Cyclic 3-Hydroxymelatonin: A Melatonin Metabolite Generated as a Result of Hydroxyl Radical Scavenging

Tan, Dun Xian; Manchester, Lucien C.; Reíter, Russel J.; Plummer, Benjamin F.

doi:10.1159/000014571

Cited by 68 publications

(55 citation statements)

References 25 publications

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“…The formation of this molecule demonstrates the relevance of the aliphatic side chain for the redox properties of melatonin, although this was originally not foreseeable. c3OHM was detected in the urine of rats and humans [138,139]. Its concentration increased considerably after exposure of rats to ionizing radiation [139].…”

Section: Non-enzymatic Hydroxylation and Nitro-sationmentioning

confidence: 98%

“…To date, the production of c3OHM in the absence of hydroxyl radicals has been convincingly demonstrated with a synthetic, low-reactivity radical, the ABTS cation radical [ABTS = 2,2´-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)] [135]. In mice, c3OHM was especially detected in the urine after administration of exogenous melatonin [135,138]. However, the major fraction of c3OHM was reported to be present as a sulfate conjugate [80].…”

Section: Non-enzymatic Hydroxylation and Nitro-sationmentioning

confidence: 99%

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Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

114

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: Non-enzymatic Hydroxylation and Nitro-sationmentioning

confidence: 98%

Section: Non-enzymatic Hydroxylation and Nitro-sationmentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

114

110

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“…This kind of reactivity is common for the pro-and antioxidative activity of hydroxy group-containing vitamins such as vitamin C and vitamin E and naturally occurring thiol-containing compounds such as GSH [89,90]. Once a melatonin molecule scavenges two HO W , it is metabolized to a ther- mostatic end-product, cyclic-3-hydroxymelatonin, and excreted in the urine [55,91]. When a melatonin molecule scavenges a H 2 O 2 , it transforms to form AFMK.…”

Section: Classical Antioxidants and Melatoninmentioning

confidence: 99%

Significance of Melatonin in Antioxidative Defense System: Reactions and Products

et al. 2000

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Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant. Melatonin has been reported to scavenge hydrogen peroxide (H₂O₂), hydroxyl radical (HO·), nitric oxide (NO·), peroxynitrite anion (ONOO^–), hypochlorous acid (HOCl), singlet oxygen (¹O₂), superoxide anion (O₂^–·) and peroxyl radical (LOO·), although the validity of its ability to scavenge O₂^–· and LOO· is debatable. Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms. The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione. As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it. Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine. Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions. From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants. Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole. Indeed, one melatonin molecule scavenges two HO·. Also, its secondary and tertiary metabolites, for example, N¹-acetyl-N²-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers. The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction. Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals. Melatonin has been detected in vegetables, fruits and a variety of herbs. In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates. Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals.

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“…Melatonin, being a potential free radical scavenger [26][27][28][29][30][31] with a soporific effect, may be considered as an adjunct anaesthetic agent to halothane in the future.…”

Section: Discussionmentioning

confidence: 99%

Effects of Halothane, Pentobarbital and Ketamine on Serum Melatonin Levels in the Early Scotophase in New Zealand White Rabbits

et al. 2001

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In mammals, the nocturnal rise in pineal melatonin is regulated by signals from the endogenous clock, the hypothalamic suprachiasmatic nuclei. There have been few reports on whether anaesthetics which modulate multisynaptic neuronal functions affect melatonin secretion. We studied the effects of three commonly used anaesthetics, halothane, pentobarbital and ketamine, on serum melatonin levels in male New Zealand white rabbits. Seven blood samples were collected, 30–60 min apart, before, during and after anaesthesia. Experiments were performed in the late light and early dark period, so that changes in melatonin secretion would be reflected in the onset and/or level of nocturnal serum melatonin. Serum melatonin levels were determined by radioimmunoassay. Our results indicated that halothane attenuated the release of melatonin and pentobarbital had no apparent effect, whereas ketamine potentiated the release of melatonin. These findings suggest that melatonin levels may be affected in patients anaesthetized with halothane or ketamine, resulting in disturbed biological rhythms, especially the sleep-wake cycle following recovery.

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Cyclic 3-Hydroxymelatonin: A Melatonin Metabolite Generated as a Result of Hydroxyl Radical Scavenging

Cited by 68 publications

References 25 publications

Melatonin Metabolism in the Central Nervous System

Melatonin Metabolism in the Central Nervous System

Significance of Melatonin in Antioxidative Defense System: Reactions and Products

Effects of Halothane, Pentobarbital and Ketamine on Serum Melatonin Levels in the Early Scotophase in New Zealand White Rabbits

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