MECHANISMS INVOLVED IN THE PROTECTIVE EFFECT OF ESTRADIOL-17-BETA ON LIPID-PEROXIDATION AND DNA-DAMAGE

Previous studies from our laboratory have shown that estrogens can pro tect against lipoprotein peroxidation and DNA damage. In this study, t he mechanism of estradiol-l7 beta (E-2) action was investigated by com paring E-2 with selective scavengers of reactive oxygen species (ROS) in terms of inhibition of I)human low-density Lipoprotein (LDL) peroxi dation (measured by the diene conjugation method) and 2) DNA damage !m easured by the formation of strand breaks in supercoiled OX-174 RFI DN A). In addition, the direct effect of E-2 on the generation of individ ual ROS was also measured. By use of ROS scavengers, it was determined that lipoprotein peroxidation was predominantly due to superoxide (39 %), with some contributions from hydrogen peroxide (23%) and peroxy (3 8%) radicals. E-2 was a more effective inhibitor of peroxidation than all the ROS scavengers combined. In DNA damage, scavengers of hydrogen peroxide, hydroxyl, and superoxide radical offered significant protec tion (49-65%). E-2 alone offered a similar degree of protection, and n o additional effect was evident when it was combined with ROS scavenge rs. E-2 caused a significant reduction (37%) in the production of supe roxide radical by bovine heart endothelial cells in culture but had no effect on the formation of either hydrogen peroxide or hydroxyl radic als. These studies show that 1) the protection offered by E-2 in terms of lipid peroxidation could be due to its ability to inhibit generati on of superoxide radical and prevent further chain propagation, and 2) in DNA damage protection, E-2 mainly appears to inhibit chain propaga tion.