- Further insights into the reaction of melatonin with hydroxyl radical
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Recent interest has focused on the use of exogenous melatonin as an antioxidant, particularly to scavenge the highly cytotoxic hydroxyl radical (HO?) which may be generated in many pathological conditions. However, in vitro and in vivo studies aimed at assessing the antioxidant properties of melatonin have produced conflicting results. While it is known that HO? reacts with melatonin at a diffusion limited rate, very little is known about the products of this reaction. In this investigation it is shown that incubation of melatonin with a Fenton-type HO?-generating system at pH 7.4 forms a complex mixture of primary products. These include 2-hydroxymelatonin, which was isolated as its more stable oxindole tautomer, 4- and 6-hydroxymelatonin, N-acetyl-N2-formyl-5-methoxykynurenine and 7,7′-bi-(5-methoxy-N-acetyltryptamine-4-one). Reaction pathways that might lead to these products are described. The differing biological effects of these products, while currently incompletely understood, might account for the controversy concerning the antioxidant properties of melatonin.
- Horstman, Joseph A.,Wrona, Monika Z.,Dryhurst, Glenn
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- Uses of melatonin in skin
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Melatonin, which can be produced in the skin, exerts a protective effect against damage induced by ultraviolet radiation (UVR). The present study investigated the effect of UVB, the most damaging component of UVR, on melatonin metabolism in HaCaT keratinocytes and in a cell-free system. Four metabolites were identified by HPLC and LC-MS: 6-hydroxymelatonin, AFMK, 2-hydroxymelatonin (the main intermediate between melatonin and AFMK) and 4-hydroxymelatonin. Concentrations of these photoproducts were directly proportional to UVR-dose and to melatonin substrate content, and their accumulation was time dependent. The UVR-dependent increase of AFMK and 2-hydroxymelatonin was also detected in keratinocytes, where it was accompanied by simultaneous consumption of intracellular melatonin. Of note, melatonin and its two major metabolites, 2-hydroxymelatonin and AFMK, were also detected in untreated keratinocytes, neither irradiated nor preincubated with melatonin. Thus, intracellular melatonin metabolism is enhanced under exposure to UVR. The additional biological activity of these individual melatonin metabolites increases the spectrum of potential actions of the recently identified cutaneous melatoninergic system.
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Page/Page column 2; 7-9; sheet 2; sheet 6
(2008/06/13)
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- An efficient synthesis of 6-hydroxymelatonin, a human metabolite of melatonin
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A four-step synthesis of 6-hydroxymelatonin 5, major human metabolite of melatonin 1, is reported starting from melatonin. The synthesis involves in the keys steps a regioselective Friedel-Crafts acylation followed by a Baeyer-Villiger oxidation. The overall yield is 48%.
- Karam, Omar,Zunino, Fabien,Chagnaut, Vincent,Jouannetaud, Marie Paule,Jacquesy, Jean Claude
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p. 1511 - 1513
(2007/10/03)
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- Reaction of peroxynitrite with melatonin: A mechanistic study
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The pH profile of the peroxynitrite/melatonin reaction suggests that both peroxynitrous acid (ONOOH) and its anion (ONOO-) are reactive toward melatonin, but at physiological pH most of the reaction with melatonin involves ONOOH and the activated form of peroxynitrous acid (ONOOH*). The formation of hydroxylated products (mainly 6-hydroxymelatonin) suggests that melatonin also reacts with ONOOH*. The overall peroxynitrite/melatonin reaction is first-order in melatonin and first-order in peroxynitrite, but the hydroxylation of melatonin is presumed to be zero-order in melatonin. Melatonin is metabolized in the liver, mainly to 6-hydroxymelatonin, so we do not think this metabolite is a useful biomarker for melatonin's antioxidant activity; however, 6-hydroxymelatonin is a better chain-breaking antioxidant than melatonin and may contribute to the beneficial effects of melatonin in vivo. As is now well-known, CO2 modulates the reactions of peroxynitrite. The reaction of peroxynitrite with melatonin in the absence of added bicarbonate produces mainly 6-hydroxymelatonin and 1,2,3,3a,8,8a-hexahydro- 1-acetyl-5-methoxy-8a-hydroxypyrrolo[2,3-b]indole, with some isomeric 1,2,3,3a,8,8a-hexahydro-1-acetyl-5-methoxy-3a-hydroxypyrrolo[2,3-b]indole. In the presence of added bicarbonate, product yields decrease and 6- hydroxymelatonin is not formed. These facts suggest that melatonin scavenges reactive species (such as CO3(°-) and °NO2) that are produced from the peroxynitrite/CO2 reaction. The spectrum of the melatoninyl radical cation is observed both in the absence and in the presence of added bicarbonate, suggesting that the melatoninyl radical cation is the initial product and the hydroxypyrrolo[2,3-b]indole products are derived from it. Unlike tyrosine, where both nitrated and hydroxylated products can be isolated, nitromelatonin is not found in the final products from the melatonin/peroxynitrite reaction in either the absence or presence of added bicarbonate. However, we suggest that 2-hydroxy-3-nitro- and/or 2-hydroxy-3-peroxynitro-2,3-dihydromelatonin are formed as intermediates and subsequently decompose to give 1,2,3,3a,8,8a- hexahydro-1-acetyl-5-methoxy-8a-hydroxypyrrolo[2,3-b]indole. Since peroxynitrite/CO2 governs the reactions of peroxynitrite in vivo, we suggest that the hydroxypyrrolo[2,3-b]indole products are the main products from the oxidation of melatonin by peroxynitrite-derived species in vivo, and that these products may serve as indexes for melatonin's antioxidant activity.
- Zhang, Houwen,Squadrito, Giuseppe L.,Uppu, Rao,Pryor, William A.
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p. 526 - 534
(2007/10/03)
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