title: Demethylzeylasteral exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A6 and 2B7.
abstract: Inhibition of UDP-glucuronosyltransferase (UGT) isoforms can result in severe clinical results, including clinical drug-drug interactions (DDI) and metabolic disorders of endogenous substances. The present study aims to investigate the inhibition of demethylzeylasteral (an important active component isolated from Tripterygium wilfordii Hook F.) towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7. The results showed that 100 μM of demethylzeylasteral exhibited strong inhibition towards UGT1A6 and UGT2B7, with negligible influence towards UGT1A9. Furthermore, Dixon and Lineweaver-Burk plots showed the inhibition of UGT1A6 and UGT2B7 by demethylzeylasteral was best fit to competitive inhibition, and the inhibition kinetic parameters (Ki) were calculated to be 0.6 μM and 17.3 μM for UGT1A6 and UGT2B7, respectively. This kind of inhibitory effect need much attention when demethylzeylasteral and demethylzeyasteral-containing herbs (e.g., Tripterygium wilfordii Hook F.) were co-administered with the drugs mainly undergoing UGT1A6, UGT2B7-catalyzed metabolism. However, when extrapolating the in vivo clinical results using our present in vitro data, many complex factors might affect final results, including the contribution of UGT1A6 and UGT2B7 to the metabolism of compounds, and the herbal or patients' factors affecting the in vivo concentration of demethylzeylasteral.
authors.affiliation: Department of Nephrology, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu 223300, China. zhaojinwei1985@gmail.com
authors.forename: Jin-Wen
authors.initials: JW
authors.lastname: Zhao
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Lian-Hua
authors.initials: LH
authors.lastname: Cheng
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Ji
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000737:chemistry; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry*; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014315:Triterpenes; C000715591:UGT1A9 protein, human; C099855:demethylzeylasteral; D006923:Hymecromone; C110655:UDP-glucuronosyltransferase, UGT1A6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9