title: 5-lipoxygenase deficiency reduces acetaminophen-induced hepatotoxicity and lethality.
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 gp91(phox) 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.
authors.affiliation: Department 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.
authors.forename: Miriam S N
authors.initials: MS
authors.lastname: Hohmann
authors.forename: Renato D R
authors.initials: RD
authors.lastname: Cardoso
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.forename: Jefferson
authors.initials: J
authors.lastname: Crespigio
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Rosiane V
authors.initials: RV
authors.lastname: da Silva
authors.forename: Phileno
authors.initials: P
authors.lastname: Pinge-Filho
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000097:blood / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000097:blood / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D013481:Superoxides / Q000097:blood
chemical_list: D018712:Analgesics, Non-Narcotic; D016207:Cytokines; D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013481:Superoxides; D000082:Acetaminophen; D001094:Arachidonate 5-Lipoxygenase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000410:Alanine Transaminase