Inhibition of LDL oxidation in vitro but not ex vivo by troglitazone

Diabetic subjects are at increased risk for developing coronary artery dise ase, in part because of increased oxidation of LDL, which promotes atheroge nesis, Troglitazone, a new antidiabetic drug of the thiazolidinedione class , acts as an insulin sensitizer and improves hyperglycemia, Structurally, i t contains a tocopherol moiety similar to vitamin E and has been shown to h ave antioxidant properties in vitro. Therefore, we evaluated whether trogli tazone inhibited LDL oxidation both in vitro and in type 2 diabetic subject s ex vivo. Troglitazone inhibited oxidation of LDL induced by Cu2+ or 2'2'- azobis-2-amidinopropane hydrochloride (AAPH) with 50% inhibition at I mu mo l/l and 100% inhibition at 5-10 mu mol/l troglitazone. The inhibition of LD L oxidation by troglitazone also was time dependent. In addition, troglitaz one inhibited oxidation of I-125-labeled LDL and its subsequent uptake and degradation by macrophages, To determine whether troglitazone was incorpora ted into LDL particles or acted in the aqueous milieu, troglitazone was inc ubated overnight at 37 degrees C with LDL or plasma before LDL re-isolation . After re-isolation, LDL that was incubated with troglitazone was no longe r protected from oxidation, compared with probucol-treated LDL, which remai ned protected. Further, [C-14]troglitazone did not get incorporated into LD L, This suggests that troglitazone exerts its antioxidant effect in the aqu eous milieu of LDL, Consistent with this was the observation that the lag p hases of copper-induced conjugated diene formation, a measure of the suscep tibility in vivo, was similar for subjects taking troglitazone (76 +/- 5 mi n, 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 t o its effect on glucose homeostasis.