title: Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin.
abstract: Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, respectively. Based on the inhibition evaluation standard ([I]/Ki  < 0.1, low possibility; 0.1 < [I]/Ki  < 1, medium possibility; [I]/Ki  > 1, high possibility), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmacy, the Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou, Zhejiang Province, P.R China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, P.R China.|Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P.R China.
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of pharmacy, Tianjin Central Hospital of Gynecology Obstetrics, 156 Nankai 3rd Road, Nankai District, Tianjin, 300100, P.R China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P.R China.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, the Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Western Road, Wenzhou, Zhejiang Province, P.R China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Cui
authors.affiliation: Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P.R China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhang
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
mesh_terms: D005663:Furans / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D041743:Herb-Drug Interactions; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D017705:Lignans / Q000494:pharmacology*
chemical_list: D005663:Furans; D005960:Glucosides; D007527:Isoenzymes; D017705:Lignans; D014453:Glucuronosyltransferase; C077992:arctiin; C071942:arctigenin
keywords: UDP-glucuronosyltransferases (UGTs); arctigenin; arctiin; herb-drug interaction