Oxidation of melatonin and its catabolites, N1‐acetyl‐N 2‐formyl‐5‐methoxykynuramine and N1‐acetyl‐5‐methoxykynuramine, by activated leukocytes

Silva, Sueli de Oliveira; Rodrigues, Maria Rita; Carvalho, Sandra Regina Quintal; Catalani, Luiz H.; Čampa, Ana; Ximenes, Valdecir Farias

doi:10.1111/j.1600-079x.2004.00149.x

Cited by 99 publications

(95 citation statements)

References 18 publications

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“…It remains to be studied whether microglia responds in a similar way to melatonin and AFMK. Activated microglia could convert melatonin by two enzymes, indoleamine 2,3-dioxygenase, although its main substrate is tryptophan, not melatonin [50,51,122,132], and myeloperoxidase [27,50,111,123,157,158]. Additionally, melatonin might be oxidized to AFMK by reactive oxygen species [38,39,47,50,136,141] transiently formed in excess.…”

Section: The Kynuramine Pathwaymentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

112

110

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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Section: The Kynuramine Pathwaymentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

112

110

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“…Some melatonin metabolites that have scavenger properties, like N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) and N 1 -acetyl-5-methoxykynuramine (AMK), [55] help inactivate immune-competent cells [8,56] .…”

Section: Shuttle Between Endocrine and Paracrine Melatonin Sources Atmentioning

confidence: 99%

The Immune-Pineal Axis: A Shuttle between Endocrine and Paracrine Melatonin Sources

Markus

Ferreira

Fernandes

et al. 2007

Neuroimmunomodulation

132

144

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The time course of the innate immunological response involves a pro-inflammatory phase followed by an anti-inflammatory phase. Pro-inflammatory responses serve as a defense against several stressor conditions, and sequential processes that shut down these responses are necessary to avoid exacerbation or the development of chronic diseases. In the present review, we put together recent data that show that the pineal gland is a player in bidirectional control of the inflammatory response. Healthy organisms stay in standby mode, ready to react. The nocturnal melatonin surge impairs the rolling and adherence of leukocytes to endothelial layers, limiting cell migration, and stimulates nocturnal production of IL-2 by T helper lymphocytes, exerting an immunostimulatory effect. Otherwise, the release of TNF-α from activated macrophages suppresses the nocturnal melatonin surge, allowing a full cell migration and inhibiting IL-2 production. In sequence, activated mononuclear and polymorphonuclear cells produce melatonin in a paracrine manner at the site of injury, which scavenges free radicals and collaborates to resolve the inflammatory response. The sequential diminution of TNF-α production is followed by the recovery of the nocturnal melatonin surge and IL-2 production. In summary, the immune-pineal axis, implicated in the sequential involvement of the melatonin produced by the pineal gland and immune-competent cells, is an integral participant of the innate immune response.

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“…We have found that neutrophils and macrophages oxidize melatonin to a chemiluminescent product, presumably N 1 -acetyl-N 2 -formyl-5-methoxykynuramide (AFMK) (21)(22)(23). The reaction required superoxide and was blocked by azide, which is an inhibitor of heme enzymes.…”

mentioning

confidence: 99%

Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase

Ximenes

Silva

Rodrigues

et al. 2005

Journal of Biological Chemistry

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Myeloperoxidase uses hydrogen peroxide to oxidize numerous substrates to hypohalous acids or reactive free radicals. Here we show that neutrophils oxidize melatonin to N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) in a reaction that is catalyzed by myeloperoxidase. Production of AFMK was highly dependent on superoxide but not hydrogen peroxide. It did not require hypochlorous acid, singlet oxygen, or hydroxyl radical. Purified myeloperoxidase and a superoxide-generating system oxidized melatonin to AFMK and a dimer. The dimer would result from coupling of melatonin radicals. Oxidation of melatonin was partially inhibited by catalase or superoxide dismutase. Formation of AFMK was almost completely eliminated by superoxide dismutase but weakly inhibited by catalase. In contrast, production of melatonin dimer was enhanced by superoxide dismutase and blocked by catalase. We propose that myeloperoxidase uses superoxide to oxidize melatonin by two distinct pathways. One pathway involves the classical peroxidation mechanism in which hydrogen peroxide is used to oxidize melatonin to radicals. Superoxide adds to these radicals to form an unstable peroxide that decays to AFMK. In the other pathway, myeloperoxidase uses superoxide to insert dioxygen into melatonin to form AFMK. This novel activity expands the types of oxidative reactions myeloperoxidase can catalyze. It should be relevant to the way neutrophils use superoxide to kill bacteria and how they metabolize xenobiotics.Catalysis of hypochlorous acid production is the accepted physiological function of myeloperoxidase (MPO) 2 (1, 2). This heme enzyme is the major protein in neutrophils and is also present in monocytes, macrophages, microglia (3), and neurons (4, 5). It reacts with hydrogen peroxide to form the redox intermediate compound I, which oxidizes chloride to hypochlorous acid with coincident regeneration of the native enzyme (Reactions 1 and 2). HOCl indicates hypochlorous acid.Myeloperoxidase also promotes the oxidation of numerous substrates (RH) to free radical intermediates via the classical peroxidase cycle involving compound I and compound II (Reactions 3 and 4).Klebanoff (6) was the first to show that myeloperoxidase has potent antimicrobial activity because of its ability to generate hypochlorous acid. He proposed that myeloperoxidase produces hypochlorous acid inside phagosomes where it reacts with and kills ingested bacteria. However, during microbial killing myeloperoxidase functions in the presence of a high flux of superoxide (7). Superoxide reacts rapidly with native enzyme to produce oxymyeloperoxidase or compound III (Reaction 5; k 5 ϭ 2 ϫ 10 6 M Ϫ1 s Ϫ1 (8)), which is the dominant form of myeloperoxidase in stimulated neutrophils (9). Reactions of superoxide with myeloperoxidase are likely to be important in host defense because it has been demonstrated that superoxide enhances myeloperoxidasedependent killing of Staphylococcus aureus by isolated human neutrophils (10). The nature of this interaction has yet to be revealed.Compound II...

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Oxidation of melatonin and its catabolites, N¹‐acetyl‐N ²‐formyl‐5‐methoxykynuramine and N¹‐acetyl‐5‐methoxykynuramine, by activated leukocytes

Cited by 99 publications

References 18 publications

Melatonin Metabolism in the Central Nervous System

Melatonin Metabolism in the Central Nervous System

The Immune-Pineal Axis: A Shuttle between Endocrine and Paracrine Melatonin Sources

Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase

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