Potentiation of the hepatotoxic effect of acetaminophen by prior administration of salicylate.
The effect of sodium salicylate (SS) pretreatment on acetaminophen (APAP) metabolism and hepatotoxicity in mice was studied. Mice were given a single oral dose of SS (100 mg/kg) 1 hr before graded doses of APAP (150-500 mg/kg). Liver histology, serum hepatic enzymes (serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase and isocitric dehydrogenase) and APAP metabolites in urine were examined 24 hr after APAP treatment. Free plasma APAP and liver glutathione were determined over 24 hr after treatment with 400 mg/kg of APAP alone or after SS pretreatment. At 500 mg of APAP per kg, mortality rate was 38% in SS + APAP group; no mortality was seen among animals treated with APAP alone. Centrilobular hepatic hemorrhagic necrosis and/or vacuolation were observed in both treatments. Mitosis of hepatocytes was increased in all APAP-treated mice. Incidence of hepatic necrosis and mean lesion grades at 300- and 500-mg/kg doses increased in mice pretreated with SS. Mice that received SS + APAP had significantly higher levels of serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase and isocitric dehydrogenase at all doses compared to mice treated with APAP alone. APAP glucuronide and sulfate conjugates decreased and APAP mercapturate conjugate increased in urine of mice receiving SS + APAP treatment. Free plasma APAP was significantly higher 2 hr after APAP treatment in SS + APAP-treated mice as compared to mice that received APAP alone. Hepatic glutathione levels were similarly decreased over 24 hr in both groups. These data demonstrate that SS pretreatment alters APAP biotransformation profile and potentiates the hepatotoxic effect of APAP in mice.
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D012459:Salicylates / Q000633:toxicity*
D012459:Salicylates; D000082:Acetaminophen; D005978:Glutathione