EFFECTS OF N-ACETYLCYSTEINE ON ACETAMINOPHEN COVALENT BINDING AND HEPATIC-NECROSIS IN MICE
- 1 January 1985
- journal article
- research article
- Vol. 232 (3) , 864-872
Abstract
The protective effect of N-acetylcysteine against acetaminophen hepatotoxicity was tested in mice to determine if it precedes arylation of tissue or whether protection occurs after arylation of tissue. Investigation of potential postarylation actions showed that N-acetylcysteine was unable to attenuate the liver necrosis caused by acetaminophen or several other hepatotoxins that act through chemically reactive metabolites. Varying the time and route of N-acetylcysteine treatment indicated that the late protection against acetaminophen mortality probably was a consequence of pharmacokinetic factors rather than postarylation intervention in the process of cell death. The antidote was found to inhibit covalent binding of acetaminophen by about 70% when N-acetylcysteine protected against liver necrosis. Treatment regimens that had no effect upon covalent binding also had no effect on acetaminophen hepatotoxicity. Previous failures to detect this relationship apparently occurred because of a failure to consider biological events important in the pathophysiology of acetaminophen-induced necrosis, particularly the marked intrahepatic hemorrhage and vascular congestion with liver engorgement by protein and fluid. Sulfhydryl nucleophiles such as N-acetylcysteine act primarily through prearylation mechanisms to decrease the amount of reactive metabolite available for initiation of hepatic injury.This publication has 16 references indexed in Scilit:
- EVIDENCE THAT ACETAMINOPHEN AND N-HYDROXYACETAMINOPHEN FORM A COMMON ARYLATING INTERMEDIATE, N-ACETYL-PARA-BENZOQUINONEIMINE1980
- Evidence for the involvement of N-ACETYL-p-quinoneimine in acetaminophen metabolismBiochemical Pharmacology, 1979
- Varying effects of sulfhydryl nucleophiles on acetaminophen oxidation and sulfhydryl adduct formationBiochemical Pharmacology, 1979
- Liver cytosol catalyzed conjugation of reduced glutathione with a reactive metabolite of acetaminophenToxicology and Applied Pharmacology, 1979
- Renal necrosis, glutathione depletion, and covalent binding after acetaminophenToxicology and Applied Pharmacology, 1978
- Synthesis of N-hydroxyacetaminophen, a postulated toxic metabolite of acetaminophen, and its phenolic sulfate conjugateJournal of Medicinal Chemistry, 1978
- Pharmacokinetics of Oral AcetylcysteineClinical Pharmacokinetics, 1978
- Paracetamol-induced hepatic necrosis in the mouse—Relationship between covalent binding, hepatic glutathione depletion and the protective effect of α-mercaptopropionylglycineBiochemical Pharmacology, 1977
- Micro-Method for Intravenous Injection and Blood SamplingJournal of Pharmaceutical Sciences, 1963
- Serum Glutamic Pyruvic Transaminase in Cardiac and Hepatic Disease.Experimental Biology and Medicine, 1956