Department of Clinical Sciences Lund, Mitochondrial Medicine, Lund University, Lund, Sweden.
NeuroVive Pharmaceutical AB, Medicon Village, Lund, Sweden.
PLoS One. 2020 Apr 6;15(4):e0231173. doi: 10.1371/journal.pone.0231173. eCollection 2020.
Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.
对乙酰氨基酚是世界上最常用的非处方止痛药之一，在治疗剂量下被认为是安全的。然而，在西方国家，故意和无意的过量用药导致多达 70%的急性肝衰竭病例。广泛的研究表明，氧化应激和线粒体功能障碍的诱导是导致对乙酰氨基酚肝损伤的核心。尽管对乙酰氨基酚毒性的机制有了更深入的了解，但目前只有一种临床批准的药理治疗选择，即 N-乙酰半胱氨酸。N-乙酰半胱氨酸增加了细胞的抗氧化防御能力，保护肝细胞免受进一步的对乙酰氨基酚引起的氧化损伤。由于它主要保护健康的肝细胞，而不是挽救已经受损的细胞，因此需要针对后者的细胞群体的替代治疗策略。在这项研究中，我们研究了线粒体作为治疗靶点，以开发治疗对乙酰氨基酚引起的肝损伤的新治疗策略。使用详细的呼吸分析方法在体外研究人类细胞中急性对乙酰氨基酚过量引起的线粒体毒性，结果表明，对乙酰氨基酚抑制了与复合物 I 相关的（NADH 依赖性）线粒体呼吸，但不抑制与复合物 II 相关的（琥珀酸依赖性）线粒体呼吸。用一种新型的可穿透细胞膜的琥珀酸前体药物治疗可挽救对乙酰氨基酚引起的线粒体呼吸受损。这表明可穿透细胞膜的琥珀酸前体药物是一种潜在的替代治疗策略，可以对抗对乙酰氨基酚引起的肝损伤。
