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

作者：Roos Jessica^*; Peters Marcus; Maucher Isabelle V; Kuehn Benjamin; Fettel Jasmin; Hellmuth Nadine; Brat Camilla; Sommer Benita; Urbschat Anja; Piesche Matthias; Vogel Anja; Proschak Ewgenij; Bloecher Rene; Buscato Estella; Haefner Ann Kathrin; Matrone Carmela; Werz Oliver; Heidler Juliana; Wittig Ilka; Angioni Carlo; Geisslinger Gerd; Parnham Michael J; Zacharowski Kai; Steinhilber Dieter; Maier Thorsten J

来源：Antioxidants and Redox Signaling, 2018, 28(14): 1265-1285.

DOI：10.1089/ars.2017.7155

• pulmonary inflammation
• NO-donating NSAIDs
• cysteines
• nitrosylation

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.

• 出版日期2018-5