EFFECT OF NIFEDIPINE, VERAPAMIL, DILTIAZEM AND TRIFLUOPERAZINE ON ACETAMINOPHEN TOXICITY IN MICE

The hepatotoxicity of acetaminophen overdose depends on the metabolic activation to a toxic reactive metabolite by the hepatic mixed functio n oxidases. There is evidence that an increase in cytosolic Ca2+ is in volved in acetaminophen hepatotoxicity. The effects of the Ca2+-antago nists nifedipine (NF). verapamil (V), diltiazem (DL) and of the calmod ulin antagonist trifluoperazine (TFP) on the activity of some drug-met abolizing enzyme systems, lipid peroxidation and acute acetaminophen t oxicity were studied in male albino mice. No changes in the drug-metab olizing enzyme activities studied and in the cytochrome P-450 and b(5) contents were observed Ih after oral administration of V (20 mg/kg), DL (70 mg/kg) and TFP (3 mg/kg). NF (50 mg/kg) increased cytochrome P- 450 content: NADPH-cytochrome c reductase and ethylmorphine-N-demethyl ase activities. DL and TFP significantly decreased lipid peroxidation. NF, V, DL and TFP administered Ih before acetaminophen (700 mg/kg ora lly) increased the mean survival time of animals. A large increase of serum aspartate aminotransferase (AST), and liver weight and depletion of liver reduced glutathione (GSH) occurred in animals receiving toxi c acetaminophen dose. NF, V and DL prevented and TFP decreased the ace taminophen-induced hepatic damage measured both by plasma AST and by l iver weight. NF, V, DL and TFP changed neither the hepatic GSH level n or the GSH depletion provoked by the toxic dose of acetaminophen. This suggests that V, DL and TFP do not influence the amount of the acetam inophen toxic metabolite formed in the liver. The possible mechanism o f the protective effect of NF, V, DL and TFP on the acetaminophen-indu ced toxicity is discussed.