INTERACTIONS OF MDL-29,311 AND PROBUCOL METABOLITES WITH CHOLESTERYL ESTERS

The hypothesis that the efficacy of hydrophobic antioxidants in animal models of atherogenesis may, in part, be related to physical effects on cholesteryl. esters in cells was probed with analogs and metabolite s of probucol. The interactions of an effective bis-thiomethane analog (MDL 29,311) and selected metabolites of probucol with cholesteryl ol eate were examined by differential scanning calorimetry and polarized light microscopy. Like probucol, MDL 29,311 and the bisphenol metaboli te decrease the liquid-crystalline phase transition enthalpy of choles teryl oleate with increasing concentrations. At 20 mol%, no transition is detectable. By contrast, the spiroquinone metabolite of probucol a nd the diphenoquinone metabolite common to both molecules have minimal effects on the liquid-crystalline transitions of cholesteryl oleate. At 20 mol%, neither compound has as great an effect as 1 mol% MDL 29,3 11. Consistent with their effects on dry cholesteryl oleate, MDL 29,31 1 and the bisphenol metabolite convert lipid inclusions in cells suppl emented with cholesterol to an isotropic physical state similar to tha t observed with probucol. The number of anisotropic inclusions in the cells decreases with increasing concentration in the medium in the ran ge of 50 to 250 mu g/mL. In cells fed with the spiroquinone or dipheno quinone metabolites, the lipid inclusions are liquid-crystalline and r esemble those observed with cholesterol-fed controls. These data are i nterpreted in terms of a model in which hydrophobic antioxidants close ly related to probucol disrupt the packing of cellular cholesteryl est ers.