Molecular docking and enzyme kinetic studies of dihydrotanshinone on metabolism of a model CYP2D6 probe substrate in human liver microsomes
Publication in refereed journal


摘要The effects of Danshen and its active components (tanshinone I, tanshinone IIA, dihydrotanshinone and cryptotanshinone) on CYP2D6 activity was investigated by measuring the metabolism of a model CYP2D6 probe substrate, dextromethorphan to dextrorphan in human pooled liver microsomes. The ethanolic extract of crude Danshen (6.25-100 mu g/ml) decreased dextromethorphan O-demethylation in vitro (IC50 = 23.3 mu g/ml) and the water extract of crude Danshen (0.0625-1 mg/ml) showed no inhibition. A commercially available Danshen pill (31.25-500 mu g/ml) also decreased CYP2D6 activity (IC50 = 265.8 mu g/ml). Among the tanshinones, only dihydrotanshinone significantly inhibited CYP2D6 activity (IC50 = 35.4 mu M), compared to quinidine, a specific CYP2D6 inhibitor (IC50 = 0.9 mu M). Crytotanshinone, tanshinone I and tanshinone IIA produced weak inhibition, with IC20 of 40.8 mu M, 16.5 mu M and 61.4 mu M, respectively. Water soluble components such as salvianolic acid B and danshensu did not affect CYP2D6-mediated metabolism. Enzyme kinetics studies showed that inhibition of CYP2D6 activity by the ethanolic extract of crude Danshen and dihydrotanshinone was concentration-dependent, with K-i values of 4.23 mu g/ml and 2.53 mu M, respectively, compared to quinidine, K-i = 0.41 mu M. Molecular docking study confirmed that dihydrotanshinone and tanshinone I interacted with the Phe120 amino acid residue in the active cavity of CYP2D6 through Pi-Pi interaction, but did not interact with GIu216 and Asp301, the key residues for substrate binding. The logarithm of free binding energy of dihydrotanshinone (-7.6 kcal/mol) to Phe120 was comparable to quinidine (-7.0 kcal/mol) but greater than tanshinone I (-5.4 kcal/mol), indicating dihydrotanshinone has similar affinity to quinidine in binding to the catalytic site on CYP2D6. (C) 2012 Elsevier GmbH. All rights reserved.
著者Zhou XL, Wang Y, Or PMY, Wan DCC, Kwan YW, Yeung JHK
詳細描述To ORKTS: doi: 10.1016/j.phymed.2012.01.005
頁次648 - 657
關鍵詞CYP2D6 activity; Danshen (Salvia miltiorrhiza); Dextromethorphan metabolism; Dihydrotanshinone; Human liver microsomes; Molecular docking
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 2020-18-09 於 00:39