Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes
Publication in refereed journal


摘要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 (IC50 = 1.73 mu M) and CYP2C9 (IC50 = 8.61 mu M), and weak inhibition on CYP2D6 (IC50=30.20 mu M) and CYP3A4 (IC50=33.88 mu M). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (K-i=1.48 mu M), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with K-i values of 3.17 mu M, 24.25 mu M and 35.09 mu M, 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. (C) 2012 Elsevier GmbH. All rights reserved.
著者Zhou XL, Wang Y, Hu T, Or PMY, Wong J, Kwan YW, Wan DCC, Hoi PM, Lai PBS, Yeung JHK
詳細描述To ORKTS: doi: 10.1016/j.phymed.2012.09.021
頁次367 - 374
關鍵詞Cytochrome P450; Miltirone; Molecular docking; Probe substrates; Salvia miltiorrhiza
Web of Science 學科類別Chemistry, Medicinal; CHEMISTRY, MEDICINAL; Integrative & Complementary Medicine; INTEGRATIVE & COMPLEMENTARY MEDICINE; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY; Plant Sciences; PLANT SCIENCES

上次更新時間 2020-27-09 於 01:21