PT - JOURNAL ARTICLE AU - Dong-Zhu Tu AU - Xu Mao AU - Feng Zhang AU - Rong-Jing He AU - Jing-Jing Wu AU - Yue Wu AU - Xiao-Hua Zhao AU - Jiang Zheng AU - Guang-Bo Ge TI - <strong>Reversible and </strong><strong>irreversible</strong><strong> inhibition of cytochrome P450 enzymes by methylophiopogonanone A</strong> AID - 10.1124/dmd.120.000325 DP - 2021 Jan 01 TA - Drug Metabolism and Disposition PG - DMD-AR-2020-000325 4099 - http://dmd.aspetjournals.org/content/early/2021/04/01/dmd.120.000325.short 4100 - http://dmd.aspetjournals.org/content/early/2021/04/01/dmd.120.000325.full AB - Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl (MDP) moiety, is one of the major consitituents in the Chinese herb Ophiopogon japonicas. This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes, as well as to decipher the molecular mechanisms for CYP inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYPs1A, 2C8, 2C9, 2C19 and 3A in human liver microsomes (HLMs) in a reversible way, with IC50 values varying from 1.06 μM to 3.43 μM. By contrast, MOA time-, concentration- and NADPH-dependently inhibited CYP2D6 and CYP2E1, along with KI and kinact values of 207 µM and 0.07 min-1 for CYP2D6, as well as 20.9 µM and 0.03 min-1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-qunione intermediate. Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Significance Statement Methylophiopogonanone A (MOA), an abundant homoisoflavonoid isolated from the Chinese herb Ophiopogon japonicas, is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-qunione intermediate.