| Oxidation of low density lipoproteins (LDL) results in increased macrophage uptake of LDL which may contribute to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. In this study we show that thyronines, L-ascorbic acid and probucol inhibit Cu$sp{2+}$-catalyzed LDL oxidation in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation by mouse macrophages. In Cu$sp{2+}$-catalyzed LDL oxidation at 24 hr TBARS is 80 nmoles/mg LDL protein/24 hr incubation. No differences in inhibitory potency are observed when rT$sb3,$ T$sb3,$ the optical antipodes of T$sb4$ and the hydrophobic antioxidant drug, probucol are compared. In air-induced LDL oxidation TBARS is 16.1 nmoles/mg LDL protein/6 hr incubation. IC$sb{50}$ concentrations ($mu$M) for TBARS and diene conjugation, respectively, are 0.187, 0.336 for D-T$sb4;$ 0.205, 0.243 for L-T$sb4$ and 0.9, 3.02 for probucol. With air or EC-induced LDL oxidation conditions, the L-T$sb4$ concentrations including the physiological range, inhibited LDL Oxidation. Thyroid-binding globulin does not modify the inhibitory effect of the endogenous enantiomer, L-T$sb4$. Putative uptake of this stereoisomer into LDL inhibits oxidation of these lipoproteins. Moreover, there was synergistic interaction between thyroxine and ascorbic acid in inhibiting both Cu$sp{2+}$ and EC-induced LDL oxidation. Since concentrations of these thyronines which blocked air and EC-induced LDL oxidation are in the physiological range, we conclude that thyronines, like the pharmacological agent probucol, limit the oxidative modification of LDL and thus may serve as natural inhibitors of atherogenesis. |
