title: Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III.
abstract: Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs-catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 μM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism.
authors.affiliation: Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, 116001, Liaoning, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, 200032, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Rui-Xue
authors.initials: RX
authors.lastname: Ran
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Rong-Shan
authors.initials: RS
authors.lastname: Li
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian, 116023, China.|Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The Affiliated Zhongshan Hospital of Dalian University, No. 6, Jiefang Street, Dalian, 116001, Zhongshan District, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Institute of integrative Medicine, Dalian Medical University, Dalian, 116044, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of Sciences and The first Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian, 116023, China.|The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, 121001, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Cui-Min
authors.initials: CM
authors.lastname: Hu
authors.affiliation: Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, 116001, Liaoning, China.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Wang
mesh_terms: D004347:Drug Interactions; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006923:Hymecromone / Q000378:metabolism; D007700:Kinetics; D007783:Lactones / Q000737:chemistry*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry*
chemical_list: D007783:Lactones; D020033:Protein Isoforms; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C424804:atractylenolide I; C424802:atractylenolide III; D006923:Hymecromone; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase
keywords: atractylenolide I; atractylenolide III; drug-drug interaction