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Kevin M. Beggs, Aaron M. Fullerton, Kazuhisa Miyakawa, Patricia E. Ganey, Robert A. Roth, Molecular Mechanisms of Hepatocellular Apoptosis Induced by Trovafloxacin-Tumor Necrosis Factor-alpha Interaction, Toxicological Sciences, Volume 137, Issue 1, January 2014, Pages 91–101, https://doi.org/10.1093/toxsci/kft226
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Abstract
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.
- apoptosis
- tumor necrosis factors
- drug-induced liver disease
- caspases
- cell lines
- combined modality therapy
- dna damage
- hepatocytes
- liver failure, acute
- necrosis
- time factors
- mice
- neoplasms
- trovafloxacin
- signal pathway
- cytotoxicity
- toxic effect
- signal transduction pathways
- drug concentration
- tumor necrosis factor-alpha
- attenuation
- painful bladder syndrome
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