Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice

J Hepatol. 2005 Jan;42(1):110-6. doi: 10.1016/j.jhep.2004.09.015.

Abstract

Background/aims: Although mitochondria have been demonstrated as primary targets in acetaminophen hepatotoxicity, the mechanism for mitochondria-mediated toxicity has not been defined. We examined the role of mitochondrial permeability transition (MPT) in the acetaminophen-induced liver injury.

Methods: Male CD-1 mice were given intraperitoneally acetaminophen (350 mg/kg) without or with cyclosporin A (50 mg/kg), a specific inhibitor of MPT. Serum alanine aminotransferase (ALT), a marker of liver injury, and other biochemical parameters were determined.

Results: Acetaminophen-induced ALT leakage was attenuated by co-administration of cyclosporin A. Cyclosporin A did not affect acetaminophen-induced early decrease in hepatic reduced glutathione (GSH) contents, indicating lack of the effect on the metabolic activation. Acetaminophen-induced decrease in mitochondrial GSH and ATP contents, and cytosolic leakage of cytochrome c were attenuated by cyclosporin A, suggesting that mitochondrial oxidative stress and ATP depletion resulting from MPT are principle mechanisms involved in acetaminophen-induced liver injury. Mitochondrial swelling by calcium was exacerbated in the mitochondria isolated from the acetaminophen-treated mice. In vitro exposure of intact mitochondria to N-acetyl-p-benzoquinone imine (NAPQI) with calcium caused mitochondrial swelling.

Conclusions: The present data indicate that the MPT is the principal mechanism in the acetaminophen-induced liver injury and NAPQI is a candidate to open the transition pore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / toxicity*
  • Adenosine Triphosphate / analysis
  • Animals
  • Benzoquinones / metabolism
  • Calcium / metabolism
  • Cyclosporine / pharmacology
  • Glutathione Disulfide / metabolism
  • Imines / metabolism
  • Liver / drug effects*
  • Male
  • Membrane Potentials
  • Mice
  • Mitochondria, Liver / metabolism*
  • Permeability

Substances

  • Benzoquinones
  • Imines
  • Acetaminophen
  • Cyclosporine
  • Adenosine Triphosphate
  • N-acetyl-4-benzoquinoneimine
  • Calcium
  • Glutathione Disulfide