ANTIOXIDANT - A NEW ROLE FOR RU-486 AND RELATED-COMPOUNDS

RU-486 (17 beta-hydroxy 4-dimethylaminophenyI-17-alpha-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-mu M concentrations, decreased the formation of oxidized LDL, LDL isolated from plasma of subjects who were orally supplemented with RU486 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-muM 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.