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

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.

Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling

“…Our results demonstrated MGF metabolite norathyriol shown more potent effect to decrease intracellular TG content, as well as regulating SREBP-1c activity in SO-induced TG accumulation HepG2 cells, compared with MGF. It is reported that norathyriol was a competitive inhibitor of protein tyrosine phosphatase 1B ( Ding et al, 2014 ) and UDP-glucuronosyltransferase isoforms ( Sun et al, 2017 ) to improve glucose homeostasis. In this study, we firstly reported the lipid lowering effect of norathyriol and its underlying mechanism in regulating hepatic lipid metabolism.…”

Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity

“…Inhibition of drug-metabolic enzymes in drug combination therapies is considered an important origin of adverse effects. It can lead to withdrawal of several approved drugs from the markets, causing clinical problems and economic losses [ 7 , 26 ]. Along with the upsurge of herb–drug combinations, inhibition of herbs towards drug-metabolic enzymes in HDIs has been raised as an important reason that limits clinical applications of herbs and drugs [ 17 , 27 ].…”

“…However, in vitro results referring the inhibitory effects of herbs based on IC 50 and K i values are not sufficient to provide relevance to in vivo results especially at clinical levels. This is because more various metabolic pathways and other elimination pathways except metabolism (e.g., urinary excretion or biliary excretion) can be involved in HDIs in vivo [ 26 , 31 , 32 ]. For example, discrepancies of HDI for milk thistle, garlic extract, Panax quinquefolius , and Panax ginseng between in vitro and clinical results have been reported [ 18 , 31 , 33 , 34 , 35 ].…”

“…However, initial evaluation of HDIs at a clinical level has been a concern due to serious problems with HDI. Hence, prediction of HDIs at preclinical level has been utilized as basic evidence to provide the potential of HDIs and its underlying mechanisms along with in vitro results [ 18 , 26 ].…”

“…To predict the magnitude of HDI as described in drug-drug interactions, the most common equation for HDI prediction is based on in vivo AUC alternation of a drug as a substrate and in vitro K i and in vivo concentration of herb as an inhibitor as previously reported [ 26 , 31 , 36 ]. Parameters used to explain in vivo and in vitro inhibition potency should dictate the likelihood of pharmacokinetic drug interactions as Equation (1) …”