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Role of caspases in acetaminophen-induced liver injury

Hartmut Jaeschke1, Cathleen Cover, Mary Lynn Bajt

  • 1Liver Research Institute University of Arizona 1501 N. Campbell Ave, Room 6309 Tucson, AZ 85724, USA. jaeschke@email.arizona.edu

Life Sciences
|October 18, 2005
PubMed

Insights

Dimethyl sulfoxide (DMSO), not Z-VAD-fmk, protects against acetaminophen (AAP) overdose. Low DMSO doses prevent AAP-induced liver injury, oxidant stress, and DNA damage, highlighting DMSO

Area of Science:

  • Hepatology
  • Toxicology
  • Cell Death Research

Background:

  • Acetaminophen (AAP) overdose causes liver injury through mechanisms that are not fully understood.
  • Previous studies suggested a protective role for pancaspase inhibitors like Z-VAD-fmk against AAP toxicity in vivo.
  • The exact mechanism behind this reported protection, and the role of the solvent dimethyl sulfoxide (DMSO), remained unclear.

Purpose of the Study:

  • To investigate whether Z-VAD-fmk or its solvent, dimethyl sulfoxide (DMSO), is responsible for the protective effects observed in acetaminophen (AAP) overdose models.
  • To clarify the role of caspases in the mechanism of AAP-induced liver injury.

Main Methods:

  • Mice were treated with Z-VAD-fmk or diluted DMSO before or after AAP administration.
  • Evaluated markers of oxidant stress (glutathione disulfide, nitrotyrosine staining), DNA fragmentation (ELISA, TUNEL assay), and liver injury (ALT activities).
  • Assessed Z-VAD-fmk's effect on AAP-induced cell death in primary cultured mouse hepatocytes.

Main Results:

  • Pretreatment with Z-VAD-fmk or diluted DMSO (0.25 ml/kg) 15 minutes before AAP prevented liver injury, oxidant stress, and DNA fragmentation.
  • Even lower doses of DMSO (0.1 ml/kg) showed partial protection and attenuated the initial decline in hepatic glutathione.
  • Z-VAD-fmk (10 microM) did not prevent AAP-induced cell death in cultured hepatocytes, indicating caspases are not involved.

Conclusions:

  • Z-VAD-fmk does not protect against acetaminophen-induced liver injury; caspases are not implicated in this process.
  • The protective effect observed in vivo is attributed to the diluted DMSO used as a solvent for Z-VAD-fmk.
  • Low doses of DMSO can significantly impact drug toxicity, especially when metabolic activation is key to the injury mechanism.

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