期刊
DRUG METABOLISM AND DISPOSITION
卷 49, 期 6, 页码 459-469出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.120.000325
关键词
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资金
- National Natural Science Foundation of China [81773810, 81922070, 81973286, 81773687]
- National Key Research and Development Program of China [2020YFC0845400, 2017YFC1700200]
- Program of Shanghai Academic/Technology Research Leader [18XD1403600]
- Shanghai Talent Development Fund [2019093]
- Shuguang Program [18SG40]
- Shanghai Education Development Foundation
- Shanghai Municipal Education Commission
- Key R&D and Transformation Science and Technology Cooperation Project of Qinghai Province [2019-HZ-819]
- Program for Innovative Leading Talents of Qinghai Province
Methylophiopogonanone A (MOA), an abundant homoisoflavonoid from Ophiopogon japonicas, acts as a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A, but inactivates CYP2D6 and CYP2E1 through a pathway involving glutathione trapping of a quinone metabolite catalyzed by CYP2D6, 1A2, and 2E1 in human liver microsomes.
Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl moiety, is one of the major constituents in the Chinese herb Ophiopogon japonicas. This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes and to decipher the molecular mechanisms for P450 inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYP1A, 2C8, 2C9, 2C19, and 3A in human liver microsomes (HLMs) in a reversible way, with IC50 values varying from 1.06 to 3.43 mu M. By contrast, MOA time-, concentration-, and NADPH-dependently inhibited CYP2D6 and CYP2E1, along with K-I and k(inact) values of 207 mu M and 0.07 minute(-1) for CYP2D6, as well as 20.9 mu M and 0.03 minutes(-1) for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in an HLM incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone 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 CYP1A, 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 CYP1A, 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 glutathione in a human liver microsome incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate.
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