Adelusi Olamide B, Venkatraman Aparna, Akakpo Jephte Y, Ramachandran Anup, Jaeschke Hartmut
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA; Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.
Toxicology. 2025 Nov;517:154221. doi: 10.1016/j.tox.2025.154221. Epub 2025 Jun 13.
Acetaminophen (APAP) overdose can cause liver injury and is the leading cause of acute liver failure in Western countries. Hepatocellular necrosis induced by APAP involves the formation of a reactive metabolite, triggering mitochondrial oxidant stress and peroxynitrite formation. Iron-catalyzed protein nitration is critical for mitochondrial dysfunction and cell death in the absence of lipid peroxidation (LPO). However, co-treatment of APAP and ferrous sulfate aggravated protein nitration and liver injury but also triggered extensive LPO (measured as malondialdehyde and hydroxy eicosatetraenoic acid (HETE) species). The objective of this study was to evaluate whether the aggravated injury under these conditions is caused by a combination of protein nitration and LPO or if LPO is now the dominant injury mechanism. To test this, C57BL/6 J mice were co-treated with APAP (300 mg/kg) and a moderate dose of ferrous sulfate (0.15 mmol/kg) for 6 h. Some animals also received a dose of Mito-TEMPO, the mitochondria-targeted SOD mimetic, or minocycline, an inhibitor of mitochondrial iron uptake. Although Mito-TEMPO and minocycline eliminated protein nitration and liver injury after APAP alone, these interventions did not affect LPO and only had a moderate effect on protein nitration and liver injury in the APAP+Fe group, suggesting LPO as the main mechanism of cell death. Consistent with these findings, delayed treatment with clinically relevant antidotes N-acetylcysteine and fomepizole did not reduce LPO or liver injury. Thus, liver injury after APAP+Fe is no longer primarily driven by mitochondrial oxidant stress and peroxynitrite-mediated necrosis but by lipid peroxidation and a ferroptosis-like cell death.
对乙酰氨基酚（APAP）过量可导致肝损伤，是西方国家急性肝衰竭的主要原因。APAP诱导的肝细胞坏死涉及活性代谢物的形成，引发线粒体氧化应激和过氧亚硝酸盐的形成。在没有脂质过氧化（LPO）的情况下，铁催化的蛋白质硝化对于线粒体功能障碍和细胞死亡至关重要。然而，APAP与硫酸亚铁联合处理会加重蛋白质硝化和肝损伤，但也会引发广泛的LPO（以丙二醛和羟基二十碳四烯酸（HETE）种类来衡量）。本研究的目的是评估在这些条件下加重的损伤是由蛋白质硝化和LPO共同作用引起的，还是LPO现在是主要的损伤机制。为了验证这一点，将C57BL/6 J小鼠用APAP（300 mg/kg）和中等剂量的硫酸亚铁（0.15 mmol/kg）联合处理6小时。一些动物还接受了线粒体靶向超氧化物歧化酶模拟物Mito-TEMPO或线粒体铁摄取抑制剂米诺环素的剂量。尽管单独使用APAP后，Mito-TEMPO和米诺环素消除了蛋白质硝化和肝损伤，但这些干预措施并未影响LPO，并且仅对APAP+Fe组的蛋白质硝化和肝损伤有中等程度的影响，这表明LPO是细胞死亡的主要机制。与这些发现一致，临床上相关的解毒剂N-乙酰半胱氨酸和甲吡唑的延迟治疗并未降低LPO或肝损伤。因此，APAP+Fe后的肝损伤不再主要由线粒体氧化应激和过氧亚硝酸盐介导的坏死驱动，而是由脂质过氧化和铁死亡样细胞死亡驱动。
