title: Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol.
abstract: Human liver microsomal cytochrome P450s (P450s or CYP) involved in the oxidative biotransformation of the anesthetic agent propofol were investigated. Of six cDNA-expressed human P450 enzymes tested, CYP2B6 and CYP1A2, followed by CYP3A4, had high catalytic activities at a 20 microM propofol concentration, corresponding to clinical plasma levels. K(m) and k(cat) values for propofol omega- and 4-hydroxyation were 27 microM and 21 nmol omega-hydroxypropofol formed/min/nmol CYP2B6 and 30 microM and 42 nmol 4-hydroxypropofol formed/min/nmol CYP2B6, respectively. CYP2B6 expressed in HepG2 cells also effectively catalyzed propofol omega- and 4-hydroxylation. In a panel of individual human liver microsomes, propofol omega- and 4-hydroxylation activities (at the substrate concentration of 20 microM) were highly correlated with CYP2B6 contents, and moderately with CYP3A4 contents. Anti-CYP2B6 antibody inhibited both omega- and 4-hydroxylation activities in human liver samples that contained relatively high levels of CYP2B6, whereas alpha-naphthoflavone and an anti-CYP1A2 antibody showed inhibitory effects on the 4-hydroxylation activity in a liver microsomal sample in which the CYP1A2 level was relatively high. These results suggest that CYP2B6 has an important role in propofol omega- and 4-hydroxylation in human livers and that the hepatic contents of CYP2B6, CYP3A4, and CYP1A2 determine which P450 enzymes play major roles in propofol oxidation in individual humans.
authors.affiliation: Showa Pharmaceutical University, Gakuen, Machida, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Murayama
authors.forename: M
authors.initials: M
authors.lastname: Minoshima
authors.forename: M
authors.initials: M
authors.lastname: Shimizu
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: H
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000201:enzymology; D015742:Propofol / Q000493:pharmacokinetics*; D013250:Steroid Hydroxylases / Q000502:physiology*
chemical_list: D018686:Anesthetics, Intravenous; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D015742:Propofol