title: Role of human CYP2B6 in S-mephobarbital N-demethylation.
abstract: The role of cytochrome P-450s (CYPs) in S-mephobarbital N-demethylation was investigated by using human liver microsomes and cDNA-expressed CYPs. Among the 10 cDNA-expressed CYPs studied (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), only CYP2B6 could catalyze S-mephobarbital N-demethylation. The apparent K(m) values of human liver microsomes for S-mephobarbital N-demethylation were close to that of cDNA-expressed CYP2B6 (about 250 microM). The N-demethylase activity of S-mephobarbital in 10 human liver microsomes was strongly correlated with immunodetectable CYP2B6 levels (r = 0.920, p<.001). Orphenadrine (300 microM), a CYP2B6 inhibitor, inhibited the N-demethylase activity of S-mephobarbital in human liver microsomes to 29% of control activity. Therefore, it appears that CYP2B6 mainly catalyzes S-mephobarbital N-demethylation in human liver microsomes.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. kaoruk@p.chiba-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
authors.forename: N
authors.initials: N
authors.lastname: Shimada
authors.forename: M
authors.initials: M
authors.lastname: Tani
authors.forename: K
authors.initials: K
authors.lastname: Chiba
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000927:Anticonvulsants / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008618:Mephobarbital / Q000378:metabolism*; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013223:Statistics as Topic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000927:Anticonvulsants; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D008618:Mephobarbital; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating