Mechanistic insights into the direct antioxidant effects of estrogens

Free-radical scavenging by estrogens has been implicated as one of their non-genomic (estrogen-receptor independent) mechanisms of cytoprotection. This activity is associated with the presence of the phenolic A-ring in the structure of these molecules, thus rendering them members of the class of compounds called phenolic antioxidants. Direct oxyradical-scavenging by estrogens has been thought to cause interruption of free-radical chain reactions such as lipid peroxidation, and to prevent free-radical induced oxidative damage to biological macromolecules such as DNA and proteins. These antioxidant effects are determined not only by chemical reactivities toward reactive oxygen or reactive nitrogen species, but also by the mobility and/or distribution of estrogens in the biological microenvironment and by the fate of the estrogen-derived radicals. Recent results have highlighted the importance of investigations aimed at understanding mechanistic details of the underlying chemistry, especially with a focus on estrogen neuroprotection. Such fundamental studies have facilitated the discovery of a previously unrecognized antioxidant cycle for estrogens in which estrogen-derived quinols are key intermediates. Additionally, the use of these quinols as prodrugs in animal models has revealed a significant reduction of side effects compared to treatment directly with the feminizing hormones.