title: Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes.
abstract: Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC(50)=1.73 μM) and CYP2C9 (IC(50)=8.61 μM), and weak inhibition on CYP2D6 (IC(50)=30.20 μM) and CYP3A4 (IC(50)=33.88 μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (K(i)=1.48 μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with K(i) values of 3.17 μM, 24.25 μM and 35.09 μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. zhouxuelin@cuhk.edu.hk
authors.forename: Xuelin
authors.initials: X
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.forename: Penelope M Y
authors.initials: PM
authors.lastname: Or
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Kwan
authors.forename: David C C
authors.initials: DC
authors.lastname: Wan
authors.forename: Pui Man
authors.initials: PM
authors.lastname: Hoi
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.forename: John H K
authors.initials: JH
authors.lastname: Yeung
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003915:Dextromethorphan; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver; D062105:Molecular Docking Simulation; D010615:Phenacetin; D010616:Phenanthrenes / Q000494:pharmacology*; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013739:Testosterone; D014044:Tolbutamide
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; C068880:miltirone; D013739:Testosterone; D003915:Dextromethorphan; D014044:Tolbutamide; D010615:Phenacetin