Troglitazone-binding to Ldl and its glycated modifications: Its role in cell-catalysed and Cu-mediated Ldl-oxidation

• Published in: Life sciences (1973) 2000-06, Vol.67 (6), p.695-707
• Main Authors: Sobal, G., Sinzinger, H., Menzel, E.J.
• Format: Article
• Language: English
• Subjects: 8-Epi-prostaglandin F 2α; Adult; Cell Survival - drug effects; Chromans - blood; Copper - pharmacology; Dinoprost - analogs & derivatives; Dinoprost - blood; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Glycoproteins - metabolism; Human umbilical vein endothelial cells; Humans; Hypoglycemic Agents - blood; Lipid Peroxidation - drug effects; Lipoproteins, LDL - metabolism; Low density lipoprotein; Malondialdehyde - blood; Oxidation-Reduction; Oxidative modification; Protein Binding; Thiazoles - blood; Thiazolidinediones; Thiazolidines; Thiobarbituric Acid Reactive Substances - metabolism; Troglitazone
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(00)00662-7

Troglitazone (T), an anti-diabetic drug improving insulin resistance, was studied as to its inhibition of copper ion-catalysed oxidation of native, glycated and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition was noted in the concentration range 40–160 μg/ml. An almost complete inhibition of oxidation (2–8 h), as monitored by the formation of thiobarbituric acid-reactive substances, was observed for both native and glycated LDL at a concentration of 160 μg/ml T, while the maximal inhibition for glycoxidated LDL amounted only to 60% at this concentration of the drug. This is reflected by differences in the affinity of the drug for the different types of LDL modification: While the binding of T both to native or glycated LDL increased linearly with increasing T concentration and was not saturable in the concentration range tested (0–160 μg/ml), binding of the drug to glycoxidated LDL was already nearly saturated at 10 μg/ml. The nearly complete inhibitory action of T towards oxidation of native and glycated LDL was lost, however, upon increasing the total oxidation time to 24 h. In human umbilical vein endothelial cell-mediated oxidation of LDL, T at a concentration of 20 μg/ml significantly reduced formation of oxidation-dependent fluorescent chromophores and liberation of 8-epi-PGF 2α. In contrast, generation of thiobarbituric acid-reactive substances was not significantly inhibited. As opposed to copper-mediated LDL-oxidation, different binding of T to LDL-modifications does not govern inhibition of human umbilical vein endothelial cell-mediated LDL-oxidation.