Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation.

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Takahashi M, Saito T, Ito M, Tsukada C, Katono Y, Hosono H, Maekawa M, Shimada M, Mano N, Oda A, Hirasawa N, Hiratsuka M

Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation.

Pharmacogenomics J. 2015 Feb;15(1):26-32. doi: 10.1038/tpj.2014.30. Epub 2014 Jul 8.

PubMed ID

25001882 [ View in PubMed

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Abstract

Genetic variations in cytochrome P450 2C19 (CYP2C19) contribute to interindividual variability in the metabolism of therapeutic agents such as clopidogrel. Polymorphisms in CYP2C19 are associated with large interindividual variations in the therapeutic efficacy of clopidogrel. This study evaluated the in vitro oxidation of clopidogrel by 21 CYP2C19 variants harboring amino acid substitutions. These CYP2C19 variants were heterologously expressed in COS-7 cells, and the kinetic parameters of clopidogrel 2-oxidation were estimated. Among the 21 CYP2C19 variants, 12 (that is, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.14, CYP2C19.16, CYP2C19.19, CYP2C19.22, CYP2C19.24 and CYP2C19.25) showed no or markedly low activity compared with the wild-type protein CYP2C19.1B. This comprehensive in vitro assessment provided insights into the specific metabolic activities of CYP2C19 proteins encoded by variant alleles, and this may to be valuable when interpreting the results of in vivo studies.

DrugBank Data that Cites this Article

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*22	Not Available	557G>C (rs140278421) 991A>G	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*22	Not Available	557G>C (rs140278421) 991A>G	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clobazam	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*22	Not Available	557G>C (rs140278421) 991A>G	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*22	Not Available	557G>C (rs140278421) 991A>G	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Mephenytoin	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*22	Not Available	557G>C (rs140278421) 991A>G	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Esomeprazole	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*22	Not Available	557G>C (rs140278421) 991A>G	Effect Inferred	Poor metabolizer, lower dose requirement, improved drug efficacy	Details
Clopidogrel	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*22	Not Available	557G>C (rs140278421) 991A>G	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*22	Not Available	557G>C (rs140278421) 991A>G	Effect Inferred	Poor metabolizer, lower dose requirement	Details
Gliclazide	Cytochrome P450 2C19 Gene symbol: CYP2C19 UniProt: P33261	CYP2C19*22	Not Available	557G>C (rs140278421) 991A>G	Effect Inferred	Poor drug metabolizer.	Details