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

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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.

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This work was supported by the Japan Society for the Promotion of Science (KAKENHI 23659070), Smoking Research Foundation, Takeda Science Foundation and Japan Research Foundation for Clinical Pharmacology. We thank the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support.

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Correspondence to M Hiratsuka.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

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Takahashi, M., Saito, T., Ito, M. et al. Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation. Pharmacogenomics J 15, 26–32 (2015) doi:10.1038/tpj.2014.30

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