5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

• Published in: BioMed research international Vol. 2013; no. 2013; pp. 1 - 13
• Main Authors: Cunha, Fernando Queiroz, Casagrande, Rúbia, Verri, Waldiceu A., Pinge-Filho, Phileno, da Silva, Rosiane V., Alves-Filho, José C., Cunha, Thiago Mattar, Crespigio, Jefferson, Pinho-Ribeiro, Felipe A., Cardoso, Renato D. R., Hohmann, Miriam S. N., Ferreira, Sergio Henrique
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2013; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Acetaminophen; Acetaminophen - adverse effects; Acetaminophen - pharmacology; Alanine Transaminase - blood; Alanine Transaminase - genetics; Analgesics, Non-Narcotic - adverse effects; Analgesics, Non-Narcotic - pharmacology; Analysis; Animals; Arachidonate 5-Lipoxygenase; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Cytokines - blood; Cytokines - genetics; Health aspects; Inflammation; Inflammation - chemically induced; Inflammation - enzymology; Inflammation - genetics; Inflammation - pathology; Ischemia; Membrane Glycoproteins - blood; Membrane Glycoproteins - genetics; Mice; Mice, Knockout; Mortality; NADPH Oxidase 2; NADPH Oxidases - blood; NADPH Oxidases - genetics; NF-E2-Related Factor 2 - blood; NF-E2-Related Factor 2 - genetics; Oxidation-Reduction - drug effects; Oxidative stress; Participation; Pathogenesis; Proteins; Risk factors; Rodents; Studies; Superoxides - blood
• ISSN: 2314-6133; 2314-6141
• DOI: 10.1155/2013/627046

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 gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-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.