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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 drug‐metabolizing 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 (IC50 = 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 Ki 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. [ABSTRACT FROM AUTHOR]

Strong inhibition of the human UDP-glucuronosyltransferase enzymes (UGTs) may lead to undesirable effects, including hyperbilirubinaemia and drug/herb-drug interactions. Currently, there is no good way to examine the inhibitory effects and specificities of compounds toward all the important human UGTs, side-by-side and under identical conditions. Herein, we report a new, broad-spectrum substrate for human UGTs and its uses in screening and characterizing of UGT inhibitors. Following screening a variety of phenolic compound(s), we have found that methylophiopogonanone A (MOA) can be readily O -glucuronidated by all tested human UGTs, including the typical N -glucuronidating enzymes UGT1A4 and UGT2B10. MOA- O -glucuronidation yielded a single mono- O -glucuronide that was biosynthesized and purified for structural characterization and for constructing an LC-UV based MOA- O -glucuronidation activity assay, which was then used for investigating MOA- O -glucuronidation kinetics in recombinant human UGTs. The derived K m values were crucial for selecting the most suitable assay conditions for assessing inhibitory potentials and specificity of test compound(s). Furthermore, the inhibitory effects and specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate for all tested UGTs. Collectively, MOA is a broad-spectrum substrate for the human UGTs, which offers a new and practical tool for assessing inhibitory effects and specificities of UGT inhibitors. • MOA is a broad substrate for human UGTs with O -glucuronidation activity. • MOA- O -glucuronidation kinetics in 13 human UGTs were investigated. • An LC-UV based MOA- O -glucuronidation activity assay was developed and used for screening and characterizing UGT inhibitors. • The specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate. [ABSTRACT FROM AUTHOR]