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

Genetic variations in cytochrome P450 2C19 (CYP2C19) contribute to interindividual variability in the metabolism of therapeuticagents such as clopidogrel. Polymorphisms in CYP2C19 are associated with large interindividual variations in the therapeuticefficacy of clopidogrel. This study evaluated the in vitro oxidation of clopidogrel by 21 CYP2C19 variants harboring amino acidsubstitutions. These CYP2C19 variants were heterologously expressed in COS-7 cells, and the kinetic parameters of clopidogrel2-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 markedlylow activity compared with the wild-type protein CYP2C19.1B. This comprehensive in vitro assessment provided insights intothe specific metabolic activities of CYP2C19 proteins encoded by variant alleles, and this may to be valuable when interpretingthe results of in vivo studies.The Pharmacogenomics Journal (2015) 15, 26–32; doi:10.1038/tpj.2014.30; published online 8 July 2014INTRODUCTIONCytochrome P450 2C19 (CYP2C19) is a major protein within thehuman cytochrome P450 family that metabolizes B10% of allclinically used drugs.