Mechanisms involved in the protective effect of estradiol-17β on lipid peroxidation and DNA damage

Abstract

Previous studies from our laboratory have shown that estrogens can protect against lipoprotein peroxidation and DNA damage. In this study, the mechanism of estradiol-17β (E2) action was investigated by comparing E2 with selective scavengers of reactive oxygen species (ROS) in terms of inhibition of 1) human low-density lipoprotein (LDL) peroxidation (measured by the diene conjugation method) and 2) DNA damage (measured by the formation of strand breaks in supercoiled OX-174 RFI DNA). In addition, the direct effect of E2 on the generation of individual 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 (38%) radicals. E2 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 protection (49–65%). E2 alone offered a similar degree of protection, and no additional effect was evident when it was combined with ROS scavengers. E2caused a significant reduction (37%) in the production of superoxide radical by bovine heart endothelial cells in culture but had no effect on the formation of either hydrogen peroxide or hydroxyl radicals. These studies show that 1) the protection offered by E2 in terms of lipid peroxidation could be due to its ability to inhibit generation of superoxide radical and prevent further chain propagation, and 2) in DNA damage protection, E2 mainly appears to inhibit chain propagation.

Effects of estrogens and androgens on erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase activities during the menstrual cycle

“…Furthermore, estrogen replacement in postmenopausal women has been shown to have antioxidant effects based on scavenging mechanism (Sack et al 1994), and cardioprotective effects (Stampfer et al 1991). In particular, estrogen decreases oxidative modification of low-density lipoproteins both in vitro and in vivo (Ayres et al 1998). Furthermore, beneficial effects of estrogen in Alzheimer's disease have been reported and may be partly attributable to its potent antioxidant activity (Paganini-Hill 1996).…”

Estrogen Provides Neuroprotection in Transient Forebrain Ischemia Through Perfusion-Independent Mechanisms in Rats

“…Brain damage after TFI has been linked to enhanced leukocyte adhesion/infiltration, 19 free radical mechanisms, 20 upregulation of the inducible NOS (iNOS) isoform, 21 altered cerebral glucose transport, 22,23 and apoptosis. 24 Estrogens, E 2 in particular, have been shown to possess anti-inflammatory functions, 25 antioxidant actions, 26,27 an ability to block the induction of iNOS, 2 a capacity to improve glucose transport, 28 and antiapoptotic effects. 29,30 Because none of those possibilities were specifically addressed in this report, no further comment can be made at this time.…”

“…7,8 These findings would appear to be consistent with a nongenomic process and might be viewed as evidence of antioxidant actions of estrogens, as some investigators have suggested. 26,27,33,34 On the other hand, there are indications that E 2 -related neuroprotection, to some degree, may involve interactions with classic receptors (see, for example, Singer et al 35 ). The present finding of detectable blood E 2 levels in the OVX rats (30 pg ⅐ mL…”

Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer

“…Estrogens have been shown to inhibit lipoprotein peroxidation in vivo and in vitro (50,51,(81)(82)(83)(84)(85)(86)(87)(88). Some clinical studies have also found that estrogen treatment inhibited the susceptibility of low-density lipoprotein to oxidative modification (50,86), whereas others found that oxidation of lowdensity lipoprotein particles was not generally influenced by estrogen (89,90).…”