Freshly isolated hepatocytes as a model for studying the toxicity of paracetamol.
The toxicity of paracetamol has been investigated in freshly isolated hamster hepatocytes. Two phases of toxicity have been identified. In phase 1, metabolic activation of paracetamol occurs with depletion of glutathione. In phase 2, there is progressive morphological damage, leading ultimately to cell death. This occurs even in the absence of further exposure to paracetamol. The thiol reductant, dithiothreitol, added at the start of phase 2, prevents and reverses the toxicological damage that would otherwise occur. Thus, it is most likely that paracetamol causes hepatotoxicity through oxidation of SH groups in key enzymes. N-Acetylcysteine, but not methionine, has an effect similar to that of dithiothreitol. This difference is probably due to oxidation of the enzymes involved in the conversion of methionine to cysteine, whereas N-acetylcysteine can still serve as a precursor of glutathione. The glutathione can act both by adduct formation with the metabolite of paracetamol and as a thiol reductant. Species differences in sensitivity to paracetamol toxicity were shown to be due to differences in the rate of oxidation of the drug to its toxic metabolite. Most people are relatively poor activators of paracetamol, but in few subjects the reaction proceeds quite rapidly, rendering such individuals more sensitive to the hepatotoxic effects of the drug.
D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D016227:Benzoquinones; D006224:Cricetinae; D004229:Dithiothreitol / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D006801:Humans; D007097:Imines / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects*; D051379:Mice; D051381:Rats; D013045:Species Specificity
D000931:Antidotes; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione; D004229:Dithiothreitol; D000111:Acetylcysteine