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ToxSci Advance Access published online on July 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg181
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received May 6, 2003; accepted June 21, 2003
© 2003 Society of Toxicology

Systems Toxicology

Effect of N-Acetylcysteine on Acetaminophen Toxicity in Mice: Relationship to Reactive Nitrogen and Cytokine Formation

Laura P. James 1*, Sandra S. McCullough 1, Laura W. Lamps 2, and Jack A. Hinson 3

1 Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR; Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock, AR
2 Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR
3 Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock, AR

* To whom correspondence should be addressed. E-mail: jameslaurap{at}uams.edu.


  Abstract

The relationship between acetaminophen (APAP) reactive metabolite formation, nitrotyrosine (NT) production and cytokine elevation in APAP toxicity was investigated. Mice were dosed with 300 mg/kg APAP and sacrificed at 1, 2, 4, 8, and 12 hours. Serum AST was elevated by 4 hours. The relative amount of NT correlated with toxicity and localized in the necrotic cells. IL-1{beta} was increased at 1 hour, whereas IL-6, MIP-2 and MCP-1 were increased by 4-8 hours. To determine the importance of reversible versus toxic events, N-acetylcysteine (NAC) was administered to mice either before APAP or 1, 2, or 4 hours after APAP. Animals were sacrificed at 12 hours. NAC treatment before APAP resulted in serum AST, serum nitrate plus nitrite as a measure of nitric oxide (NO) production, and hepatic cytokine levels that were similar to controls. No APAP protein adducts or NT was present in these animals. In mice treated with NAC at 1 hour, cytokines and serum AST were normal at 12 hours, but APAP protein adducts were present in the hepatic centrilobular areas. No NT was present in these animals. In mice treated with NAC at 2 hours and sacrificed at 12 hours, serum AST was reduced by 80%. APAP adducts and NT were present in the centrilobular areas. Mice receiving NAC at 4 hours had no protection from toxicity and serum nitrate plus nitrite, NT and cytokine levels were similar to those of mice receiving APAP alone. The data suggest a relationship between metabolic events in APAP toxicity and the upregulation of NO and IL-1{beta}. IL-6, MIP-2 and MCP-1 appear to follow the toxicity. While it is a pre-requisite event, covalent binding per se does not appear to be a toxic event in the development of toxicity.


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