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

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-/- mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR , a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO-/- 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.National Science Foundation of China [81270926, 81471068]; Distinguished Young Scientists of Sichuan Province [2014JQ0034]; Young Scientist Fellowship of Sichuan University [2013SCU04A17]SCI(E)PubMedARTICLEJinhanhe@scu.edu.cn166-7617