Functional characterization of 32 CYP2C9 allelic variants

Y. Niinuma; T. Saito; M. Takahashi; C. Tsukada; Mi Ito; N. Hirasawa; M. Hiratsuka

doi:10.1038/tpj.2013.22

Functional characterization of 32 CYP2C9 allelic variants

Y. Niinuma, T. Saito, M. Takahashi, C. Tsukada, Mi Ito, N. Hirasawa, M. Hiratsuka

PHA - Pharmacy

Tohoku University

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

Abstract

Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy.

Original language	English
Pages (from-to)	107-114
Number of pages	8
Journal	Pharmacogenomics Journal
Volume	14
Issue number	2
DOIs	https://doi.org/10.1038/tpj.2013.22
Publication status	Published - 2014 Apr

Keywords

CYP2C9
Cytochrome P450
Genetic polymorphisms
Tolbutamide
Warfarin

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10.1038/tpj.2013.22

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title = "Functional characterization of 32 CYP2C9 allelic variants",

abstract = "Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy.",

keywords = "CYP2C9, Cytochrome P450, Genetic polymorphisms, Tolbutamide, Warfarin",

author = "Y. Niinuma and T. Saito and M. Takahashi and C. Tsukada and Mi Ito and N. Hirasawa and M. Hiratsuka",

note = "Funding Information: This work was supported by the Japan Society for the Promotion of Science (KAKENHI 23659070), in part by a grant from the 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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doi = "10.1038/tpj.2013.22",

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AU - Niinuma, Y.

AU - Saito, T.

AU - Takahashi, M.

AU - Tsukada, C.

AU - Ito, Mi

AU - Hirasawa, N.

AU - Hiratsuka, M.

N1 - Funding Information: This work was supported by the Japan Society for the Promotion of Science (KAKENHI 23659070), in part by a grant from the 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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N2 - Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy.

AB - Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy.

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Functional characterization of 32 CYP2C9 allelic variants

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