Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin

Abstract

Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, 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), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd.

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.…”

Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

“…Natural lignans from Arctii Fructus could inhibit the activity of P-gp 405 . Furthermore, Arctiin and Arctigenin showed an inhibitory effect on UGTs 406 . UGT1A9, UGT2B7, and UGT2B17 were the major isoforms responsible for the 4′- O -glucuronidation of Arctigenin in human intestine microsomes 407 .…”

Arctigenin Prevents Retinal Edema in a Murine Retinal Vein Occlusion Model

“…Arctigenin and arctiin have many therapeutic properties including anti-tumor and anti-inflammatory activities. 6,7) Since arctiin is metabolized into arctigenin by intestinal bacteria, 8,9) the physiological effects of arctiin in vivo may be attributed to the physiological activity of arctigenin. Arctigenin may affect the vascular endothelial cells because it has reported to suppresses tumor growth via inducing changes of vascular structure.…”