INHIBITION OF LDL OXIDATION BY A NEW ESTRADIOL-RECEPTOR MODULATOR COMPOUND LY-139478, COMPARATIVE EFFECT WITH OTHER STEROIDS

Oxidation of low-density lipoprotein (LDL) is postulated to be essenti al for the development of atherosclerosis. LY-139478 is a new non-ster oidal potent estrogen analog, but its effects on in vitro LDL oxidatio n have not been completely elucidated. We investigated the ability of LY-139478 to inhibit in vitro copper sulfate-mediated LDL oxidation us ing several methods, including conjugated diene (CD) accumulation, rel ative electrophoretic mobility on agarose gel, thiobarbituric acid-rea ctive substances (TEARS) assay, and superoxide anions scavenging activ ity. The antioxidative potential of LY-139478 was compared to testoste rone (T), 17-alpha-estradiol (17 alpha E), 17-beta-estradiol (17 beta E), dehydroepiandrosterone (D), and dehydroepiandrosterone-3-sulfate ( DS). LY-139478 was superior to 17 alpha E and 17 beta E in prolonging the lag phase and decreasing the slope and peak concentration of the c onjugated diene accumulation, decreasing the rate of migration of LDL on agarose gel electrophoresis, and inhibiting the production of melon yldialdehyde (MDA) in the TEARS assay. T, D and DS were ineffective in all three assays. It was previously shown that when native LDL is oxi dized by previously oxidized LDL (secondary oxidation) the lag phase i s lost (Schnitzer et al. Free Rad Res 1995:23:137). LY-139478 was at l east 15-fold more effective than 17 alpha E, and 17 beta E in slowing the propagation phase and reducing CD accumulation in this secondary o xidation, with 50% inhibition at 10 mu M and 98% inhibition at 100 mu M. However, none restored the lag phase. T, D and DS were ineffective. Superoxide anion generation was inhibited only by DS at high doses (5 00 mu M). These results demonstrate that LY-139478 is an effective inh ibitor of LDL oxidation and is superior to natural steroidal hormones, including 17 beta E, in protecting against primary and secondary LDL oxidation. (C) 1998 Elsevier Science Ireland Ltd.