Antioxidant protection of LDL by physiologic concentrations of estrogens is specific for 17-beta-estradiol

Risk for coronary artery disease is reduced by exposure to estrogens, although the mechanisms of protection are not fully defined. Recent observations have shown that physiologic concentrations of 17-beta-estradiol (E2) exhibit antioxidant activity in vitro, slowing the formation of atherogenic, oxidized low-density lipoprotein (LDL). Using concentrations physiologically relevant for premenopausal women, we compared the antioxidant potency of estrone (E1), E2, and estriol (E3) as measured by their ability to inhibit LDL oxidation. Plasma was incubated with 10 nmol/l estrogens for 4 h at 37 degrees C, followed by LDL isolation and Cu2+-mediated oxidation in conjugated diene assays. Only E2 demonstrated antioxidant activity at these physiologic concentrations. Resistance to oxidation was not associated with sparing of endogenous alpha-tocopherol during plasma incubations. Incubation of plasma with radiolabeled estrogens yielded similar association of E1 and E2 with LDL which was 5-8-fold greater than the association of E3. Chromatographic analysis revealed the association of authentic E1 with LDL, while plasma-derived E2 esters were the major form of E2 associated with LDL which was resistant to oxidation. Thus, conjugation in plasma and association of E2 esters with LDL appear to be specific for E2 among these estrogens and render this LDL resistant to oxidation by Cu2+. This antioxidant activity may be another means whereby E2 protects against coronary artery disease in women.