Functional characterization of CYP2C8.13 and CYP2C8.14: Catalytic activities toward paclitaxel

Nobumitsu Hanioka, Kimiaki Matsumoto, Yoshiro Saito, Shizuo Narimatsu

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Cytochrome P450 2C8 (CYP2C8) plays important roles in the metabolism of various drugs, including the anti-cancer drug, paclitaxel. We recently identified two novel CYP2C8 alleles (CYP2C8*13 and CYP2C8 *14; wild-type, CYP2C8*1A) with non-synonymous single nucleotide polymorphisms in a Japanese population. To precisely investigate the effect of amino acid substitutions (CYP2C8*13, Ile223Met; CYP2C8*14, Ala238Pro) on CYP2C8 function, CYP2C8 proteins of the wild-type (CYP2C8.1) and variants (CYP2C8.13 and CYP2C8.14) were heterologously expressed in yeast cells, and their paclitaxel 6α-hydroxylation activities were determined. The Km, V max and CLint values for paclitaxel 6α-hydroxylation of CYP2C8.1 were 2.3 μM, 4.1 pmol/min./pmol CYP and 1.7 μl/min./pmol CYP, respectively. The Km value of CYP2C8.14 was significantly higher (2.9-fold) than that of CYP2C8.1. The Vmax value of CYP2C8.14 was comparable to that of CYP2C8.1 and the CLint value was reduced to 46% of CYP2C8.1. In contrast, the Km, Vmax and CL int values of CYP2C8.13 were similar to those of CYP2C8.1. These results suggest that Ala238Pro substitution in CYP2C8.14 decreases the affinity toward paclitaxel of the CYP2C8 enzyme, and that the genetic polymorphism of the CYP2C8*14 allele may influence the clinical response to drugs metabolized mainly by CYP2C8.

Original languageEnglish
Pages (from-to)565-569
Number of pages5
JournalBasic and Clinical Pharmacology and Toxicology
Volume107
Issue number1
DOIs
Publication statusPublished - Jul 2010

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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