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 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.

Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice

“…This is also an analgesic, antioxidant and anti-inflammatory pathway [23,24,49,50]. Nrf2 also induces GSH production [51], therefore, this result is in agreement with the quercetin prevention of GSH depletion.…”

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“…Tissue neutrophil ( Figure 3C) and macrophage ( Figure 3D) recruitment was assessed in the mice paw skin tissue by determining the myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity, respectively. 22 No effect was observed with the doses of 3 and 10 …”

Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF-κB activation

“…The quantitation of O 2 •-production in tissue homogenates was performed using the NBT assay as described previously [36]. Skin samples were collected 3 h after the stimulus.…”

“…RT-qPCR was performed as previously described [36]. Skin samples were collected 3 h after stimulus, homogenized in trizol reagent, and total RNA was isolated according to manufacturer's directions.…”