* Department of Pharmacology & Toxicology and.
Toxicol Sci. 2014 Jan;137(1):91-101. doi: 10.1093/toxsci/kft226. Epub 2013 Oct 4.
Idiosyncratic drug-induced liver injury (IDILI) continues to be a significant human health problem. IDILI is characterized as occurring in a minority of individuals exposed to a drug, yet it accounts for as much as 17% of all cases of acute liver failure. Despite these concerns, the mechanisms underlying IDILI remain unknown. Trovafloxacin (TVX), which causes IDILI in humans, also causes hepatocellular death in vitro when combined with tumor necrosis factor-alpha (TNF) treatment. However, the molecular mechanisms involved in this toxicity are not fully characterized. The purpose of this study was to identify mechanisms by which TVX and TNF interact to cause hepatocellular death, with a focus on a human hepatocyte cell line. TVX and TNF interacted to cause cytotoxicity in HepG2 cells at drug concentrations similar to those in people undergoing TVX therapy. TVX/TNF treatment caused apoptosis and DNA damage in HepG2 cells that depended on caspase activation. Prolonged activation of JNK occurred in TVX/TNF-induced cytotoxicity, and treatment with the JNK selective inhibitor SP600125 attenuated cytotoxicity. TVX/TNF cotreatment also caused cytotoxicity in isolated primary murine hepatocytes that was dependent on caspase activation. These results increase understanding of molecular signaling pathways involved in hepatocellular death caused by a drug with idiosyncratic liability in the presence of TNF.
特发性药物性肝损伤（IDILI）仍然是一个严重的人类健康问题。IDILI 的特征是少数接触药物的个体发生，但它占所有急性肝功能衰竭病例的 17%。尽管存在这些担忧，但 IDILI 的机制仍不清楚。曲伐沙星（TVX）在人类中引起 IDILI，当与肿瘤坏死因子-α（TNF）联合治疗时，也会导致体外肝细胞死亡。然而，这种毒性涉及的分子机制尚未完全阐明。本研究的目的是确定 TVX 和 TNF 相互作用导致肝细胞死亡的机制，重点是人类肝细胞系。在与接受 TVX 治疗的人体中相似的药物浓度下，TVX 和 TNF 在 HepG2 细胞中相互作用导致细胞毒性。TVX/TNF 处理导致 HepG2 细胞中的细胞凋亡和 DNA 损伤，这依赖于半胱天冬酶的激活。在 TVX/TNF 诱导的细胞毒性中，JNK 的持续激活发生，而 JNK 选择性抑制剂 SP600125 的处理减轻了细胞毒性。TVX/TNF 共同处理也导致分离的原代小鼠肝细胞发生细胞毒性，这依赖于半胱天冬酶的激活。这些结果增加了对 TNF 存在下具有特发性不良反应的药物引起肝细胞死亡所涉及的分子信号通路的理解。
