Loss of 5‐lipoxygenase activity protects mice against paracetamol‐induced liver toxicity

Abstract

BACKGROUND AND PURPOSEParacetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. EXPERIMENTAL APPROACHBoth genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. KEY RESULTSDeletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO À/À mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO À/À mice. CONCLUSIONS AND IMPLICATIONSThe activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress. Abbreviations

Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet–Induced Obesity and Insulin Resistance by Inhibiting Lipolysis

“…Real-time PCR and chromatin immunoprecipitation (ChIP) assay were performed as described (26,27). Primer sequences are listed in Supplementary Tables 2 and 3.…”

Aqueous Partition of Methanolic Extract of Dicranopteris linearis Leaves Protects against Liver Damage Induced by Paracetamol

“…The LOXs pathway is involved in the metabolism of leukotrienes and has been implicated in hepatic inflammation and liver damage [48]. Interestingly, further studies by Li et al [49] revealed that inhibition of LOX pathway attenuates acute liver failure by inhibiting macrophage activation, while Pu et al [50] demonstrated the critical role of 5-LO activity in PCM-induced liver injury by regulating paracetamol metabolism and oxidative stress. It was found that pharmacological inhibition of 5-LO in mice markedly ameliorated PCM-induced liver injury while inhibition of 5-LO induced hepatoprotective effect, which was associated with induction of the antitoxic phase II conjugating enzyme (sulfotransferase2a1), suppression of the pro-toxic phase I (CYP3A11), and reduction of the hepatic transporter (MRP3).…”

BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils

“…A recent report 47 showed that a lack of the 5-LOX gene and pharmacological inhibition of 5-LOX synthase reduce APAP-induced liver injury, as demonstrated by decreases in the ALT level and hepatic necrosis. The protective effect of 5-LOX inhibition on APAP hepatotoxicity is attributed to attenuation of APAP bioactivation and oxidative stress.…”