title: Effects of tanshinones from Salvia miltiorrhiza on CYP2C19 activity in human liver microsomes: enzyme kinetic and molecular docking studies.
abstract: OBJECTIVE
  This study aimed to investigate the effects of five tanshinones, the lipophilic components from Danshen (Salvia miltiorrhiza), on CYP2C19 activity in pooled human liver microsomes (HLMs).
  
  
  METHODS
  The effects of tanshinones on CYP2C19 activity were compared by enzyme inhibition study using omeprazole 5-hydroxylation in pooled HLMs. The inhibition constant (Ki) values and inhibition modes of effective tanshinones were evaluated by enzyme kinetic study. Molecular docking analysis was used to simulate the binding conformations of tanshinones to the active cavity of human CYP2C19.
  
  
  RESULTS
  Dihydrotanshinone and miltirone showed potent inhibitory effects on CYP2C19 activity in a concentration-dependent manner. Tanshinone I showed weaker inhibitory effect, whereas tanshinone IIA and cryptotanshinone had no inhibitory effect. Further enzyme kinetic study showed that the inhibition by dihydrotanshinone and miltirone was a mixed type. The effects of tanshinones were also confirmed by a molecular docking study. Besides, the ethanol extract of Danshen also showed a mixed type of inhibition, whereas the water extract had no inhibitory effect.
  
  
  CONCLUSIONS
  The current findings demonstrate the inhibition of CYP2C19 activity by the ethanol extract of Danshen and its components tanshinones, implicating the potential herb-drug interactions between Danshen and therapeutic agents metabolized by CYP2C19 in clinical practice.
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: taohu1985@hotmail.com.
authors: Tao
authors: T
authors: Hu
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: Xuelin
authors: X
authors: Zhou
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: Lin
authors: L
authors: Wang
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: Penelope M Y
authors: PM
authors: Or
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: John H K
authors: JH
authors: Yeung
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: Yiu Wa
authors: YW
authors: Kwan
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors: Chi Hin
authors: CH
authors: Cho
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D020134:Catalytic Domain; D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19 / Q000737:chemistry / Q000378:metabolism*; D065689:Cytochrome P-450 CYP2C19 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D000431:Ethanol; D041743:Herb-Drug Interactions; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D062105:Molecular Docking Simulation; D010616:Phenanthrenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D027561:Salvia miltiorrhiza / Q000737:chemistry*
chemical_list: D045784:Abietanes; D065689:Cytochrome P-450 CYP2C19 Inhibitors; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; C021751:tanshinone; C028972:dan-shen root extract; C068880:miltirone; D000431:Ethanol; C037886:cryptotanshinone; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C19; Human liver microsomes; Molecular docking; Omeprazole; Tanshinones