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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]