Role of apoptosis in acetaminophen hepatotoxicity.

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Kon K, Ikejima K, Okumura K, Aoyama T, Arai K, Takei Y, Lemasters JJ, Sato N

Role of apoptosis in acetaminophen hepatotoxicity.

J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S49-52.

PubMed ID

17567465 [ View in PubMed

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Abstract

Acetaminophen overdose causes liver injury by mechanisms involving glutathione depletion, oxidative stress and mitochondrial dysfunction. The role of apoptosis in acetaminophen-induced cell killing is still controversial. Here, our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. Acetaminophen (10 micromol/L) induced necrotic killing in approximately 50% of hepatocytes after 6 h and cyclosporin A (CsA), MPT inhibitor, temporarily decreased necrotic killing after 6 h, but cytoprotection was lost after 16 h. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization at approximately 4.5 h after acetaminophen. CsA delayed these changes indicative of the MPT to about 11 h after acetaminophen. TUNEL labeling and caspase 3 activation also increased after acetaminophen. Fructose (20 mmol/L, an ATP-generating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis. In conclusion, acetaminophen induces the MPT and ATP-depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glycine	Serine hydroxymethyltransferase	Protein	Humans	Unknown	Product of	Details