During inflammatory events, neutrophils and platelets interact to release a variety of mediators. Neutrophils generate superoxide and hydrogen peroxide, and also discharge the haem enzyme myeloperoxidase. Among numerous other mediators, platelets liberate serotonin (5-hydroxytryptamine), which is a classical neurotransmitter and vasoactive amine that has significant effects on inflammation and immunity. In the present study, we show that serotonin is a favoured substrate for myeloperoxidase because other physiological substrates for this enzyme, including chloride, did not affect its rate of oxidation. At low micromolar concentrations, serotonin enhanced hypochlorous acid production by both purified myeloperoxidase and neutrophils. At higher concentrations, it almost completely blocked the formation of hypochlorous acid. Serotonin was oxidized to a dimer by myeloperoxidase and hydrogen peroxide. It was also converted into tryptamine-4,5-dione, especially in the presence of superoxide. This toxic quinone was produced by stimulated neutrophils in a reaction that required myeloperoxidase. In plasma, stimulated human neutrophils oxidized serotonin to its dimer using the NADPH oxidase and myeloperoxidase. We propose that myeloperoxidase will oxidize serotonin at sites of inflammation. In doing so, it will impair its physiological functions and generate a toxic metabolite that will exacerbate inflammatory tissue damage. Consequently, oxidation of serotonin by myeloperoxidase may profoundly influence inflammatory processes.
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Research Article|
December 14 2009
Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione
Valdecir F. Ximenes;
Valdecir F. Ximenes
*Departamento de Química, Faculdade de Ciências, Universidade Estadual Paulista Júlio de Mesquita Filho, Bauru, SP, Brazil, †Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Medical Foundation Building K25, 92-94 Parramatta Road, Camperdown, NSW 2006, Australia
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Ghassan J. Maghzal;
Ghassan J. Maghzal
‡Free Radical Research, Department of Pathology, University of Otago Christchurch, P.O. Box 4345, Christchurch, New Zealand
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Rufus Turner;
Rufus Turner
§School of Human Science and Environment, University of Hyogo, Himeji 670-0092, Japan
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Yoji Kato;
Yoji Kato
§School of Human Science and Environment, University of Hyogo, Himeji 670-0092, Japan
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Christine C. Winterbourn;
Christine C. Winterbourn
§School of Human Science and Environment, University of Hyogo, Himeji 670-0092, Japan
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Anthony J. Kettle
Anthony J. Kettle
1
§School of Human Science and Environment, University of Hyogo, Himeji 670-0092, Japan
1To whom correspondence should be addressed (email tony.kettle@otago.ac.nz).
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Publisher: Portland Press Ltd
Received:
May 21 2009
Revision Received:
October 06 2009
Accepted:
October 14 2009
Accepted Manuscript online:
October 14 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 425 (1): 285–293.
Article history
Received:
May 21 2009
Revision Received:
October 06 2009
Accepted:
October 14 2009
Accepted Manuscript online:
October 14 2009
Citation
Valdecir F. Ximenes, Ghassan J. Maghzal, Rufus Turner, Yoji Kato, Christine C. Winterbourn, Anthony J. Kettle; Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione. Biochem J 1 January 2010; 425 (1): 285–293. doi: https://doi.org/10.1042/BJ20090776
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