Inhibition of low-density lipoprotein oxidation by the pure antiestrogens ICI 182780 and EM-652 (SCH 57068)

Objective: The use of modulators of estrogen receptors activation is receiving increasing interest in menopausal medicine. Pure antiestrogens define a group of compounds exhibiting universal antagonistic properties. Nevertheless, we cannot disregard the possibility that they may still have some agonistic actions. Because estradiol (E-2) has antioxidant properties, we tested the antioxidant capacity of two pure antiestrogens, ICI 182780 and EM-652 (SCH 57068). Design: The ability of both compounds to protect isolated low-density lipoproteins against copper-induced oxidation in vitro was used as an index of their antioxidant properties. Results: When compared with control (vehicle alone), ICI 182780 and EM-652 significantly increased the lag time of low-density lipoprotein oxidation when present at concentrations of 10 and 0.5 muM or greater, respectively. When compared with estrogens, ICI 182780 was as effective as E-2 at the lower concentrations tested (0.1 and I muM) but less effective at higher concentrations. EM-652 had similar antioxidant potency as E-2 but exerted maximal effects at lower concentration. Combined exposure to E-2 and each of the antiestrogens resulted in a higher antioxidant effect than that of antiestrogen alone. Another estrogen (estrone), and selective estrogen-receptor modulators, such as tamoxifen and hydroxytamoxifen, displayed an antioxidant potency that was close to ICI 182780 but lower than EM-652. Progestogens, such as progesterone or medroxyProgesterone acetate, had no antioxidant effect. Conclusions: Both ICI 182780 and EM-652 exhibited potent antioxidant activity, which could have important biological implications.