Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms

Abstract

As one of the main active ingredients from Radix Astragali (RA), orally dosed astragaloside IV (AST) is easily transformed to sapogenin-cycloastragenol (CAG) by deglycosylation in the gastrointestinal tract. Because the potential adverse effects of AST and CAG remain unclear, the present study in this article was carried out to investigate the inhibition effects of AST and CAG on UDP-glucuronosyltransferases (UGTs) to explore potential clinical toxicity. An in vitro UGTs incubation mixture was employed to study the inhibition of AST and CAG towards UGT isoforms. Concentrations of 100 µM for each compound were used to initially screen the inhibitory efficiency. Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all of the tested UGT isoforms, with an IC 50 of 0.84 µM and 11.28 µM for UGT1A8 and UGT2B7, respectively. Ulteriorly, the inhibition type and kinetics of CAG towards UGT1A8 and UGT2B7 were evaluated depending on the initial screening results. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that CAG competitively inhibited UGT1A8 and noncompetitively inhibited UGT2B7. From the second plot drawn with the slopes from the Lineweaver-Burk plot versus the concentrations of CAG, the inhibition constant (Ki) was calculated to be 0.034 µM and 20.98 µM for the inhibition of UGT1A8 and UGT2B7, respectively. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1 > [I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), it was successfully predicted here that an in vivo herb-drug interaction between AST/CAG and drugs mainly undergoing UGT1A8-or UGT2B7-catalyzed metabolism might occur when the plasma concentration of CAG is above 0.034 µM and 20.98 µM, respectively.

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 ].…”

“…UGTs are phase II metabolic enzymes that predominantly catalyze glucuronidation of xenobiotics, including approximately 35% of drugs and consequently, facilitating elimination of glucuronidated metabolites through bile and urine [ 6 , 7 ]. Glucuronidation clears drugs because glucuronidated metabolites have more polarity and water solubility.…”

“…It also detoxifies drugs because glucuronidated metabolites possess less activity or toxicity than their parent forms [ 8 ]. Many cases of UGT inhibition-mediated drug interactions have been reported [ 5 , 7 ] including UGT1A1 inhibition by psoralidin that causes irinotecan’ toxicity [ 9 ], UGT1A3 inhibition by gemfibrozil that enhances susceptibility of statins [ 10 ], UGT1A6 inhibition by silybin that attenuates fenofibrate-induced UGT1A6 [ 11 ], UGT1A6 inhibition by phenobarbital and phenytoin that causes hepatotoxicity of acetamoniphen [ 12 , 13 ], UGT1A9 inhibition by mefenamic acid that changes exposure of dapagliflozin’s metabolite [ 14 ], and UGT2B7 inhibition by valproic acid that changes efficacy and toxicity of zidovudine [ 15 ]. Regulatory agencies have recognized the importance of UGT-mediated drug interactions in drug discovery research and patients’ safety [ 2 , 16 , 17 ].…”

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

“…In our experiments, it was found that MGF and NTR activated UGT 1A10 and deglycosylation of MGF into NTR strongly increased the inhibitory effects towards others tested UGT isoforms except UGT1A10. The deglycosylation of saponin to aglycone always exhibited a different inhibition profile, such as astragaloside IV and cycloastragenol, glucoaurantio-obtusin and aurantio-obtusin, liquiritin and liquiritigenin, icariin and its intestinal metabolites (icariside I, icariside II and icaritin), arctiin and arctigenin, scutellarin and scutellarein, and in most situations, aglycone showed stronger inhibitory effects than saponin [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. In our study, in silico docking method was used to explain why the inhibition potential of NTR was stronger than MGF on the activity of UGT1A3, UGT1A7 and UGT1A9.…”

“…Fluconazole itself is not metabolized by UGT but alter pharmacokinetic parameters of co-administrated zidovudine in AIDS patients, because the glucuronidation of zidovudine by UGT2B7 is strongly inhibited by fluconazole [ 32 ]. Cycloastragenol has been proven to specifically inhibit UGT1A8 and UGT2B7, thus affecting drugs undergoing UGT1A8- and UGT2B7-catalyzed metabolism [ 33 ].…”