephenytoin. The phenotype was confirmed by determining the S/R enantiomeric ratio after acid treatment of urine samples, and for some subjects, by determining urinary recovery of 4'-hydroxymephenytoin using capillary electrophoresis analysis. DNA was analysed for the m1 and m2 mutations of CYP2C19. Three of 152 subjects (2.0%; 95% confidence limits: 0.0-4.2%) were phenotypically classified as poor metabolizers (PMs). Genotype analysis characterized three individuals as homozygous, and 28 individuals as heterozygous for the m1 mutation, the remaining individuals being homozygous for the wild-type allele. The genotype of the three PMs was concordant with that of the phenotype. DNA fingerprinting confirmed that these three individuals were genetically unrelated. The allele frequency of the CYP2C19m1 mutation, determined in unrelated subjects, was 0.12 (95% confidence limits: 0.07-0.17). CYP2C19m2 was not detected in this population. Thus, the Canadian Inuit resemble Caucasian rather than Asian populations in both the incidence of PM phenotype and the molecular basis of the polymorphism.
Jurima-Romet
M
M
Bureau of Drug Research, Health Canada, Banting Research Centre 2201C, Tunney's Pasture, Ottawa, Ontario, Canada. mjromet@hph.hwc.ca
Goldstein
J A
JA
LeBelle
M
M
Aubin
R A
RA
Foster
B C
BC
Walop
W
W
Rode
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D004930:Inuit; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic
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