Functional assessment of 12 rare allelic cyp2c9 variants identified in a population of 4773 japanese individuals

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Abstract

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contrib-utes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxyla-tion were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydrox-ylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appro-priate warfarin dose.

Original languageEnglish
Article number94
Pages (from-to)1-17
Number of pages17
JournalJournal of Personalized Medicine
Volume11
Issue number2
DOIs
Publication statusPublished - 2021 Feb

Keywords

  • (S)-warfarin
  • Cytochrome P450 2C9
  • Drug metabolism
  • Genetic variation
  • Tolbutamide

ASJC Scopus subject areas

  • Medicine (miscellaneous)

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