Back to Search
Start Over
Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity
- Source :
- Archives of toxicology. 93(1)
- Publication Year :
- 2018
-
Abstract
- We previously reported that delayed treatment with Mito-tempo (MT), a mitochondria-targeted superoxide dismutase mimetic, protects against the early phase of acetaminophen (APAP) hepatotoxicity by inhibiting peroxynitrite formation. However, whether this protection is sustained to the late phase of toxicity is unknown. To investigate the late protection, C57Bl/6J mice were treated with 300 mg/kg APAP followed by 20 mg/kg MT 1.5 h or 3 h later. We found that both MT treatments protected against the late phase of APAP hepatotoxicity at 12 and 24 h. Surprisingly, MT-treated mice demonstrated a significant increase in apoptotic hepatocytes, while the necrotic phenotype was observed almost exclusively in mice treated with APAP alone. In addition, there was a significant increase in caspase-3 activity and cleavage in the livers of MT-treated mice. Immunostaining for active caspase-3 revealed that the positively stained hepatocytes were exclusively in centrilobular areas. Treatment with the pan-caspase inhibitor ZVD-fmk (10 mg/kg) 2 h post-APAP neutralized this caspase activation and provided additional protection against APAP hepatotoxicity. Treatment with N-acetylcysteine, the current standard of care for APAP poisoning, protected but did not induce this apoptotic phenotype. Mechanistically, MT treatment inhibited APAP-induced RIP3 kinase expression, and RIP3-deficient mice showed caspase activation and apoptotic morphology in hepatocytes analogous to MT treatment. These data suggest that while necrosis is the primary cause of cell death after APAP hepatotoxicity, treatment with the antioxidant MT may switch the mode of cell death to secondary apoptosis in some cells. Modulation of mitochondrial oxidative stress and RIP3 kinase expression play critical roles in this switch.
- Subjects :
- 0301 basic medicine
Male
Programmed cell death
Necrosis
Health, Toxicology and Mutagenesis
Apoptosis
010501 environmental sciences
Pharmacology
Toxicology
medicine.disease_cause
01 natural sciences
Antioxidants
Article
Superoxide dismutase
03 medical and health sciences
chemistry.chemical_compound
Organophosphorus Compounds
Piperidines
medicine
Animals
0105 earth and related environmental sciences
Acetaminophen
biology
Chemistry
Caspase 3
digestive, oral, and skin physiology
General Medicine
Acetylcysteine
Mice, Inbred C57BL
030104 developmental biology
Receptor-Interacting Protein Serine-Threonine Kinases
Toxicity
biology.protein
Hepatocytes
medicine.symptom
Chemical and Drug Induced Liver Injury
Peroxynitrite
Oxidative stress
medicine.drug
Subjects
Details
- ISSN :
- 14320738
- Volume :
- 93
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Archives of toxicology
- Accession number :
- edsair.doi.dedup.....227b968bb4b39043ff23c337d5362bd3