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BioMed Research International
Volume 2013 (2013), Article ID 627046, 13 pages
http://dx.doi.org/10.1155/2013/627046
Research Article

5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

1Department of Pathology, Biological Science Centre, State University of Londrina, Rodovia Celso Garcia Cid Pr 445, Km 380. Cx. Postal 6001, 86051-990 Londrina PR, Brazil
2Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil
3Department of Pharmaceutical Sciences, Health Sciences Centre, State University of Londrina, Rodovia Celso Garcia Cid Pr 445, Km 380, Cx. Postal 10011, 86051-990 Londrina, PR, Brazil

Received 30 April 2013; Revised 4 September 2013; Accepted 6 September 2013

Academic Editor: Chun-Ming Wong

Copyright © 2013 Miriam S. N. Hohmann et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

5-Lipoxygenase (5-LO) converts arachidonic acid into leukotrienes (LTs) and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP)-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/-) mice and background wild type mice were challenged with APAP (0.3–6 g/kg) or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10), superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2, -azinobis(3-ethylbenzothiazoline 6-sulfonate) assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.