Strong Specific Inhibition of UDP‐glucuronosyltransferase 2B7 by Atractylenolide I and III

• Published in: Phytotherapy research 2016, Vol.30 (1), p.25-30
• Main Authors: Zhang, Qian, Cao, Yun‐Feng, Ran, Rui‐Xue, Li, Rong‐Shan, Wu, Xue, Dong, Pei‐Pei, Zhang, Yan‐Yan, Hu, Cui‐Min, Wang, Wei‐Ming
• Format: Article
• Language: English
• Subjects: atractylenolide I; atractylenolide III; Atractylodes; Drug Interactions; drug-drug interaction; drugs; enzymes; Glucuronosyltransferase - antagonists & inhibitors; Glucuronosyltransferase - metabolism; Humans; hydrogen bonding; hydrophobic bonding; Hymecromone - metabolism; ingredients; Kinetics; Lactones - chemistry; metabolism; molecular models; oral administration; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Recombinant Proteins - metabolism; Sesquiterpenes - chemistry; uridine
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.5496

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. Copyright © 2015 John Wiley & Sons, Ltd.