Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28, except CYP2B6.22).
Cytochrome P450 2B6 (CYP2B6) is a potentially important enzyme for the metabolism of clinical drugs, and it exhibits genetic polymorphism. Thus far, 29 allelic variants of CYP2B6 (CYP2B6*1-CYP2B6*29) have been identified. This study aimed to investigate whether 26 of the variant alleles of CYP2B6 (CYP2B6*2-CYP2B6*21 and CYP2B6*23-CYP2B6*28) affect its kinetics in the metabolism of 7-ethoxy-4-trifluoromethylcoumarin (7-EFC) and selegiline. Wild-type CYP2B6.1 and the allelic variants were heterologously expressed in COS-7 cells. In-vitro kinetic analysis revealed that when compared with the wild-type protein CYP2B6.1, CYP2B6.10 and CYP2B6.14 exhibited significantly lower V(max)/K(m) values for selegiline N-demethylation. The kinetic parameters of CYP2B6.8, CYP2B6.11, CYP2B6.12, CYP2B6.13, CYP2B6.15, CYP2B6.18, CYP2B6.21, CYP2B6.24, and CYP2B6.28 could not be determined because these enzymes were inactive in the deethylation of 7-EFC and the N-demethylation/N-depropagylation of selegiline. These findings provide useful information for further genotype-phenotype studies on interindividual differences in the metabolism of CYP2B6 substrate drugs.
Watanabe
Takashi
T
Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Sendai, Japan.
Sakuyama
Kanako
K
Sasaki
Takamitsu
T
Ishii
Yuya
Y
Ishikawa
Masaaki
M
Hirasawa
Noriyasu
N
Hiratsuka
Masahiro
M
D000483:Alleles; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D065702:Cytochrome P-450 CYP2B6; D006801:Humans; D007700:Kinetics; D050505:Mutant Proteins / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*
D050505:Mutant Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating