Melatonin, a potent agent in antioxidative defense: actions as a natural food constituent, gastrointestinal factor, drug and prodrug

Abstract

Melatonin, originally discovered as a hormone of the pineal gland, is also produced in other organs and represents, additionally, a normal food constituent found in yeast and plant material, which can influence the level in the circulation. Compared to the pineal, the gastrointestinal tract contains several hundred times more melatonin, which can be released into the blood in response to food intake and stimuli by nutrients, especially tryptophan. Apart from its use as a commercial food additive, supraphysiological doses have been applied in medical trials and pure preparations are well tolerated by patients. Owing to its amphiphilicity, melatonin can enter any body fluid, cell or cell compartment. Its properties as an antioxidant agent are based on several, highly diverse effects. Apart from direct radical scavenging, it plays a role in upregulation of antioxidant and downregulation of prooxidant enzymes, and damage by free radicals can be reduced by its antiexcitatory actions, and presumably by contributions to appropriate internal circadian phasing, and by its improvement of mitochondrial metabolism, in terms of avoiding electron leakage and enhancing complex I and complex IV activities. Melatonin was shown to potentiate effects of other antioxidants, such as ascorbate and Trolox. Under physiological conditions, direct radical scavenging may only contribute to a minor extent to overall radical detoxification, although melatonin can eliminate several of them in scavenger cascades and potentiates the efficacy of antioxidant vitamins. Melatonin oxidation seems rather important for the production of other biologically active metabolites such as N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), which have been shown to also dispose of protective properties. Thus, melatonin may be regarded as a prodrug, too. AMK interacts with reactive oxygen and nitrogen species, conveys protection to mitochondria, inhibits and downregulates cyclooxygenase 2.

Figure 1

The kynuric pathway of melatonin metabolism.

Figure 2

Overview of the pleiotropic actions of melatonin and some of its metabolites in antioxidative protection.

Figure 3

A model of mitochondrial radical avoidance and support of electron flux by melatonin and its metabolite AMK. The potent electron donors melatonin and AMK are thought to feed electrons into the respiratory chain, thereby forming resonance-stabilized cation radicals which may efficiently compete with molecular oxygen for electrons leaking from iron-sulfur cluster N2 or from ubisemiquinone. The competition reduces superoxide anion formation and, thereby, the generation of secondary radicals; at the same time, electrons re-fed to the electron transport chain contribute to the maintenance of the proton potential and, thus, to ATP synthesis. The model is partially hypothetical, but might explain observations of reductions in electron leakage and oxidant formation as well as an enhancement of ATP formation.