Inhibition of LDL oxidation in vitro but not ex vivo by troglitazone.
Diabetic subjects are at increased risk for developing coronary artery disease, in part because of increased oxidation of LDL, which promotes atherogenesis. Troglitazone, a new antidiabetic drug of the thiazolidinedione class, acts as an insulin sensitizer and improves hyperglycemia. Structurally, it contains a tocopherol moiety similar to vitamin E and has been shown to have antioxidant properties in vitro. Therefore, we evaluated whether troglitazone inhibited LDL oxidation both in vitro and in type 2 diabetic subjects ex vivo. Troglitazone inhibited oxidation of LDL induced by Cu2+ or 2'2'-azobis-2-amidinopropane hydrochloride (AAPH) with 50% inhibition at 1 micromol/l and 100% inhibition at 5-10 micromol/l troglitazone. The inhibition of LDL oxidation by troglitazone also was time dependent. In addition, troglitazone inhibited oxidation of 125I-labeled LDL and its subsequent uptake and degradation by macrophages. To determine whether troglitazone was incorporated into LDL particles or acted in the aqueous milieu, troglitazone was incubated overnight at 37 degrees C with LDL or plasma before LDL re-isolation. After re-isolation, LDL that was incubated with troglitazone was no longer protected from oxidation, compared with probucol-treated LDL, which remained protected. Further, [14C]troglitazone did not get incorporated into LDL. This suggests that troglitazone exerts its antioxidant effect in the aqueous milieu of LDL. Consistent with this was the observation that the lag phases of copper-induced conjugated diene formation, a measure of the susceptibility in vivo, was similar for subjects taking troglitazone (76 +/- 5 min, n = 9) to subjects not taking the drug (77 +/- 3 min, n = 11; NS). Thus, troglitazone may be of value as an aqueous-phase antioxidant in addition to its effect on glucose homeostasis.
Crawford
R S
RS
Department of Medicine, University of Washington, Seattle 98195-6426, USA.
Mudaliar
S R
SR
Henry
R R
RR
Chait
A
A
D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D003300:Copper / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D008264:Macrophages / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011341:Probucol / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones; D000077288:Troglitazone
D000975:Antioxidants; D002839:Chromans; D008077:Lipoproteins, LDL; D013844:Thiazoles; D045162:Thiazolidinediones; C099252:oxidized low density lipoprotein; D003300:Copper; D000077288:Troglitazone; D011341:Probucol