Role of caspases in acetaminophen-induced liver injury

Hartmut Jaeschke, Cathleen Cover, Mary Lynn Bajt

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

The mode of cell death after acetaminophen (AAP) overdose is controversially discussed. A recent study reported a protective effect of the pancaspase inhibitor Z-VAD-fmk against AAP toxicity in vivo but the mechanism of protection remained unclear. Therefore, the objective of this investigation was to assess if Z-VAD-fmk or the low doses of dimethyl sulfoxide (DMSO) used as solvent were responsible for the protection. Treatment with 10 mg/kg Z-VAD-fmk or diluted DMSO (0.25 ml/kg) for 15 min before but not 2.5 h after AAP prevented the oxidant stress (hepatic glutathione disulfide content; nitrotyrosine staining), DNA fragmentation (anti-histone ELISA, TUNEL assay) and liver injury (plasma ALT activities) at 6 h after administration of 300 mg/kg AAP. Even a lower dose (0.1 ml/kg) of DMSO was partially effective. DMSO pretreatment also attenuated the initial decline in hepatic glutathione levels. On the other hand, 10 μM Z-VAD-fmk was unable to prevent AAP-induced cell death in primary cultured mouse hepatocytes. We conclude that Z-VAD-fmk does not protect against AAP-induced liver injury and, therefore, caspases are not involved in the mechanism of AAP-induced liver injury. In contrast, the protection in vivo is caused by the diluted DMSO, which is used to solubilize the inhibitor Z-VAD-fmk. The results emphasize that even very low doses of DMSO, which are generally necessary to dissolve water-insoluble inhibitors, can have a profound impact on the toxicity of drugs and chemicals when metabolic activation is a critical aspect of the mechanism of cell injury.

Original languageEnglish (US)
Pages (from-to)1670-1676
Number of pages7
JournalLife Sciences
Volume78
Issue number15
DOIs
StatePublished - Mar 6 2006

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Keywords

  • Acetaminophen
  • Caspase inhibitors
  • Drug hepatotoxicity
  • Drug-induced apoptosis
  • Oncotic necrosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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