Methysticin 作为基于机制的细胞色素 P450 2C9 灭活剂,Chemical Research in Toxicology

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Methysticin 作为基于机制的细胞色素 P450 2C9 灭活剂
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2022-05-18 , DOI: 10.1021/acs.chemrestox.2c00098
Qiuying Zhang ₁ , Hui Liu ₂ , Dongmei Wu ₁ , Hongyan Yu ₁ , Kun Wang ₁ , Weijie Jiao ₁ , Xu Zhao ₁

Affiliation

Methysticin 是从Piper methysticum Forst中提取的天然存在的生物活性成分之一。在本研究中，我们打算研究甲基霉素对细胞色素 P450 (P450) 酶的抑制作用。使用双氯芬酸作为探针底物，Methysticin 对 CYP2C9 表现出时间、浓度和 NADPH 依赖性抑制。在存在 NADPH 的情况下，与人肝微粒体预孵育 30 分钟后，约 85% 的 CYP2C9 活性被 50 μM methysticin 抑制。动力学参数K _I、k _inact和t _1/2,inact分别为 13.32 ± 1.35 μM、0.054 ± 0.005 min ^–1，和 12.83 ± 3.23 分钟，分别。Sulfaphenazole（CYP2C9 的竞争性抑制剂）对 methysticin 诱导的 CYP2C9 失活显示出显着的保护作用。然而，过氧化氢酶/超氧化物歧化酶或谷胱甘肽 (GSH) 的加入没有显示出这种保护作用。_{由于 K 3} Fe(CN) ₆恢复了 14.96% 的 CYP2C9 活性，因此假定卡宾中间体参与了 methysticin 诱导的 CYP2C9 失活。methysticin 衍生的邻依赖于NADPH的-醌中间体被GSH捕获，并且该中间体被认为与CYP2C9失活有关。CYP1A2、2C9 和 3A4 是负责 methysticin 生物活化的主要酶。总之，目前的工作表明，methysticin 是一种基于机制的 CYP2C9 灭活剂。邻醌和卡宾中间体似乎都参与了由甲基霉素诱导的 CYP2C9 的失活。

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Methysticin Acts as a Mechanism-Based Inactivator of Cytochrome P450 2C9

Methysticin is one of the naturally occurring bioactive constituents extracted from Piper methysticum Forst. In the present study, we intended to investigate the inhibitory effect of methysticin on cytochrome P450 (P450) enzymes. Methysticin exhibited time-, concentration-, and NADPH-dependent inhibition on CYP2C9 using diclofenac as a probe substrate. Approximately 85% of CYP2C9 activity was inhibited by methysticin at 50 μM after a 30 min preincubation with human liver microsomes in the presence of NADPH. The kinetic parameters K_I, k_inact, and t_1/2,inact were 13.32 ± 1.35 μM, 0.054 ± 0.005 min^–1, and 12.83 ± 3.23 min, respectively. Sulfaphenazole (competitive inhibitor of CYP2C9) displayed a significant protective effect on methysticin-induced CYP2C9 inactivation. However, the inclusion of catalase/superoxide dismutase or glutathione (GSH) showed no such protection. A carbene intermediate was postulated to be involved in methysticin-induced CYP2C9 inactivation as K₃Fe(CN)₆ recovered 14.96% of CYP2C9 activity. A methysticin-derived ortho-quinone intermediate dependent on NADPH was trapped by GSH, and this intermediate was believed to be involved in CYP2C9 inactivation. CYP1A2, 2C9, and 3A4 were the major enzymes responsible for methysticin bioactivation. Taken together, the present work demonstrated that methysticin was a mechanism-based inactivator of CYP2C9. Both ortho-quinone and carbene intermediates appeared to be involved in the inactivation of CYP2C9 induced by methysticin.

更新日期：2022-05-18

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