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Drug-Mediated Intracellular Donation of Nitric Oxide Potently Inhibits 5-Lipoxygenase

A Possible Key to Future Antileukotriene Therapy
: Roos, J.; Peters, M.; Maucher, I.V.; Kühn, B.; Fettel, J.; Hellmuth, N.; Brat, C.; Sommer, B.; Urbschat, A.; Piesche, M.; Vogel, A.; Proschak, E.; Blöcher, R.; Buscató, E.; Häfner, A.-K.; Matrone, C.; Werz, O.; Heidler, J.; Wittig, I.; Angioni, C.; Geisslinger, G.; Parnham, M.J.; Zacharowski, K.; Steinhilber, D.; Maier, T.J.


Antioxidants & redox signaling : ARS 28 (2018), No.14, pp.1265-1285
ISSN: 1523-0864 (print)
ISSN: 1557-7716 (online)
Journal Article
Fraunhofer IME ()

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.