A review of the evidence supporting melatonin's role as an antioxidant

Abstract: This survey summarizes the findings, accumulated within the last 2 years, concerning melatonin's role in defending against toxic free radicals. Free radicals are chemical constituents that have an unpaired electron in their outer or‐bital and, because of this feature, are highly reactive. Inspired oxygen, which sustains life, also is harmful because up to 5% of the oxygen (O₂) taken in is converted to oxygen‐free radicals. The addition of a single electron to O₂ produces the superoxide anion radical (O₂); C₂: is catalytic‐reduced by superoxide dismutase, to hydrogen peroxide (H₂O₂). Although H₂O₂ is not itself a free radical, it can be toxic at high concentrations and, more importantly, it can be reduced to the hydroxyl radical (OH). The OH is the most toxic of the oxygen‐based radicals and it wreaks havoc within cells, particularly with macromolecules. In recent in vitro studies, melatonin was shown to be a very efficient neutralizer of the OH; indeed, in the system used to test its free radical scavenging ability it was found to be significantly more effective than the well known antioxidant, glutathione (GSH), in doing so. Likewise, melatonin has been shown to stimulate glutathione peroxidase (GSH‐Px) activity in neural tissue; GSH‐PX metabolizes reduced glutathione to its oxidized form and in doing so it converts H₂O₂ to H₂O, thereby reducing generation of the OH by eliminating its precursor. More recent studies have shown that melatonin is also a more efficient scavenger of the peroxyl radical than is vitamin E. The peroxyl radical is generated during lipid peroxidation and propagates the chain reaction that leads to massive lipid destruction in cell membranes. In vivo studies have demonstrated that melatonin is remarkably potent in protecting against free radical damage induced by a variety of means. Thus, DNA damage resulting from either the exposure of animals to the chemical carcinogen safrole or to ionizing radiation is markedly reduced when melatonin is co‐administered. Likewise, the induction of cataracts, generally accepted as being a consequence of free radical attack on lenticular macromolecules, in newborn rats injected with a GSH‐depleting drug are prevented when the animals are given daily melatonin injections. Also, paraquat‐induced lipid peroxidation in the lungs of rats is overcome when they also receive melatonin during the exposure period. Paraquat is a highly toxic herbicide that inflicts at least part of its damage by generating free radicals. Finally, bacterial endotoxin (lipopolysaccharide or LPS)‐induced free radical damage to a variety of organs is highly significantly reduced when melatonin is also administered; LPS, like paraquat, produces at least part of its damage to cells by inducing the formation of free radicals. Physiological melatonin concentrations have also been shown to inhibit the nitric oxide (NO)‐generting enzyme, nitric oxide synthase. The reduction of NO‐ production would contribute to melatonin's antioxidant action since NO‐ can generate the peroxynitrite anion, which can degrade into the OH. Thus, melatonin seems to have multiple ways either to reduce free radical generation or, once produced, to neutralize them. Melatonin accomplishes these actions without membrane receptors, indicating that the indole has important metabolic functions in every cell in the organism, not only those that obviously contain membrane receptors for this molecule.