Arzuk Ege, Tokdemir Mehmet, Orhan Hilmi
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, İzmir, Turkey.
Department of Forensic Medicine, Faculty of Medicine, İzmir Kâtip Çelebi University, İzmir, Turkey.
Toxicol Lett. 2022 Jun 15;363:36-44. doi: 10.1016/j.toxlet.2022.05.005. Epub 2022 May 17.
Mitochondria appeared to be a major target for paracetamol (PAR)-induced hepatotoxicity. Studies suggested that microsomal CYPs catalyse bioactivation of PAR to N-acetyl-p-benzoquinone imine (NAPQI), which alkylates mitochondrial proteins, and causes transmission of death signal from mitochondria to nucleus. We hypothesised that local formation of NAPQI within mitochondria seems more likely compared to the translocation of NAPQI. We therefore tested whether the formation of NAPQI may be catalysed by mitochondrial CYPs. Cellular fractions were isolated from human liver and kidney to compare the metabolic capacities. Liver and kidney mitochondria are capable to generate NAPQI. Mitochondrial CYP2E1 and CYP3A4 activities were comparable to the microsomal counterparts in both organs. Previously reported higher kidney microsomal CYP2E1 activity in men compared women were observed in mitochondrial CYP2E1 as well in the present study. On the other hand, no correlation between kidney CYP2E1 activity and quantity of NAPQI formation, as well as no induction on mitochondrial permeability transition pore (mPTP) opening by PAR in kidney mitochondria strongly suggested a different toxicity mechanism in this organ.
线粒体似乎是对乙酰氨基酚（PAR）诱导的肝毒性的主要靶点。研究表明，微粒体细胞色素P450（CYPs）催化PAR生物活化生成N - 乙酰 - 对苯醌亚胺（NAPQI），后者使线粒体蛋白烷基化，并导致死亡信号从线粒体传递至细胞核。我们推测，与NAPQI的转运相比，NAPQI在线粒体内的局部形成似乎更有可能。因此，我们测试了NAPQI的形成是否可能由线粒体CYPs催化。从人肝脏和肾脏中分离细胞组分以比较代谢能力。肝脏和肾脏线粒体均能够生成NAPQI。在这两个器官中，线粒体CYP2E1和CYP3A4的活性与微粒体中的相当。在本研究中，在线粒体CYP2E1中也观察到先前报道的男性肾脏微粒体CYP2E1活性高于女性。另一方面，肾脏CYP2E1活性与NAPQI形成量之间无相关性，并且PAR对肾脏线粒体的线粒体通透性转换孔（mPTP）开放无诱导作用，这强烈提示该器官存在不同的毒性机制。
