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.
Highlights
Pharmacokinetic have revealed thatbioavailability mangiferin is absorbed rapidly and exhibitsto poor bioavailabilityresults in rat [12,13]. This poor may be partially attributed the low bioavailability in rat [12,13]. This poor bioavailability may be partially attributed to the absorption, the hepatic first pass effect that is a phenomenon of drug metabolism whereby the concentration low absorption, the hepatic first pass effect that is a phenomenon of drug metabolism whereby the of a drug is greatly reduced before it reaches the systemic circulation [14,15] and extensive metabolism concentration of a drug is greatly reduced before it reaches the systemic circulation [14,15] and extensive of mangiferin
The inhibitory effects of MGF and NTR on UGT isoforms were studied and led to the conclusion that deglycosylation of MGF to NTR can strongly increase the inhibitory effects to the conclusion that deglycosylation of MGF to NTR can strongly increase the inhibitory effects towards almost all tested UGT isoforms
1A10 and deglycosylation of MGF into NTR strongly increased the inhibitory effects towards others towards others tested UGT isoforms except UGT1A10
Summary
Mangiferin (1,3,6,7-tetrahydroxyxanthone-C-2-β-D-glucoside, MGF, Figure 1), the predominant constituent of extracts of the mango plant Mangifera Indica L., has been investigated extensively becauseMolecules 2017, 22, 1008; doi:10.3390/molecules22061008 www.mdpi.com/journal/molecules of its remarkable pharmacological effects, including antioxidant, anti-inflammatory, antidiabetic, of its remarkable pharmacological effects, including antioxidant, anti-inflammatory, antidiabetic, anticancer, antibacterial, anti-HIV, radioprotective activities and promising diabetes treatment [1,2,3,4,5,6,7,8,9,10,11].anticancer, antibacterial, anti-HIV, radioprotective activities and promising diabetes treatmentPharmacokinetic results have revealed that mangiferin is absorbed rapidly and exhibits poorPharmacokinetic have revealed thatbioavailability mangiferin is absorbed rapidly and exhibitsto poor bioavailability (only 1.2%)results in rat [12,13].This poor may be partially attributed the low bioavailability (only 1.2%) in rat [12,13]. Pharmacokinetic results have revealed that mangiferin is absorbed rapidly and exhibits poor. Pharmacokinetic have revealed thatbioavailability mangiferin is absorbed rapidly and exhibitsto poor bioavailability (only 1.2%)results in rat [12,13]. This poor may be partially attributed the low bioavailability (only 1.2%) in rat [12,13]. Mangiferin itself underwent phase II metabolism into monomethylated, dimethylated, monoglucuronidated, diglucuronidated, monoglucuronidated, to be converted into monomethylated, dimethylated, monoglucuronidated, diglucuronidated, monoglucuronidated, monoglucuronidated and monosulfated conjugates.
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