Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA.

Abstract

Oxidative stress mediates chemical damage to DNA yielding a wide variety of products. In this work, the potential capability of melatonin and several of its metabolites to repair directly (chemically) oxidative lesions in DNA was explored. It was found that all the investigated molecules are capable of repairing guanine-centered radical cations by electron transfer at very high rates, that is, diffusion-limited. They are also capable of repairing C-centered radicals in the sugar moiety of 2'-deoxyguanosine (2dG) by hydrogen atom transfer. Although this was identified as a rather slow process, with rate constants ranging from 1.75 to 5.32×102 M-1 s-1 , it is expected to be fast enough to prevent propagation of the DNA damage. Melatonin metabolites 6-hydroxymelatonin (6OHM) and 4-hydroxymelatonin (4OHM) are also predicted to repair OH adducts in the imidazole ring. In particular, the rate constants corresponding to the repair of 8-OH-G adducts were found to be in the order of 104 M-1 s-1 and are assisted by a water molecule. The results presented here strongly suggest that the role of melatonin in preventing DNA damage might be mediated by its capability, combined with that of its metabolites, to directly repair oxidized sites in DNA through different chemical routes.