title: Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity.
abstract: OBJECTIVE
  Paracetamol (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.
  
  
  METHODS
  Both 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.
  
  
  RESULTS
  Deletion 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 α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO(-/-) mice.
  
  
  CONCLUSIONS
  The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Shiyun
authors.initials: S
authors.lastname: Pu
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ren
authors.affiliation: Laboratory of Clinical Pharmacy and Adverse Drug Reaction, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Qinhui
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Jiangying
authors.initials: J
authors.lastname: Kuang
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Shihai
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Division of Endocrinology and Metabolism, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pharmacy, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.|Laboratory of Clinical Pharmacy and Adverse Drug Reaction, Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008084:Lipoxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D015238:Sulfotransferases / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D008565:Membrane Proteins; D047493:PPAR alpha; D020011:Protective Agents; D017392:Thiobarbituric Acid Reactive Substances; C543400:mitogen-regulated protein 3, mouse; D000082:Acetaminophen; D006861:Hydrogen Peroxide; D008084:Lipoxygenase; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D015238:Sulfotransferases; D005978:Glutathione