Abstract
The incidence of the S-mephenytoin polymorphism was compared in two Chinese ethnic groups, Han (n = 101) and Bai (n = 202) by phenotype and genotype analysis. The frequency of poor metabolizers (PMs) in Han vs. Bai subjects was 19.8% vs. 13.4%. Han subjects had a higher frequency of the mutant CYP2C19m1 allele (0.366vs. 0.257, P < .01) and a lower frequency of the wild-type allele (0.559 vs. 0.688, P < .01) than Bai subjects, which is consistent with the difference in the frequencies of PMs between the two ethnic groups. This results in a lower percentage of homozygous wild-type extensive metabolizers of mephenytoin (EMs) in Han subjects than in Bai subjects (40% vs. 59%, P = .005). Therefore, Han subjects may be more susceptible than Bai subjects to the drugs metabolized by the CYP2C19 enzyme. Ratios of urinary S/R-mephenytoin in homozygous EMs were lower than those of heterozygous EMs for both Han and Bai subjects, which shows a gene-dosage effect. Genotype analysis identified all but one PM as homozygous or heterozygous for the two known mutantCYP2C19m1 and/orCYP2C19m2 alleles. A single Bai PM outlier was shown to be heterozygous for CYP2C19m1 and a new mutant CYP2C19 allele containing a single amino acid change of Arg433 → Trp433. A genotyping test demonstrated that only this one individual carried this rare allele (frequency of 0.0025 in Bai subjects).
Footnotes
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Send reprint requests to: Joyce Goldstein, Ph.D., NIEHS, P.O. Box 12233, Research Triangle Park, NC 27709; or Dr. Hong-Hao Zhou, Professor and Vice-President, Hunan Medical University, Changsha, Hunan 41007B, China.
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↵1 Supported by National Natural Science Foundation of China grants 39330230, 39270794 and 39460079 and by China Medical Board grant 92-568 and the National Institute of Environmental Health Sciences, Research Triangle Park, NC.
- Abbreviations:
- PMs
- poor metabolizers of mephenytoin
- EMs
- extensive metabolizers of mephenytoin
- PCR
- polymerase chain reaction
- CYP2C19wt
- normal (wild-type allele)
- CYP2C19m1 and CYP2C19m2
- mutant CYP2C19 alleles
- 4′-OH-M
- 4′-hydroxymephenytoin
- Received July 18, 1996.
- Accepted December 11, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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