Troglitazone-binding to LDL and its glycated modifications: its role in cell-catalysed and Cu-mediated LDL-oxidation.
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 microg/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 microg/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 microg/ml), binding of the drug to glycoxidated LDL was already nearly saturated at 10 microg/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 microg/ml significantly reduced formation of oxidation-dependent fluorescent chromophores and liberation of 8-epi-PGF2alpha. 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.
Sobal
G
G
Department of Nuclear Medicine, Radiopharmacology Unit, University of Vienna, Währinger Guertel 18-20, A-1090 Vienna, Austria.
Sinzinger
H
H
Menzel
E J
EJ
D000328:Adult; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000097:blood*; D003300:Copper / Q000494:pharmacology*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood*; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008315:Malondialdehyde / Q000097:blood; D010084:Oxidation-Reduction; D011485:Protein Binding; D013844:Thiazoles / Q000097:blood*; D045162:Thiazolidinediones; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D000077288:Troglitazone
D002839:Chromans; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D013844:Thiazoles; D045162:Thiazolidinediones; D017392:Thiobarbituric Acid Reactive Substances; C075750:8-epi-prostaglandin F2alpha; D008315:Malondialdehyde; D003300:Copper; D015237:Dinoprost; D000077288:Troglitazone