In vitro radical-scavenging mechanism of melatonin and its in vivo protective effect against radiation-induced lipid peroxidation

Melatonin (N-acetyl-5-methoxytryptamine, MLT), an evolutionarily conserved indoleamine, is known to act as an antioxidant. However, the evidence indicating the role of MLT as a powerful chain-breaking antioxidant by scavenging peroxyl radical remains controversial. The radical-scavenging rate of MLT determined in this study in methanol using galvinoxyl radical (GO•) was much lower than that of an α-tocopherol model compound. The acceleration of the GO•-scavenging reaction by MLT was observed in the presence of magnesium ion (Mg2+), a bio-related redox-inactive metal ion, suggesting that this reaction may proceed via a rate-determining electron transfer followed by proton transfer. The coordination of Mg2+ to the carbonyl oxygen in the one-electron reduced species of GO• (GO–) may stabilize the product, resulting in the acceleration of the electron-transfer process. We also demonstrated that prophylactically administrated MLT efficiently inhibited the lipid peroxide-derived protein modification, which can be detected by a sensitive marker, Nε-(hexanoyl)lysine adduct, in the plasma of X-irradiated mice. The relatively weak GO•-scavenging activity of MLT suggests that the ameliorative effect of MLT against in vivo lipid peroxidation does not result from the direct scavenging of lipid peroxyl radicals by MLT. Therefore, the observed superior protective efficiency of MLT against in vivo lipid peroxidation may partly support the earlier studies, which reported the synergistic antioxidative effect of the metabolites of MLT.