Modulation of N-Hydroxyparacetamol Cytotoxicity in Suspensions of Isolated Rat Hepatocytes

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Abstract
The effect of inhibitors of toxicity of N‐hydroxyparacetamol(N‐OH‐pHAA), a postulated proximate metabolite of paracetamol, was studied in isolated rat hepatocytes. Additions of ascorbate, menadione, thiol‐containing amino acids and glutathione (GSH) led to an increased stability of N‐OH‐pHAA, reduced the covalent binding of N‐OH‐pHAA to cellular protein and decreased GSH depletion caused by N‐OH‐pHAA. Two to three hours elapsed after a 30 min. exposure of the cells to N‐OH‐pHAA before the cells responded with increased cell permeability. Ascorbate, acetylcysteine, GSH and promethazine were capable of inhibiting this second phase of N‐OH‐pHAA cytotoxicity in addition to their effects during the initial exposure phase. In contrast, the anti‐oxidant tocopherole and phenacetin were only effective during the second phase. Increasing the incubation medium pH during the second phase of N‐OH‐pHAA mediated cellular damage resulted in decreases in cytotoxicity. Lipid peroxidation, as measured by accumulation of thiobarbituric acid reactive metabolites, did not seem to be directly correlated with cytotoxicity, since cysteamine or higher concentrations of N‐OH‐pHAA inhibited lipid peroxidation without decreasing cellular damage.