An overdose of acetaminophen (APAP), the most common cause of acute liver injury, induces oxidative stress that subsequently causes mitochondrial impairment and hepatic necroptosis. N-acetyl-L-cysteine (NAC), the only recognized drug against APAP hepatotoxicity, is less effective the later it is administered. This study evaluated the protective effect of mitochondria-specific Mito-TEMPO (Mito-T) on APAP-induced acute liver injury in C57BL/6J male mice, and a three dimensional (3D)-cell culture model containing the human hepatoblastoma cell line HepG2. The administration of Mito-T (20 mg/kg, i.p.) 1 h after APAP (400 mg/kg, i.p.) injection markedly attenuated the APAP-induced elevated serum transaminase activity and hepatic necrosis. However, Mito-T treatment did not affect key factors in the development of APAP liver injury including the activation of c-jun N-terminal kinases (JNK), and expression of the transcription factor C/EBP homologous protein (CHOP) in the liver. However, Mito-T significantly reduced the APAP-induced increase in the hepatic oxidative stress marker, nitrotyrosine, and DNA fragmentation. Mito-T markedly attenuated cytotoxicity induced by APAP in the HepG2 3D-cell culture model. Moreover, liver regeneration after APAP hepatotoxicity was not affected by Mito-T, demonstrated by no changes in proliferating cell nuclear antigen formation. Therefore, Mito-T was hepatoprotective at the late-stage of APAP overdose in mice.

中文翻译：

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Mito-TEMPO的后期保护作用对小鼠和三维细胞培养模型中对乙酰氨基酚诱导的肝毒性。

过量的对乙酰氨基酚（APAP）是急性肝损伤的最常见原因，会引起氧化应激，继而引起线粒体损伤和肝坏死。N-乙酰基-L-半胱氨酸（NAC）是唯一公认的抗APAP肝毒性药物，但给药后效果较差。这项研究评估了线粒体特异性Mito-TEMPO（Mito-T）对APAP诱导的C57BL / 6J雄性小鼠急性肝损伤的保护作用，以及包含人成肝细胞瘤细胞系HepG2的三维（3D）细胞培养模型。APAP（400 mg / kg，ip）注射后1 h的Mito-T（20 mg / kg，ip）给药显着减弱了APAP诱导的血清转氨酶活性升高和肝坏死。然而，Mito-T治疗并未影响APAP肝损伤发展的关键因素，包括c-jun N末端激酶（JNK）的激活以及肝中转录因子C / EBP同源蛋白（CHOP）的表达。但是，Mito-T显着降低了APAP诱导的肝氧化应激指标，硝基酪氨酸和DNA片段的增加。Mito-T在HepG2 3D细胞培养模型中显着减弱了APAP诱导的细胞毒性。而且，APAP肝毒性后的肝再生不受Mito-T的影响，增殖细胞核抗原形成没有变化。因此，Mito-T在小鼠APAP过量时具有肝保护作用。Mito-T显着降低了APAP诱导的肝氧化应激指标，硝基酪氨酸和DNA片段的增加。Mito-T在HepG2 3D细胞培养模型中显着减弱了APAP诱导的细胞毒性。而且，APAP肝毒性后的肝再生不受Mito-T的影响，增殖细胞核抗原形成没有变化。因此，Mito-T在小鼠APAP过量时具有肝保护作用。Mito-T显着降低了APAP诱导的肝氧化应激指标，硝基酪氨酸和DNA片段的增加。Mito-T在HepG2 3D细胞培养模型中显着减弱了APAP诱导的细胞毒性。而且，APAP肝毒性后的肝再生不受Mito-T的影响，增殖细胞核抗原形成没有变化。因此，Mito-T在小鼠APAP过量时具有肝保护作用。