title: Inhibition of low density lipoprotein oxidation by thyronines and probucol.
abstract: 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 thyroxine (T4), its optical antipodes, certain desiodo analogs and probucol inhibited cupric sulfate-catalyzed oxidation of human LDL in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation in mouse macrophages. In Cu(2+)-catalyzed LDL oxidation at 24 hr, the TBARS level was 80 nmol/mg LDL protein/24-hr incubation. The concentrations (microM) of each agent producing 50% inhibition in the formation of oxidized LDL (IC50) for TBARS, electrophoretic mobility and macrophage degradation, respectively, were 1.13, 1.27 and 1.30 for reversed triiodothyronine; 1.33, 1.80 and 1.27 for triiodothyronine; 1.33, 1.37 and 1.37 for racemic thyroxine, DL-T4; 1.10, 1.40 and 1.50 for L-T4; 1.13, 1.33 and 1.23 for D-T4; and 1.47, 1.63 and 1.37 for probucol. No differences in inhibitory potency were observed when rT3, T3, the optical antipodes of T4 and the hydrophobic antioxidant drug probucol were compared. In air-induced LDL oxidation, TBARS was 16.1 nmol/mg LDL protein/6-hr incubation. The IC50 concentrations (microM) for TBARS and diene conjugation, respectively, were 0.187 and 0.336 for D-T4; 0.205 and 0.243 for L-T4 and 1.30 and 3.02 for probucol. With air-induced LDL oxidation conditions, the L-T4 concentrations included the physiological range, and thyroid-binding globulin did not modify the inhibitory effect of the endogenous enantiomer, L-T4. Putative uptake of this stereoisomer into LDL inhibited oxidation of these lipoproteins. Since concentrations of these thyronines which blocked air-induced LDL oxidation were 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.
authors.affiliation: Department of Pathology, College of Medicine, Ohio State University, Columbus 43210.
authors.forename: A N
authors.initials: AN
authors.lastname: Hanna
authors.forename: D R
authors.initials: DR
authors.lastname: Feller
authors.forename: D T
authors.initials: DT
authors.lastname: Witiak
authors.forename: H A
authors.initials: HA
authors.lastname: Newman
mesh_terms: D000388:Air; D002614:Chelating Agents; D003300:Copper; D019327:Copper Sulfate; D015195:Drug Design; D006801:Humans; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011341:Probucol / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D013970:Thyronines / Q000494:pharmacology*; D013975:Thyroxine-Binding Proteins / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D017392:Thiobarbituric Acid Reactive Substances; D013970:Thyronines; D013975:Thyroxine-Binding Proteins; D003300:Copper; D019327:Copper Sulfate; D011341:Probucol