An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians.

Article Details

Citation

Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA

An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians.

Pharmacogenetics. 1998 Apr;8(2):129-35.

PubMed ID
10022751 [ View in PubMed
]
Abstract

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism exhibits marked racial heterogeneity, with the poor metabolizer PM phenotype representing 13-23% of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more than 99% of Oriental poor metabolizer alleles but only approximately 87% of Caucasian poor metabolizer alleles. Therefore, additional defects presumably contribute to the poor metabolizer in Caucasians. Recent studies have found a third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C19*5A) (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution in the heme-binding region has been reported in a single Chinese poor metaboliser outlier belonging to the Bai ethnic group. The present study identifies a second variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese poor metabolizers and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent with the conclusion that CYP2C19*5 represents poor metabolizer alleles.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cytochrome P450 2C19P33261Details
Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
AmitriptylineCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableADR InferredThose with the AA or AG genotype are poor metabolizers of amitriptylineDetails
OmeprazoleCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor metabolizer, lower dose requirement, improved drug efficacyDetails
ClobazamCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableADR InferredClobazem is metabolized into N-desmethylclobazem (NCLB) mostly by CYP3A4. NCLB is primarily metabolized by 2C19. Those with one 2C19*2 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 CYP2C19*2.Details
LansoprazoleCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor metabolizer, lower dose requirement, improved drug efficacyDetails
MephenytoinCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor metabolizer, lower dose requirementDetails
EsomeprazoleCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor metabolizer, lower dose requirement, improved drug efficacyDetails
ClopidogrelCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
ProguanilCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor metabolizer, lower dose requirementDetails
GliclazideCytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
CYP2C19*5Not AvailableEffect InferredPoor drug metabolizer.Details