Drug-Mediated Intracellular Donation of Nitric Oxide Potently Inhibits 5-Lipoxygenase: A Possible Key to Future Antileukotriene Therapy

Antioxid Redox Signal. 2018 May 10;28(14):1265-1285. doi: 10.1089/ars.2017.7155. Epub 2017 Sep 8.


Aims: 5-Lipoxygenase (5-LO) is the key enzyme of leukotriene (LT) biosynthesis and is critically involved in a number of inflammatory diseases such as arthritis, gout, bronchial asthma, atherosclerosis, and cancer. Because 5-LO contains critical nucleophilic amino acids, which are sensitive to electrophilic modifications, we determined the consequences of a drug-mediated intracellular release of nitric oxide (NO) on 5-LO product formation by human granulocytes and on 5-LO-dependent pulmonary inflammation in vivo.

Results: Clinically relevant concentrations of NO-releasing nonsteroidal anti-inflammatory drugs and other agents releasing NO intracellularly suppress 5-LO product synthesis in isolated human granulocytes via direct S-nitrosylation of 5-LO at the catalytically important cysteines 416 and 418. Furthermore, suppression of 5-LO product formation was observed in ionophore-stimulated human whole blood and in an animal model of pulmonary inflammation.

Innovation: Here, we report for the first time that drugs releasing NO intracellularly are efficient 5-LO inhibitors in vitro and in vivo at least equivalent to approved 5-LO inhibitors.

Conclusion: Our findings provide a novel mechanistic strategy for the development of a new class of drugs suppressing LT biosynthesis by site-directed nitrosylation. The results may also help to better understand the well-recognized anti-inflammatory clinically relevant actions of NO-releasing drugs. Furthermore, our study describes in detail a novel molecular mode of action of NO. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Angel Lanas, Hartmut Kühn, Joan Clària, Orina Belton. Antioxid. Redox Signal. 28, 1265-1285.

Keywords: NO-donating NSAIDs; cysteines; nitrosylation; pulmonary inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Aspirin / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • HEK293 Cells
  • Humans
  • Leukotriene Antagonists / pharmacology*
  • Leukotrienes / metabolism*
  • Lipoxygenase Inhibitors / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Nitric Oxide / pharmacology*
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • Leukotriene Antagonists
  • Leukotrienes
  • Lipoxygenase Inhibitors
  • Nitric Oxide
  • Arachidonate 5-Lipoxygenase
  • Aspirin