Interactions of the pineal hormone melatonin with oxygen-centered free radicals: a brief review

Melatonin,N-acetyl-5-methoxytryptamine, is a hormonal product of the pineal gland. Its synthesis is higher at night than during the day in all vertebrates including man. Once melatonin is produced in the pineal gland it is quickly released into the vascular system. The rapid release of melatonin is generally believed to relate to its high lipophilicity which allows it to readily pass through the membrane of the pinealocytes and the endothelial cells which line the capillaries. The result of the nocturnal synthesis and secretion of melatonin is high blood levels at night. Also because of its highly lipophilic nature, melatonin from the blood readily escapes into every other bodily fluid and all cells in the body. Until recently it was generally thought that melatonin's action in the organism depended on its exclusive interaction with specific receptors on cells located in discrete locations. Certainly, the interactions of melatonin with these membrane-bound receptors are believed to mediate the endocrine and circadian rhythm effects of melatonin. It was recently discovered, however, that melatonin's primary action may not depend on the previously described membrane receptors. We have found that melatonin is a very potent hydroxyl radical scavenger; free radicals and the hydroxyl radical in particular, because of its very high reactivity, can be extremely damaging to macromolecules in cells. Compared to glutathione and mannitol, two well known free radical scavengers, melatonin is a more powerful scavenger and affords protection of molecules, especially DNA, from oxidative damage. Melatonin's extremely high diffusibility is important for its scavenging action because this feature allows it to enter all cells and every subcellular compartment. Whereas the free radical quenching activity of melatonin does not require a receptor, we also have evidence that it may be bound in the nucleus thereby providing on-site protection to DNA. Besides scavenging the highly toxic hydroxyl radical, melatonin also stimulates glutathione peroxidase activity which metabolizes the precursor of the hydroxyl radical, hydrogen peroxide, to water. Thus, melatonin has at least two means to protect the cell from oxidative damage, i.e., it breaks down hydrogen peroxide to harmless water and, in the event any hydroxyl radicals are formed, melatonin scavenges them. Melatonin may be the premier molecule to protect the organism from oxidative damage.