Identification of new human CYP2C19 alleles (CYP2C196 and CYP2C192B) in a Caucasian poor metabolizer of mephenytoin.

Article Details

Citation Copy to clipboard

Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J

Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin.

J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.

PubMed ID

9732415 [ View in PubMed

]

Abstract

A genetic polymorphism in the metabolism of the anticonvulsant drug S-mephenytoin has been attributed to defective CYP2C19 alleles. This genetic polymorphism displays large interracial differences with the poor metabolizer (PM) phenotype representing 2-5% of Caucasian and 13-23% of Oriental populations. In the present study, we identified two new mutations in CYP2C19 in a single Swiss Caucasian PM outlier (JOB 1) whose apparent genotype (CYP2C19*1/CYP2C19*2) did not agree with his PM phenotype. These mutations consisted of a single base pair mutation (G395A) in exon 3 resulting in an Arg132-->Gln coding change and a (G276C) mutation in exon 2 resulting in a coding change Glu92-->Asp. However, the G276C mutation and the G395A mutation resided on separate alleles. Genotyping tests of a family study of JOB1 showed that the exon 2 change occurred on the CYP2C19*2 allele, which also contained the known splice mutation in exon 5 (this variant is termed CYP2C19*2B to distinguish it from the original splice variant now termed CYP2C19*2A). The exon 3 mutation resided on a separate allele (termed CYP2C19*6). In all other respects this allele was identical to one of two wild-type alleles, CYP2C19*1B. The incidence of CYP2C19*6 in a European Caucasian population phenotyped for mephenytoin metabolism was 0/344 (99% confidence limits of 0 to 0.9%). Seven of 46 Caucasian CYP2C19*2 alleles were CYP2C19*2B(15%) and 85% were CYP2C19*2A. The Arg132Gln mutation was produced by site-directed mutatgenesis and the recombinant protein expressed in a bacterial cDNA expression system. Recombinant CYP2C19 6 had negligible catalytic activity toward S-mephenytoin compared with CYP2C19 1B, which is consistent with the conclusion that CYP2C19*6 represents a PM allele. Thus, the new CYP2C19*6 allele contributes to the PM phenotype in Caucasians.

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*2B	Not Available	681G>A (rs4244285)	ADR Inferred	Those with the AA or AG genotype are poor metabolizers of amitriptyline	Details
Amitriptyline	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	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*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Omeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clobazam	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2B	Not Available	681G>A (rs4244285)	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
Clobazam	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	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*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Lansoprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Mephenytoin	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Mephenytoin	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Esomeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Esomeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clopidogrel	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Clopidogrel	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	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*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Proguanil	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*2B	Not Available	681G>A (rs4244285)	Effect Inferred	Poor drug metabolizer.	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*6	Not Available	395G>A (rs72552267)	Effect Inferred	Poor drug metabolizer.	Details