Further insights into the reaction of melatonin with hydroxyl radical

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.