title: Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites.
abstract: 1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC50values for daphnetin (0.51∼0.53 μM) and 8-O-methyldaphnetin (22.5∼24.3 μM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (Ki) between daphnetin (competitive, 0.37 μM) and 8-O-methyldaphnetin (noncompetitive, 25.7 μM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro-in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin. 3. With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.
authors.affiliation: a Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China.|b Second Affiliated Hospital of Dalian Medical University , Dalian , China.|c Graduate University of Chinese Academy of Sciences , Beijing , China , and.
authors.forename: Si-Cheng
authors.initials: SC
authors.lastname: Liang
authors.affiliation: a Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: a Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China.
authors.forename: Yang-Liu
authors.initials: YL
authors.lastname: Xia
authors.affiliation: d College of Pharmacy, Dalian Medical University , Dalian , China.
authors.forename: Dong
authors.initials: D
authors.lastname: Pei-Pei
authors.affiliation: a Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China.
authors.forename: Wang
authors.initials: W
authors.lastname: Ping
authors.affiliation: a Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China.|b Second Affiliated Hospital of Dalian Medical University , Dalian , China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Qi
authors.affiliation: b Second Affiliated Hospital of Dalian Medical University , Dalian , China.
authors.forename: Tu
authors.initials: T
authors.lastname: Cai-Xia
authors.affiliation: a Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ling
mesh_terms: D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004298:Dopamine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D050217:Metabolic Detoxication, Phase II; D008745:Methylation; D014468:Umbelliferones / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D014468:Umbelliferones; D002394:Catechol O-Methyltransferase; D004298:Dopamine; C039952:daphnetin
keywords: 8-O-methyldaphnetin; COMT inhibitor; Daphnetin; Phase II metabolite; ligand–protein interaction; structural modification