Isoliquiritigenin showed strong inhibitory effects towards multiple UDP-glucuronosyltransferase (UGT) isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation |
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| Institution: | 1. The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001, China;2. Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of sciences and The first Affiliated Hospital of Liaoning Medical University, No.457, Zhongshan Road, Dalian, 116023, China;3. Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China;4. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, United States |
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| Abstract: | Isoliquiritigenin, a herbal ingredient with chalcone structure, has been speculated to be able to inhibit one of the most drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferase (UGT). Therefore, the aim of the present study was to investigate the inhibition of isoliquiritigenin towards important UGT isoforms in the liver and intestine, including UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9 and 1A10. The recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as probe reactions. The results showed that 100 μM of isoliquiritigenin inhibited the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10 by 95.2%, 76.1%, 78.9%, 87.2%, 67.2%, 94.8%, and 91.7%, respectively. The data fitting using Dixon plot and Lineweaver–Burk plot showed that the inhibition of UGT1A1, UGT1A9 and UGT1A10 by isoliquiritigenin was all best fit to the competitive inhibition, and the second plot using the slopes from the Lineweaver–Burk plot versus isoliquiritigenin concentrations was used to calculate the inhibition kinetic parameter (Ki) to be 0.7 μM, 0.3 μM, and 18.3 μM for UGT1A1, UGT1A9, and UGT1A10, respectively. All these results indicated the risk of clinical application of isoliquiritigenin on the drug–drug interaction and other possible diseases induced by the inhibition of isoliquiritigenin towards these UGT isoforms. |
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