Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice.
OBJECTIVE
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.
Masubuchi
Yasuhiro
Y
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Suda
Chieko
C
Horie
Toshiharu
T
D000082:Acetaminophen / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism; D007097:Imines / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D010539:Permeability
D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; D016572:Cyclosporine; D000255:Adenosine Triphosphate; C028473:N-acetyl-4-benzoquinoneimine; D002118:Calcium; D019803:Glutathione Disulfide