title: Inhibition of UDP-Glucuronosyltransferases (UGTs) Activity by constituents of Schisandra chinensis.
abstract: Structure-activity relationship for the inhibition of Schisandra chinensis's ingredients toward (Uridine-Diphosphate) UDP-glucuronosyltransferases (UGTs) activity was performed in the present study. In vitro incubation system was employed to screen the inhibition capability of S. chinensis's ingredients, and in silico molecular docking method was carried out to explain possible mechanisms. At 100 μM of compounds, the activity of UGTs was inhibited by less than 90% by schisandrol A, schisandrol B, schisandrin, schisandrin C, schisantherin A, gomisin D, and gomisin G. Schisandrin A exerted strong inhibition toward UGT1A1 and UGT1A3, with the residual activity to be 7.9% and 0% of control activity. Schisanhenol exhibited strong inhibition toward UGT2B7, with the residual activity to be 7.9% of control activity. Gomisin J of 100 μM inhibited 91.8% and 93.1% of activity of UGT1A1 and UGT1A9, respectively. Molecular docking prediction indicated different hydrogen bonds interaction resulted in the different inhibition potential induced by subtle structure alteration among schisandrin A, schisandrin, and schisandrin C toward UGT1A1 and UGT1A3: schisandrin A > schisandrin > schisandrin C. The detailed inhibition kinetic evaluation showed the strong inhibition of gomisin J toward UGT1A9 with the inhibition kinetic parameter (Ki ) to be 0.7 μM. Based on the concentrations of gomisin J in the plasma of the rats given with S. chinensis, high herb-drug interaction existed between S. chinensis and drugs mainly undergoing UGT1A9-mediated metabolism. In conclusion, in silico-in vitro method was used to give the inhibition information and possible inhibition mechanism for S. chinensis's components toward UGTs, which guide the clinical application of S. chinensis.
authors.affiliation: Affiliated Zhongshan Hospital of Dalian University, No.6, Jiefang Street, Zhongshan District, Dalian, 116001, China.
authors.forename: Jin-Hui
authors.initials: JH
authors.lastname: Song
authors.affiliation: Affiliated Zhongshan Hospital of Dalian University, No.6, Jiefang Street, Zhongshan District, Dalian, 116001, China.
authors.forename: Li
authors.initials: L
authors.lastname: Cui
authors.affiliation: Dalian University, Dalian, 116622, China.
authors.forename: Li-Bin
authors.initials: LB
authors.lastname: An
authors.affiliation: Dalian University, Dalian, 116622, China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Institute of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.affiliation: Personalized Treatment & Diagnosis Center, No.6, Jiefang Street, Zhongshan District, Dalian, 116001, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Personalized Treatment & Diagnosis Center, No.6, Jiefang Street, Zhongshan District, Dalian, 116001, China.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Wang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Personalized Treatment & Diagnosis Center, No.6, Jiefang Street, Zhongshan District, Dalian, 116001, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Affiliated Zhongshan Hospital of Dalian University, No.6, Jiefang Street, Zhongshan District, Dalian, 116001, China.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Zhao
mesh_terms: D000818:Animals; D034242:Cyclooctanes; D004149:Dioxoles; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D041743:Herb-Drug Interactions; D017705:Lignans; D010936:Plant Extracts / Q000494:pharmacology*; D011083:Polycyclic Compounds; D051381:Rats; D032141:Schisandra / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D034242:Cyclooctanes; D004149:Dioxoles; D004365:Drugs, Chinese Herbal; D017705:Lignans; D010936:Plant Extracts; D011083:Polycyclic Compounds; C520474:schisandrol A; C033585:schizandrol B; C082092:gomisin D; C034734:schizandrin A; C045309:schisanhenol; C034557:schizandrer A; C031409:schizandrin C; D014453:Glucuronosyltransferase; C011105:schizandrin; C082091:gomisin J
keywords: Schisandra chinensis; UDP-glucuronosyltransferases (UGTs); herb-drug interaction; in silico; in vitro