In vitro functional characterization of 37 CYP2C9 allelic isoforms found in Chinese Han population

Acta Pharmacol Sin. 2013 Nov;34(11):1449-56. doi: 10.1038/aps.2013.123. Epub 2013 Sep 30.

Abstract

Aim: Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme that is responsible for the metabolism of approximately 15% of clinically important drugs. The aim of this study was to assess the catalytic characteristics of 37 CYP2C9 allelic isoforms found in Chinese Han population on the metabolism of tolbutamide in vitro.

Methods: The wild-type and 36 CYP2C9 variants were expressed in sf21 insect cells using a baculovirus-mediated expression system. Then the insect microsomes were prepared for assessing the metabolic characteristics of each variant toward the CYP2C9-specific drug substrate tolbutamide.

Results: Of 36 allelic variants tested, the intrinsic clearance values of 2 allelic isoforms (CYP2C9.36 and CYP2C9.51) were much higher than the wild-type CYP2C9.1 protein, 3 allelic isoforms (CYP2C9.11, CYP2C9.56 and N418T) exhibited similar intrinsic clearance values as the wild-type enzyme, whereas the other 31 variants showed significantly reduced intrinsic clearance values, ranging from 0.08% to 66.88%, for tolbutamide.

Conclusion: Our study provides the most comprehensive data concerning the enzymatic activity of the CYP2C9 variants that are present in the Chinese Han population, and our data suggest that most of the carriers of these alleles might be paid more attention when using CYP2C9 mediated drugs clinically.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Asian Continental Ancestry Group
  • China
  • Cytochrome P-450 CYP2C9
  • Humans
  • Isoenzymes
  • Microsomes / enzymology*
  • Sf9 Cells
  • Spodoptera
  • Tolbutamide / metabolism*

Substances

  • Isoenzymes
  • Tolbutamide
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases