Functional characterization of two novel CYP2C19 variants (CYP2C19*18 and CYP2C19*19) found in a Japanese population

N. Hanioka, Y. Tsuneto, Y. Saito, T. Sumada, K. Maekawa, K. Saito, J. Sawada, S. Narimatsu

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13 Citations (Scopus)

Abstract

Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of a wide range of therapeutic drugs and exhibits genetic polymorphism with interindividual differences in metabolic activity. We have previously described two CYP2C19 allelic variants, namely CYP2C19*18 and CYP2C19*19 with Arg329His/Ile331Val and Ser51Gly/Ile331Val substitutions, respectively. In order to investigate precisely the effect of amino acid substitutions on CYP2C19 function, CYP2C19 proteins of the wild-type (CYP2C19.1B having Ile331Val) and variants (CYP2C19.18 and CYP2C19.19) were heterologously expressed in yeast cells, and their S-mephenytoin 4'-hydroxylation activities were determined. The Km value of CYP2C19.19 for S-mephenytoin 4'-hydroxylation was significantly higher (3.0-fold) than that of CYP2C19.1B. Although no significant differences in Vmax values on the basis of microsomal and functional CYP protein levels were observed between CYP2C19.1B and CYP2C19.19, the Vmax/Km values of CYP2C19.19 were significantly reduced to 29-47% of CYP2C19.1B. By contrast, the Km, Vmax or Vmax/Km values of CYP2C19.18 were similar to those of CYP2C19.1B. These results suggest that Ser51Gly substitution in CYP2C19.19 decreases the affinity toward S-mephenytoin of CYP2C19 enzyme, and imply that the genetic polymorphism of CYP2C19*19 also causes variations in the clinical response to drugs metabolized by CYP2C19.

Original languageEnglish
Pages (from-to)342-355
Number of pages14
JournalXenobiotica
Volume37
Issue number4
DOIs
Publication statusPublished - Apr 2007
Externally publishedYes

Keywords

  • CYP2C19
  • CYP2C19*18
  • CYP2C19*19
  • Genetic polymorphism
  • S-mephenytoin 4'-hydroxylation

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

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    Hanioka, N., Tsuneto, Y., Saito, Y., Sumada, T., Maekawa, K., Saito, K., Sawada, J., & Narimatsu, S. (2007). Functional characterization of two novel CYP2C19 variants (CYP2C19*18 and CYP2C19*19) found in a Japanese population. Xenobiotica, 37(4), 342-355. https://doi.org/10.1080/00498250601127038