The effectiveness of antioxidants in reducing paracetamol-induced damage subsequent to paracetamol activation

Paracetamol toxicity was studied in isolated mouse hepatocytes. This drug produced a concentration- and time-dependent loss of cell viability. Exposure to 5 mM paracetamol produced a rapid fall in intracellular reduced glutathione (GSH) followed by a decrease in plasma membrane integrity. The antioxidant, diphenyl-p-phenylenediamine (DPPD) had no effect on either the loss of GSH, the binding of 14C-paracetamol metabolites to protein or the loss of plasma membrane integrity when hepatocytes were incubated in 5 mM paracetamol. When hepatocytes were exposed to paracetamol for 1 hr they showed a loss of plasma membrane integrity during the subsequent 7 hr incubation. DPPD, alpha-tocopherol and promethazine reduced this effect when added after the paracetamol exposure. It appears that paracetamol exposure initiates toxic events subsequent to the generation of the reactive metabolite but prior to cell death and that the progression of these events can be interrupted by compounds with antioxidant properties.