title: Dissociation of cell death from covalent binding of paracetamol by flavones in a hepatocyte system.
abstract: Paracetamol metabolism and toxicity were studied in isolated rat hepatocytes. Cell damage, due to paracetamol, was shown to be dose dependent and was worse in cells from animals pre-treated with phenobarbitone. Exposure to 10 mM paracetamol for 1 hr caused a loss of intracellular reduced glutathione (GSH) and a later progressive leakage of isocitrate dehydrogenase (ICD). Treatment with (+)catechin, 3-O-methyl(+)catechin and promethazine reduced or prevented the paracetamol-induced ICD leakage. Similarly, studies on covalent binding of paracetamol showed that 3-O-methyl(+)catechin, which "protected" the cells, did so without affecting the amount of material bound covalently to cellular protein. Incubation in tissue culture for 24 hr, after prior treatment with paracetamol +/- the protective agent, showed that the protected cells remained viable and attached to tissue culture plates much better than did the "unprotected" cells. These results suggest that the protective effect is much more than just a temporarily delayed cell death. GSH loss and covalent binding of paracetamol metabolites to cell protein are not sufficient causes of cell death, although they may act as starting points in the chain of events leading to cell death.
mesh_terms: D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002392:Catechin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D005419:Flavonoids / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D005419:Flavonoids; D000082:Acetaminophen; D002392:Catechin; D007521:Isocitrate Dehydrogenase; D005978:Glutathione; D010634:Phenobarbital