Antioxidant: A new role for RU-486 and related compounds

Abstract

RU-486 (17 β-hydroxy 4-dimethylaminophenyl-17-α-propenyl estrone 4,9 diene-3-one; mifepristone) is suggested to act by binding to progesterone and glucocorticoid receptors. Based on its chemical nature, we anticipated that RU-486 may have potent antioxidant properties. We used the oxidation of LDL as our model system. RU-486 and a similar compound, onapristone, at 1-5-μM concentrations, decreased the formation of oxidized LDL. LDL isolated from plasma of subjects who were orally supplemented with RU-486 was resistant to oxidation, as compared to LDL isolated from control plasma. The antioxidant effect of RU-486 appears to reside in the dimethylaminophenyl side chain moiety. Reduction of the A-ring of the steroid molecule had no effect on its antioxidant property. Analogs of RU-486 which lack the dimethylaminophenyl group, were without antioxidant activity. Levonorgestrel, which lacks the dimethylaminophenyl group failed to inhibit the oxidation of LDL even at 100- μM levels. In contrast, ethinylestradiol and estradiol which do not possess the dimethylamino group, were able to inhibit the oxidation of LDL by virtue of their phenolic steroid 'A' ring. Thus RU-486, with its long half life, high plasma concentrations, association with lipoproteins, and ability to readily enter the cell may have additional intra- and extra-cellular antioxidant effects.