Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28, except CYP2B6.22)

• Published in: Pharmacogenetics and genomics Vol. 20; no. 7; p. 459
• Main Authors: Watanabe, Takashi, Sakuyama, Kanako, Sasaki, Takamitsu, Ishii, Yuya, Ishikawa, Masaaki, Hirasawa, Noriyasu, Hiratsuka, Masahiro
• Format: Journal Article
• Language: English
• Published: United States 01.07.2010
• Subjects: Alleles; Animals; Aryl Hydrocarbon Hydroxylases - genetics; Cercopithecus aethiops; COS Cells; Cytochrome P-450 CYP2B6; Humans; Kinetics; Mutant Proteins - genetics; Oxidoreductases, N-Demethylating - genetics
• ISSN: 1744-6880
• DOI: 10.1097/FPC.0b013e32833bba0e

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.