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In this study, we examined whether deletion or pharmacological inhibition of 5\u2010LO could protect mice against paracetamol\u2010induced hepatic toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Both genetic deletion and pharmacological inhibition of 5\u2010LO in C57BL\/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&amp;E staining, and real\u2010time PCR were used to assess liver toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Deletion or pharmacological inhibition of 5\u2010LO in mice markedly ameliorated paracetamol\u2010induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5\u2010LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro\u2010toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5\u2010LO<jats:sup>\u2212\/\u2212<\/jats:sup>mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR \u03b1, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5\u2010LO<jats:sup>\u2212\/\u2212<\/jats:sup>mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The activity of 5\u2010LO may play a critical role in paracetamol\u2010induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13336","type":"journal-article","created":{"date-parts":[[2015,9,23]],"date-time":"2015-09-23T20:03:43Z","timestamp":1443038623000},"page":"66-76","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Loss of 5\u2010lipoxygenase activity protects mice against paracetamol\u2010induced liver toxicity"],"prefix":"10.1111","volume":"173","author":[{"given":"Shiyun","family":"Pu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Collaborative Innovation Center of 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