Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein.
Troglitazone (T) is a member of a new class of antidiabetic drugs termed thiazolidinediones (TZDs), which has previously been used as an anti-diabetic agent. In this study we investigated the influence of T, a ligand for PPAR-gamma receptor, on copper-catalyzed or cell-mediated oxidation of native, glycated, and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition of copper-mediated low-density lipoprotein-oxidation, as monitored by the formation of oxidation-specific fluorescence, was observed for both native and glycated low-density lipoprotein. At the concentration of 20 microg/mL the inhibition amounted from 14.7% to 64.7% by all low-density lipoprotein forms. For glycated low-density lipoprotein we obtained the highest oxidation rate, but the most pronounced inhibition by T was found for glycoxidated low-density lipoprotein (goLDL). Inhibitory effects of T were also investigated by measurement of relative electrophoretic mobility (REM) in the concentration range of 0 to 20 microg/mL. The inhibition of 4h oxidation of native low-density lipoprotein was found in the entire concentration range, but significance was seen at 10 microg/mL. The long-term glycation and glycoxidation of low-density lipoprotein as measured by 5-hydroxymethyl-2-furaldehyde (5-HMF) formation and binding of fructosamine was found to be inhibited by T. In endothelial cell-mediated oxidation of low-density lipoprotein cytotoxicity of T in the concentration range of 0 to 160 microg/mL during 2 to 24 h oxidation was investigated. In the non-cytotoxic concentration range of 5 to 20 microg/mL, a significantly reduced liberation of isoprostane 8-epi-PGF2alpha during 24 h cell-mediated oxidation of low-density lipoprotein and its modifications was found. This inhibitory action of T was most significant in the case of goLDL and amounted to approximately 20% to 60% inhibition at 5 to 20 microg/mL T, respectively. In the concentration range of 40 to 160 microg/mL, however, T showed an increasing cytotoxic action, as evidenced by loss of cell adhesion, loss of cellular protein, morphological changes, and cell disintegration as well as by strongly enhanced troglitazone-mediated isoprostane 8-IP liberation (fivefold to sixfold). T may be used as a model to explore the thiazolidinediones' mechanism on oxidation in a more general aspect for treatment for T2DM, because T is not clinically available.
Sobal
Grazyna
G
Department of Nuclear Medicine, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Grazyna.Sobal@meduniwien.ac.at
Menzel
E J
EJ
Sinzinger
H
H
D000328:Adult; D002384:Catalysis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D000077288:Troglitazone
D002839:Chromans; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D045162:Thiazolidinediones; D000077288:Troglitazone