Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele.

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Xiao ZS, Goldstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Huang SL, Xu ZH, Zhou HH

Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele.

J Pharmacol Exp Ther. 1997 Apr;281(1):604-9.

PubMed ID

9103550 [ View in PubMed

]

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 (0.366 vs. 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 mutant CYP2C19m1 and/or CYP2C19m2 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).

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Cytochrome P450 2C19	P33261	Details

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Amitriptyline	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	ADR Inferred	Those with the AA or AG genotype are poor metabolizers of amitriptyline	Details
Omeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clobazam	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	ADR Inferred	Clobazem is metabolized into N-desmethylclobazem (NCLB) mostly by CYP3A4. NCLB is primarily metabolized by 2C19. Those with one 2C192 allele mutation (1/2) are intermediate metabolizers of NCLB. Those with two (2/2) mutations will metabolize NCLB poorly in comparisone to extensive metabolizers (1/1). Levels of NCLB can be five times higher in poor metabolizers, and two times higher in intermediate metabolizers as compared to individuals who are extensive metabolizers. The safety and efficacy of clobazem may be affected by polymorphic expression of CYP2C192.	Details
Lansoprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Mephenytoin	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Esomeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clopidogrel	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Proguanil	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*5	Not Available	1297C>T (rs56337013)	Effect Inferred	Poor drug metabolizer.	Details