Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug
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.
In several countries, melatonin is sold over the counter; in others its free sale is prohibited. The usefulness of melatonin as a food additive continues to be a matter of debate. Meanwhile, countless people have used melatonin for mitigating the symptoms of jet lag, an application which has been tested and is recommended [1-4]; any person we have spoken to has reported positive experiences. Melatonin has been and is being used in several clinical trials with different therapeutic approaches. In some of these studies, in addition to improvements of sleep, the repeatedly demonstrated antioxidant properties [5-10] were the main reason for testing the pineal hormone. This holds especially for the treatment of neurodegenerative disorders, such as Alzheimer's disease [11-13] and amyotrophic lateral sclerosis .
In terms of application it seems necessary to thoroughly analyze the mechanisms of antioxidant actions of melatonin and to distinguish between effects observed at pharmacological or physiological concentrations. These considerations must not be restricted to the melatonin released from the pineal gland into the circulation and to the classic hepatic degradation route of 6-hydroxylation followed by conjugation. On the contrary, we would like to lay emphasis on the significance of tissue melatonin and the alternate oxidative pathways of catabolism leading to different, biologically active products. The relationship between melatonin and nutrition will be discussed, with regard to the presence of the compound as a natural food constituent sometimes affecting circulating levels, to the post-prandial release of melatonin from the gastrointestinal tract, and to interactions with other antioxidants present in food. Finally, a model of mitochondrial protection is reviewed.
Melatonin in food and gastrointenstinal tract
Melatonin reactions with oxidants
Metabolites of melatonin; melatonin as a prodrug
Melatonin as antioxidant
Safety of melatonin; conclusion
List of natural melatonin sources
List of abbrevations
ABTS: 2, 2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)
ALS: amyotrophic lateral sclerosis
c3OHM: cyclic 3-hydroxymelatonin
COX-2: cyclooxygenase 2
GSSG: oxidized glutathione
1Institute of Zoology and Anthropology, University of Göttingen, Berliner Str. 28, D-37073 Göttingen, Germany
2Comprehensive Center for Sleep Medicine, Department of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, 1176 - 5th Avenue, New York, NY 10029, USA
Nutrition & Metabolism 2005, 2:22 doi:10.1186/1743-7075-2-22
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1743-7075/2/22
© 2005 Hardeland and Pandi-Perumal; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Authors declare that they have no competing interests concerning the use of melatonin or melatonin-containing preparations as a food additive.
This review was initiated by SRP-P; a first version by RH was jointly revised.