Molecular Mechanisms of Hepatocellular Apoptosis Induced by Trovafloxacin-Tumor Necrosis Factor-alpha Interaction

被引:26
作者
Beggs, Kevin M. [1 ]
Fullerton, Aaron M. [1 ]
Miyakawa, Kazuhisa [2 ]
Ganey, Patricia E. [1 ]
Roth, Robert A. [1 ]
机构
[1] Michigan State Univ, Ctr Integrat Toxicol, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA
[2] Michigan State Univ, Ctr Integrat Toxicol, Dept Pathobiol & Diagnost Investigat, E Lansing, MI 48824 USA
基金
美国国家卫生研究院;
关键词
idiosyncratic drug-induced liver injury; hepatotoxicity; caspase; JNK; trovafloxacin; N-TERMINAL KINASE; LIVER-INJURY; HEALTHY-VOLUNTEERS; IN-VITRO; JNK ACTIVATION; CELL-DEATH; LIPOPOLYSACCHARIDE; HEPATOTOXICITY; INFLAMMATION; HEPATOCYTES;
D O I
10.1093/toxsci/kft226
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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.
引用
收藏
页码:91 / 101
页数:11
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