Methylophiopogonanone A is a naturally occurring broad‐spectrum inhibitor against human UDP‐glucuronosyltransferases: Inhibition behaviours and implication in herb‐drug interactions

Abstract

Methylophiopogonanone A (MOA) is an abundant homoisoflavonoid in the Chinese herb Ophiopogonis Radix. Recent investigations revealed that MOA inhibited several human cytochrome P450 enzymes (CYPs) and stimulated OATP1B1. However, the inhibitory effects of MOA on phase II drugmetabolizing enzymes, such as human UDP-glucuronosyltransferases (hUGTs), have not been well investigated. Herein, the inhibition potentials of MOA on hUGTs were assessed. The results clearly demonstrated that MOA dose-dependently inhibited all tested hUGTs including UGT1A1 (IC 50 = 1.23 μM), one of the most important detoxification enzymes in humans. Further investigations showed that MOA strongly inhibited UGT1A1-catalysed NHPH-O-glucuronidation in a range of biological settings including hUGT1A1, human liver microsomes (HLM) and HeLa cells overexpressing UGT1A1. Inhibition kinetic analyses demonstrated that MOA competitively inhibited UGT1A1-catalysed NHPH-O-glucuronidation in both hUGT1A1 and HLM, with K i values of 0.52 and 1.22 μM, respectively. Collectively, our findings expanded knowledge of the interactions between MOA and human drug-metabolizing enzymes, which would be very helpful for guiding the use of MOA-related herbal products in clinical settings. K E Y W O R D S herb-drug interactions (HDIs), Methylophiopogonanone A (MOA), NHPH-Oglucuronidation, UDP-glucuronosyltransferases (UGTs), UGT1A1 Qi-Hang Zhou and Guang-Hao Zhu contributed equally to this work.

Discovery and Characterization of the Naturally Occurring Inhibitors Against Human Pancreatic Lipase in Ampelopsis grossedentata

“…To investigate the inhibition kinetic types and to determine the inhibition constants (K i ) of two flavonoids (such as myricetin and quercetin) against hPL, the inhibition kinetics were carefully investigated via performing a series of kinetic analyses (34)(35)(36). Briefly, increasing concentrations of each inhibitor were mixed with hPL in the above-mentioned incubation system, while the reactions were started by adding DDAO-ol (at various concentrations) following 3 min pre-incubation at 37 • C. The inhibition constants (K i ) were calculated as depicted in previous studies (37,38).…”

Metabolism-involved drug interactions with traditional Chinese medicines in cardiovascular diseases

“…Methylophiopogonanone A, an active homoisoflavonoid of Ophiopogonis Radix, has been reported to strongly inhibit UGT1A1 (IC 50 = 1.23 μM) and several other UGT isozymes (IC 50 < 8.30 μM) in HLMs [ 137 ]. Six Schisandra lignans in S. chinensis have mild-to-moderate inhibitory effects on UGT1A1 and UGT1A3 activities (IC 50 > 15 μM) in HLMs [ 138 ].…”

Identification of the metabolites of methylophiopogonanone A by ultra‐high‐performance liquid chromatography combined with high‐resolution mass spectrometry

“…12 Besides the interactions with CYPs and transporters, MOA is a naturally occurring broad-spectrum inhibitor of human UDP-glucuronosyltransferases (UGTs), especially the inhibition of UGT 1A1 (IC 50 1.23 μM). 13 Zhou et al have also indicated that MOA is a broad-spectrum substrate of UGTs. 14 These studies did provide some valuable data on the potential drug-drug interactions caused by MOA.…”

“…Chen et al demonstrated that MOA is a modulator of the transporters of OATP1B1 and OATP1B3 12 . Besides the interactions with CYPs and transporters, MOA is a naturally occurring broad‐spectrum inhibitor of human UDP‐glucuronosyltransferases (UGTs), especially the inhibition of UGT 1A1 (IC 50 1.23 μM) 13 . Zhou et al have also indicated that MOA is a broad‐spectrum substrate of UGTs 14 .…”