Study of the roles of cytochrome P450 (CYPs) in the metabolism and cytotoxicity of perhexiline.
Study of the roles of cytochrome P450 (CYPs) in the metabolism and cytotoxicity of perhexiline.
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DOI：
10.1007/s00204-022-03369-0
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发表时间：
2022-12
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
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作者：
培己胺是20世纪70年代开发的一种预防性抗心绞痛药物。尽管在治疗上，它仍然是成功的，但由于担心其严重的副作用，包括肝脏毒性，导致该药物的使用受到限制，并最终在多个国家退出市场。在临床环境中，细胞色素P450(CYP)2D6被认为是过己胺不良反应的可能危险因素。然而，CYP介导的代谢在培己胺毒性中的作用尚不清楚，特别是在完好的细胞中。利用我们先前建立的分别表达14个细胞周期蛋白(1A1、1A2、1B1、2A6、2B6、2C8、2C9、2C18、2C19、2D6、2E1、3A4、3A5和3A7)的HepG2细胞系和人肝微粒体，我们确定了CYP2D6在全己胺羟化过程中起主要作用。我们还确定了CYP1A2、2C19和3A4对全己胺的代谢有贡献。与对照细胞相比，在高表达CYP2D6的HepG2细胞中，培己胺的毒性作用显著降低。相反，过表达的细胞色素P1A2、2C19和3A4并没有显示出明显的保护作用来对抗过己胺的毒性。预先用奎尼丁(一种公认的CYP2D6抑制剂)孵育，显著减弱了对高表达CYP2D6的HepG2细胞的保护作用。此外，在高表达CYP2D6的HepG2细胞中，过己胺诱导的线粒体损伤、细胞凋亡和内质网应激也被减弱。这些发现提示，CYP2D6介导的代谢保护细胞免受过己胺诱导的细胞毒性，并支持临床观察，即CYP2D6代谢不良者可能具有较高的过己胺诱导的肝毒性风险。
Perhexiline is a prophylactic antianginal agent developed in the 1970s. Although, therapeutically, it remained a success, the concerns of its severe adverse effects including hepatotoxicity caused the restricted use of the drug, and eventually its withdrawal from the market in multiple countries. In the clinical setting, cytochrome P450 (CYP) 2D6 is considered as a possible risk factor for the adverse effects of perhexiline. However, the role of CYP-mediated metabolism in the toxicity of perhexiline, particularly in the intact cells, remains unclear. Using our previously established HepG2 cell lines that individually express 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7) and human liver microsomes, we identified that CYP2D6 plays a major role in the hydroxylation of perhexiline. We also determined that CYP1A2, 2C19, and 3A4 contribute to the metabolism of perhexiline. The toxic effect of perhexiline was reduced significantly in CYP2D6-overexpressing HepG2 cells, in comparison to the control cells. In contrast, overexpression of CYP1A2, 2C19, and 3A4 did not show a significant protective effect against the toxicity of perhexiline. Pre-incubation with quinidine, a well-recognized CYP2D6 inhibitor, significantly attenuated the protective effect in CYP2D6-overexpressing HepG2 cells. Furthermore, perhexiline-induced mitochondrial damage, apoptosis, and ER stress were also attenuated in CYP2D6-overexpressing HepG2 cells. These findings suggest that CYP2D6-mediated metabolism protects the cells from perhexiline-induced cytotoxicity and support the clinical observation that CYP2D6 poor metabolizers may have higher risk for perhexiline-induced hepatotoxicity.
影响因子：
6.1
作者：
Mueller-Schoell A;Michelet R;Weinelt F;Kloft C;Mikus G
通讯作者：
Mikus G
DOI：
10.1093/toxsci/kfw173
发表时间：
2016-12
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
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作者：
Ren Z;Chen S;Zhang J;Doshi U;Li AP;Guo L
通讯作者：
Guo L