RRC ID 67286
Author Tsukada C, Saito T, Maekawa M, Mano N, Oda A, Hirasawa N, Hiratsuka M.
Title Functional characterization of 12 allelic variants of CYP2C8 by assessment of paclitaxel 6α-hydroxylation and amodiaquine N-deethylation.
Journal Drug Metab Pharmacokinet
Abstract Cytochrome P450 2C8 (CYP2C8) is one of the enzymes primarily responsible for the metabolism of many drugs, including paclitaxel and amodiaquine. CYP2C8 genetic variants contribute to interindividual variations in the therapeutic efficacy and toxicity of paclitaxel. Although it is difficult to investigate the enzymatic function of most CYP2C8 variants in vivo, this can be investigated in vitro using recombinant CYP2C8 protein variants. The present study used paclitaxel to evaluate 6α-hydroxylase activity and amodiaquine for the N-deethylase activity of wild-type and 11 CYP2C8 variants resulting in amino acid substitutions in vitro. The wild-type and variant CYP2C8 proteins were heterologously expressed in COS-7 cells. Paclitaxel 6α-hydroxylation and amodiaquine N-deethylation activities were determined by measuring the concentrations of 6α-hydroxypaclitaxel and N-desethylamodiaquine, respectively, and the kinetic parameters were calculated. Compared to the wild-type enzyme (CYP2C8.1), CYP2C8.11 and CYP2C8.14 showed little or no activity with either substrate. In addition, the intrinsic clearance values of CYP2C8.8 and CYP2C8.13 for paclitaxel were 68% and 67% that of CYP2C8.1, respectively. In contrast, the CLint values of CYP2C8.2 and CYP2C8.12 were 1.4 and 1.9 times higher than that of CYP2C8.1. These comprehensive findings could inform for further genotype-phenotype studies on interindividual differences in CYP2C8-mediated drug metabolism.
Volume 30(5)
Pages 366-73
Published 2015-10-1
DOI 10.1016/j.dmpk.2015.07.003
PII S1347-4367(15)00043-9
PMID 26427316
MeSH Alleles Amodiaquine / analogs & derivatives Amodiaquine / pharmacokinetics* Animals Aryl Hydrocarbon Hydroxylases / genetics* Aryl Hydrocarbon Hydroxylases / metabolism* COS Cells Chlorocebus aethiops Cloning, Molecular Cytochrome P-450 CYP2C8 / genetics* Cytochrome P-450 CYP2C8 / metabolism* Genetic Variation Genetic Vectors Humans Hydroxylation Models, Molecular Paclitaxel / pharmacokinetics* Polymorphism, Genetic
IF 2.772
Human and Animal Cells COS-7(RCB0539)