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Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice
Yasuhiro Masubuchi1, Chieko Suda, Toshiharu Horie
1Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
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.
Insights
Mitochondrial permeability transition (MPT) is the main cause of liver damage from acetaminophen overdose. Cyclosporin A, an MPT inhibitor, protected against liver injury by preventing mitochondrial dysfunction.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Toxicology
Background:
- Mitochondria are key targets in acetaminophen hepatotoxicity.
- The precise mechanism of mitochondria-mediated acetaminophen toxicity remains unclear.
- This study investigates the role of mitochondrial permeability transition (MPT) in acetaminophen-induced liver injury.
Purpose of the Study:
- To elucidate the mechanism of acetaminophen-induced liver injury.
- To determine the role of mitochondrial permeability transition (MPT) in this process.
- To identify potential therapeutic targets for acetaminophen hepatotoxicity.
Main Methods:
- Male CD-1 mice were administered acetaminophen (350 mg/kg) intraperitoneally.
- Mice received either acetaminophen alone or in combination with cyclosporin A (50 mg/kg), an MPT inhibitor.
- Serum alanine aminotransferase (ALT) levels and other biochemical parameters were measured to assess liver injury.
Main Results:
- Co-administration of cyclosporin A significantly attenuated acetaminophen-induced ALT leakage.
- Cyclosporin A did not affect the initial decrease in hepatic reduced glutathione (GSH), indicating no impact on metabolic activation.
- Acetaminophen-induced mitochondrial GSH depletion, ATP reduction, and cytochrome c release were reduced by cyclosporin A, implicating MPT in oxidative stress and energy depletion.
Conclusions:
- Mitochondrial permeability transition (MPT) is the primary mechanism underlying acetaminophen-induced liver injury.
- N-acetyl-p-benzoquinone imine (NAPQI), the toxic metabolite of acetaminophen, is a likely trigger for MPT pore opening.
- Inhibition of MPT may represent a therapeutic strategy for acetaminophen hepatotoxicity.
