of Work: Melatonin (N-acetyl-5-methoxytryptamine, MLT) an indole hormone systhesized in the pineal gland and the retina, controls several essential physiological functions associated with circadian and seasonal rhthyms. It is involved in immune responses, aging processes and age-related diseases. Because all these processes are associated with oxidative damage of vital cell components, it has been postulated that melatonin may function as a natural antioxidant and free redical scavenger. The primary objective of this reasearch project was to determine rate constants for the reaction of MLT with free radicals (*OH, *CH3, *OCH3) and with singlet oxygen (1O2) a highly oxidizing form of oxygen. In addition to MLT, we studied related indoles 6-hydroxymelatonin, 6-chloromelatonin, 5-methoxytryptamine, 5-hydroxytryptamine, and a tryptophan metabolite kynurenine. It was found that all the indoles reat with *OH at near diffusion controlled rates, [kr (indole/*OH) about 1010/M sec, for MLT kr=2.6x1010/M sec]. The interaction of the indoles with *CH3 radicals is less efficient, and occurs with the rate constant of about 107/M sec. In contrast, scavenging of *OCH3 is a very fast process (k about 109/M sec). The 1O2 quenching efficacy depends on the position and the nature of the substituent(s) of the indole nucleus, and also on the reaction environment. In CH3CN and CD3OD the 1O2 quenching occurs with the rate about 107 - 10 8/M sec, while in D2O the quenching is more that ten-fold faster. The melatonin precursor serotonin generated hydroxyl radicals in the presence of ferric iron and H2O2, and the melatonin metabolite 6-hydroxymelatonin generated copius amounts of *OH radicals even in the absence of exogenously added H2O2. Given the reported low toxicity of MLT, its ready accumulation in all types of cells due to its high lipophilicity and distibution throughout the entire body via the blood stream, MLT may be considered a potential antioxidant when taken in pharmacological doses. However, the physiological concentrations of melatonin (100 pg/ml in the plasma) are probably too low for the hormone to act as a physiological antioxidant.
