title: Identification of human UDP-glucuronosyltransferase isoforms responsible for the glucuronidation of glycyrrhetinic acid.
abstract: Glycyrrhetinic acid, the active metabolite of glycyrrhizin, is primarily eliminated by glucuronidation reaction in vivo. In spite of the widespread clinical use of glycyrrhizin, UDP-glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of this drug are still unknown. This report identifies and characterizes the UGT isoforms responsible for glycyrrhetinic acid glucuronidation. In the enzymatic kinetic experiment performed with pooled human liver microsomes (HLMs), K(m) was 39.4 microM and V(max) was 609.2 pmol/min/mg protein. Of the baculosomes expressing 12 recombinant UGTs investigated, UGT1A1, 1A3, 2B4 and 2B7 showed catalytic activity and UGT1A3 exhibited the highest activity. K(m) values of recombinant UGT1A3 and 2B7 were 3.4 and 4.4 microM, respectively. Both imipramine (typical substrate of UGT1A3 and 1A4) and flurbiprofen (typical substrate of UGT2B7) inhibit the glucuronidation of glycyrrhetinic acid. Estimated IC(50) values were 138 microM for flurbiprofen and 207 microM for imipramine in the inhibition of the glucuronidation of glycyrrhetinic acid in HLMs. These results suggest that glycyrrhetinic acid glucuronidation is primarily mediated by UGT1A1, 1A3, 2B4 and 2B7.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Feifei
authors.initials: F
authors.lastname: Fu
authors.forename: Jiake
authors.initials: J
authors.lastname: He
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.forename: Lingli
authors.initials: L
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.forename: Xue
authors.initials: X
authors.lastname: Yu
authors.forename: Deen
authors.initials: D
authors.lastname: Han
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
mesh_terms: D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000378:metabolism*; D019695:Glycyrrhizic Acid / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D005480:Flurbiprofen; D014453:Glucuronosyltransferase; D006034:Glycyrrhetinic Acid; D019695:Glycyrrhizic Acid; D020033:Protein Isoforms; D000099148:UGT1A1 Enzyme; C122075:UDP-glucuronosyltransferase, UGT1A3