ABSTRACT
Melatonin, a neurosecretory product of the pineal gland, was £rst isolated from bovine pineal tissue and was structurally distinguished as N-acetyl-5-methoxytryptamine in 1958.1 Afterward, numerous reports have been announced to show various key physiological actions of melatonin. For instance, melatonin was found to be a sleep enhancer,2 a chemical signal of light and darkness, and a regulator of photoperiod-dependent seasonal reproduction in some vertebrates. Both circadian rhythms and seasonal reproductive activities are closely regulated by the —uctuating endogenous melatonin signals. Thus, the daily and seasonally changing melatonin levels serve as a bio-clock and a bio-calendar in vertebrates.3 Melatonin injection has effects on gonads, which are sometimes stimulating and sometimes inhibitory in some species, depending on the time of the day of the injection. This £nding raised the hypothesis that the diurnal change in melatonin secretion acts as a timing signal coordinating endocrine and other internal events with the light/dark cycle of the external environment. Various reports have provided evidence supporting this observation. An interesting one is that in blind people with free-running circadian rhythms, injected melatonin entrains the rhythms.4 The amphibian pineal tissue also contains the indole N-acetyl-5-methoxytryptamine, which is named as melatonin since it acts on melanophores, which results in lightening of the skin of tadpoles. On the other hand, in mammals, including humans, it appears not to play a physiological role in the regulation of skin color.4 Subsequently, melatonin was found to be a potent, endogenously generated, and diet-derived free radical scavenger and broad-spectrum antioxidant.5-7 In many lower life forms including unicellular organisms and several metazoans, it serves only as an antioxidant.8 Melatonin is a direct scavenger of several reactive oxygen and nitrogen species (ROS/RNS) such as hydroxyl (OH•), superoxide anion (O2
i−), nitric oxide (NO•), and peroxynitrite (ONOO•) radicals.9 Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to regain their antioxidant properties. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.10 Furthermore, structurally different metabolites of melatonin appear to have free radical scavenging activity as well. The ability of melatonin and its metabolites to sequentially interact with ROS/RNS is referred to as the scavenging cascade reaction of melatonin.10 The production of melatonin in the pineal gland of vertebrates shows an apparent circadian rhythm with its peak near the middle of the scotophase and basal levels during the photophase. The amount of melatonin synthesized in the pineal gland
37.1 Introduction .......................................................................................................................... 541 37.2 Melatonin Biosynthesis and Its Metabolites ......................................................................... 542 37.3 Melatonin, Free Radicals, and Oxidation .............................................................................544 37.4 Functions of Melatonin Metabolites ..................................................................................... 545 37.5 Concluding Remarks ............................................................................................................546 References ......................................................................................................................................546
