Comparison of the effects of sodium sulfate and N-acetylcysteine on the hepatotoxicity of acetaminophen in mice.
N-acetylcysteine (NAC) has been proposed to decrease the toxicity of acetaminophen (AA) via two mechanisms: by increasing cysteine availability for hepatic glutathione biosynthesis and by increasing inorganic sulfate levels, which would increase AA sulfation and elimination. Because administration of sodium sulfate also reportedly decreases AA-induced toxicity, we have investigated the role of inorganic sulfate in the antidotal properties of NAC. Simultaneous administration of NAC (4 mmol/kg) and AA (2.5 and 4 mmol/kg) to male mice prevented AA-induced lethality and hepatotoxicity whereas sodium sulfate (4 mmol/kg) did not. Neither NAC nor sodium sulfate produced significant changes in the half-life (44 min) or clearance (9.0 ml/min/kg) of AA (4.0 mmol/kg) from blood nor were the amounts of AA-sulfate, AA-cysteine or AA-mercapturate excreted in urine altered. Injection of either sodium sulfate or NAC increased serum sulfate concentration and prevented the depletion in serum sulfate produced by AA. Hepatic adenosine 3'-phosphate 5'-phosphosulfate concentrations were decreased 15 and 30 min after AA and injection of either sodium sulfate or NAC lessened this effect. The concentration of glutathione in liver was decreased markedly after AA. NAC attenuated this effect but sodium sulfate did not. Sodium sulfate did not decrease covalent binding of tritium derived from [3H]AA to liver protein whereas NAC decreased binding by 25%. These findings show that administration of sodium sulfate increases serum sulfate concentration and hepatic adenosine 3'-phosphate 5'-phosphosulfate levels but does not protect against acetaminophen-induced hepatotoxicity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000032:analysis; D006207:Half-Life; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010724:Phosphoadenosine Phosphosulfate / Q000032:analysis; D013431:Sulfates / Q000378:metabolism / Q000494:pharmacology*
D013431:Sulfates; C012036:sodium sulfate; D000082:Acetaminophen; D010724:Phosphoadenosine Phosphosulfate; C037386:acetaminophen glucuronide; D005978:Glutathione; D000111:Acetylcysteine