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Molecules 2017, 22(6), 1008; doi:10.3390/molecules22061008

In Vitro Comparative Study of the Inhibitory Effects of Mangiferin and Its Aglycone Norathyriol towards UDP-Glucuronosyl Transferase (UGT) Isoforms

1
College of Life Sciences, Nankai University, Tianjin 300071, China
2
Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
3
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
4
Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou 121001, Liaoning, China
5
Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
6
Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China
These two authors equally contributed to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 8 May 2017 / Revised: 12 June 2017 / Accepted: 13 June 2017 / Published: 16 June 2017
(This article belongs to the Section Metabolites)
View Full-Text   |   Download PDF [4010 KB, uploaded 19 June 2017]   |  

Abstract

Mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera Indica L., has been investigated extensively because of its remarkable pharmacological effects. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to investigate the inhibition of mangiferin and aglycone norathyriol towards various isoforms of UGTs in our study, which evaluated the inhibitory capacity of MGF and its aglycone norathyriol (NTR) towards UDP-glucuronosyltransferase (UGT) isoforms. Initial screening experiment showed that deglycosylation of MGF into NTR strongly increased the inhibitory effects towards almost all the tested UGT isoforms at a concentration of 100 μM. Kinetic experiments were performed to further characterize the inhibition of UGT1A3, UGT1A7 and UGT1A9 by NTR. NTR competitively inhibited UGT1A3, UGT1A7 and UGT1A9, with an IC50 value of 8.2, 4.4, and 12.3 μM, and a Ki value of 1.6, 2.0, and 2.8 μM, respectively. In silico docking showed that only NTR could dock into the activity cavity of UGT1A3, UGT1A7 and UGT1A9. The binding free energy of NTR to UGT1A3, 1A7, 1A9 were −7.4, −7.9 and −4.0 kcal/mol, respectively. Based on the inhibition evaluation standard ([I]/Ki < 0.1, low possibility; 0.1 < [I]/Ki < 1, medium possibility; [I]/Ki > 1, high possibility), an in vivo herb–drug interaction between MGF/NTR and drugs mainly undergoing UGT1A3-, UGT1A7- or UGT1A9-catalyzed metabolism might occur when the plasma concentration of NTR is above 1.6, 2.0 and 2.8 μM, respectively. View Full-Text
Keywords: mangiferin; norathyriol; UDP-glucuronosyltransferases (UGTs); herb–drug interactions mangiferin; norathyriol; UDP-glucuronosyltransferases (UGTs); herb–drug interactions
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MDPI and ACS Style

Sun, D.; Zhang, C.-Z.; Ran, R.-X.; Cao, Y.-F.; Du, Z.; Fu, Z.-W.; Huang, C.-T.; Zhao, Z.-Y.; Zhang, W.-H.; Fang, Z.-Z. In Vitro Comparative Study of the Inhibitory Effects of Mangiferin and Its Aglycone Norathyriol towards UDP-Glucuronosyl Transferase (UGT) Isoforms. Molecules 2017, 22, 1008.

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