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 function oxidases. There is evidence that an increase in cytosolic Ca2+ is involved in acetaminophen hepatotoxicity. The effects of the Ca2+-antagonists nifedipine (NF), verapamil (V), diltiazem (DL) and of the calmodulin antagonist trifluoperazine (TFP) on the activity of some drug-metabolizing enzyme systems, lipid peroxidation and acute acetaminophen toxicity were studied in male albino mice. No changes in the drug-metabolizing enzyme activities studied and in the cytochrome P-450 and b5 contents were observed 1 h 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-demethylase activities. DL and TFP significantly decreased lipid peroxidation. NF, V, DL and TFP administered 1 h before acetaminophen (700 mg/kg orally) 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 toxic acetaminophen dose. NF, V and DL prevented and TFP decreased the acetaminophen-induced hepatic damage measured both by plasma AST and by liver weight. NF, V, DL and TFP changed neither the hepatic GSH level nor the GSH depletion provoked by the toxic dose of acetaminophen. This suggests that V, DL and TFP do not influence the amount of the acetaminophen toxic metabolite formed in the liver. The possible mechanism of the protective effect of NF, V, DL and TFP on the acetaminophen-induced toxicity is discussed.
Dimova
S
S
Department of Drug Toxicology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Koleva
M
M
Rangelova
D
D
Stoythchev
T
T
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D015996:Survival Rate; D014268:Trifluoperazine / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002147:Calmodulin; D014268:Trifluoperazine; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D001219:Aspartate Aminotransferases; D004110:Diltiazem; D005978:Glutathione; D009543:Nifedipine