Abstract Context: Ganoderic acid A (GAA) is usually used to prevent cancers or other diseases, which make it likely to be used with other drugs metabolized by cytochromes P450. Objective: This study investigates the effect of GAA on eight major cytochrome P450 isoforms in human liver microsomes. Material and method: The effects of GAA (100 μM) on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs) with specific substrates for the CYPs, and the enzyme kinetic parameters were calculated. Results: The results showed that GAA inhibited the activity of CYP3A4, 2D6, and 2E1, but did not affect other isoforms. The inhibition of CYP3A4, 2D6, and 2E1 was concentration-dependent with IC50 values of 15.05, 21.83, and 28.35 μM, respectively. Additionally, GAA was not only a non-competitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP2D6 and 2E1, with Ki values of 7.16, 10.07, and 13.45 μM. Meanwhile, the inhibition of CYP3A4 was time-dependent, with the KI/Kinact value of 7.91/0.048 μM/min. Discussion and conclusion: The in vitro study indicated that GAA has the potential to result in drug-drug interactions with other drugs metabolized by CYP3A4, 2D6, and 2E1. Further clinical studies are needed for the identification of this interaction.

中文翻译：

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灵芝酸A对人肝细胞色素P450酶的体外抑制作用

摘要背景：灵芝酸A（GAA）通常用于预防癌症或其他疾病，这使得它可能与其他由细胞色素P450代谢的药物一起使用。目的：本研究调查了 GAA 对人肝微粒体中八种主要细胞色素 P450 亚型的影响。材料和方法：在体外使用人肝微粒体 (HLM) 研究 GAA (100 μM) 对八种人肝脏 CYP 同工型（即 1A2、3A4、2A6、2E1、2D6、2C9、2C19 和 2C8）的影响CYPs 的特定底物，并计算酶动力学参数。结果：结果显示GAA抑制CYP3A4、2D6和2E1的活性，但不影响其他同种型。CYP3A4、2D6 和 2E1 的抑制呈浓度依赖性，IC50 值分别为 15.05、21.83 和 28.35 μM。此外，GAA 不仅是 CYP3A4 的非竞争性抑制剂，还是 CYP2D6 和 2E1 的竞争性抑制剂，Ki 值分别为 7.16、10.07 和 13.45 μM。同时，CYP3A4的抑制具有时间依赖性，KI/Kinact值为7.91/0.048 μM/min。讨论和结论：体外研究表明，GAA 有可能导致与其他经 CYP3A4、2D6 和 2E1 代谢的药物发生药物相互作用。需要进一步的临床研究来确定这种相互作用。体外研究表明，GAA 有可能导致与其他经 CYP3A4、2D6 和 2E1 代谢的药物发生药物相互作用。需要进一步的临床研究来确定这种相互作用。体外研究表明，GAA 有可能导致与其他经 CYP3A4、2D6 和 2E1 代谢的药物发生药物相互作用。需要进一步的临床研究来确定这种相互作用。