title: Regioselective glucuronidation of oxyresveratrol, a natural hydroxystilbene, by human liver and intestinal microsomes and recombinant UGTs.
abstract: Oxyresveratrol (OXY) is a natural hydroxystilbene that shows similar bioactivity but better water solubility than resveratrol. This study aims to characterize its glucuronidation kinetics in human liver (HLMs) and intestinal (HIMs) microsomes and identify the main UDP-glucuronosyltransferase (UGT) isoforms involved. Three and four mono-glucuronides of OXY were generated in HIMs and HLMs, respectively, with oxyresveratrol-2-O-β-D-glucuronosyl (G4) as the major metabolite in both organs. The kinetics of G4 formation fit a sigmoidal model in HLMs and biphasic kinetics in HIMs. Multiple UGT isoforms catalyzed G4 formation with the highest activity observed with UGT1A9 followed by UGT1A1. G4 formation by both isoforms followed substrate inhibition kinetics. Propofol (UGT1A9 inhibitor) effectively blocked G4 generation in HLMs (IC50 63.7 ± 11.6 µM), whereas the UGT1A1 inhibitor bilirubin only produced partial inhibition in HLMs and HIMs. These findings shed light on the metabolic mechanism of OXY and arouse awareness of drug interactions.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Mei
authors.initials: M
authors.lastname: Mei
authors.forename: Jianqing
authors.initials: J
authors.lastname: Ruan
authors.forename: Wenjin
authors.initials: W
authors.lastname: Wu
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.forename: Ru
authors.initials: R
authors.lastname: Yan
mesh_terms: D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism*; D013267:Stilbenes / Q000378:metabolism*; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D020719:Glucuronides; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D010936:Plant Extracts; D011994:Recombinant Proteins; D013267:Stilbenes; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C034912:puag-haad