| Identification of human UDP-glucuronosyltransferase isoforms responsible for the glucuronidation of glycyrrhetinic acid. | |
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MedLine Citation:
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PMID: 20045987 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Yang Lu; Jing Zhu; Xijing Chen; Ning Li; Feifei Fu; Jiake He; Guangji Wang; Lingli Zhang; Yi Zheng; Zhixia Qiu; Xue Yu; Deen Han; Lei Wu |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Drug metabolism and pharmacokinetics Volume: 24 ISSN: 1880-0920 ISO Abbreviation: Drug Metab. Pharmacokinet. Publication Date: 2009 |
Date Detail:
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Created Date: 2010-01-04 Completed Date: 2010-04-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101164773 Medline TA: Drug Metab Pharmacokinet Country: Japan |
Other Details:
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Languages: eng Pagination: 523-8 Citation Subset: IM |
Affiliation:
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Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Jiangsu, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Dose-Response Relationship, Drug Flurbiprofen / metabolism* Glucuronosyltransferase / metabolism* Glycyrrhetinic Acid / metabolism* Glycyrrhizic Acid / metabolism Humans Kinetics Metabolic Clearance Rate Microsomes, Liver / drug effects, metabolism Protein Isoforms / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Protein Isoforms; 1405-86-3/Glycyrrhizic Acid; 471-53-4/Glycyrrhetinic Acid; 5104-49-4/Flurbiprofen; EC 2.4.1.-/UDP-glucuronosyltransferase, UGT1A3; EC 2.4.1.-/bilirubin uridine-diphosphoglucuronosyl transferase 1A1; EC 2.4.1.17/Glucuronosyltransferase |
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