title: Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione.
abstract: 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.
authors.affiliation: Departamento de Química, Faculdade de Ciências, Universidade Estadual Paulista Júlio de Mesquita Filho, Bauru, SP, Brazil.
authors.forename: Valdecir F
authors.initials: VF
authors.lastname: Ximenes
authors.forename: Ghassan J
authors.initials: GJ
authors.lastname: Maghzal
authors.forename: Rufus
authors.initials: R
authors.lastname: Turner
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kato
authors.forename: Christine C
authors.initials: CC
authors.lastname: Winterbourn
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kettle
mesh_terms: D002384:Catalysis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003603:Cytotoxins / Q000378:metabolism; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D045563:Indolequinones / Q000378:metabolism*; D013058:Mass Spectrometry; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012701:Serotonin / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013481:Superoxides / Q000378:metabolism*; D014363:Tryptamines / Q000378:metabolism*
chemical_list: D003603:Cytotoxins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D045563:Indolequinones; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D013481:Superoxides; D012701:Serotonin; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase