Debrisoquine and mephenytoin oxidation in Sinhalese: a population study.
The frequency distributions of the 0-8 h urinary metabolic ratios of debrisoquine and mephenytoin were measured in 111 healthy, unrelated Sinhalese resident in Sri Lanka. Blood samples were taken from 77 of these subjects for CYP2D6 genotyping. Bimodality in the distribution of the log10 debrisoquine/4-hydroxydebrisoquine ratio was not evident from visual inspection and by kernel density analysis. The results of genotyping indicated that 82% of the population were either homozygous for the wild-type CYP2D6 gene or heterozygous for the wild type allele and the whole gene deletion. Eighteen per cent of the Sinhalese population were heterozygous for the CYP2D6B mutation and the wild-type allele. All of these genotypes give rise to the extensive metaboliser phenotype in white Caucasians. No CYP2D6A mutations were identified and no individuals who were homozygous for the mutant alleles were detected, which is in accord with an absence of phenotypic poor metabolisers of debrisoquine. The mutant CYP2D6 allele frequency in Sinhalese (9%) is only half that observed in white Caucasians. The S/R-mephenytoin ratio ranged from 0.09 to 2.27 (median 0.38). By visual inspection and kernel density analysis the distribution of the S/R-mephenytoin ratio was bimodal and, using a value of 0.9 for the antimode, 16 (14%) subjects were poor metabolisers. In conclusion, the prevalence of the poor metaboliser phenotype in Sinhalese appears much lower for debrisoquine and higher for mephenytoin than in white Caucasians. These findings are similar to those observed in Indians living in Bombay and in Oriental populations.
Weerasuriya
K
K
Department of Pharmacology, University of Colombo, Sri Lanka.
Jayakody
R L
RL
Smith
C A
CA
Wolf
C R
CR
Tucker
G T
GT
Lennard
M S
MS
D000328:Adult; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000097:blood / Q000235:genetics*; D003647:Debrisoquin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000097:blood / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D013188:Sri Lanka; D044465:White People / Q000235:genetics
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D008617:Mephenytoin; D003647:Debrisoquin