Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition.

Large doses of the analgesic acetaminophen cause centrilobular hepatic necrosis in man and in experimental animals. It has been previously shown that acetaminophen is metabolically activated by CYP enzymes to N-acetyl-p-benzoquinone imine. This species is normally detoxified by GSH, but following a toxic dose GSH is depleted and the metabolite covalently binds to a number of different proteins.

Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes.

Freshly isolated mouse hepatocytes were used to determine the role of mitochondrial permeability transition (MPT) in acetaminophen (APAP) toxicity. Incubation of APAP (1 mM) with hepatocytes resulted in cell death as indicated by increased alanine aminotransferase in the media and propidium iodide fluorescence. To separate metabolic events from later events in toxicity, hepatocytes were preincubated with APAP for 2 h followed by centrifugation of the cells and resuspension of the pellet to remove the drug and reincubating the cells in media alone.