The in vitro and ex vivo antioxidant properties, and hypolipidemic activity of CGP 2881

This report describes the in vitro and ex vivo antioxidant properties of a new antioxidant, CGP 2881. This compound is structurally similar to probuco l, in that both compounds contain bis-tertiary butyl phenyl groups. However ,CGP 2881 consistently inhibited CuSO4 (Cu2+)- and macrophage (MO)-induced oxidation of human low density lipoproteins (LDL) more potently than equimo lar concentrations of probucol. CGP 2881 (1 mu mol/l) prolonged the lag pha se of diene formation during Cu2+ -induced LDL oxidation by 3.4 versus 1.5- fold prolongation with 1 mu mol/l probucol (P < 0.05 vs CGP 2881). The IC50 for inhibiting the formation of Cu2+-induced thiobarbituric acid-reactive substances (TBARS) was 0.15 mu mol/l for CGP 2881, versus similar to 10 mu mol/l for probucol. The IC50 for MO-induced oxidation of LDL (TBARS) was 0. 64 mu mol/l. In contrast, 1 mu mol/l probucol failed to inhibit MO-induced oxidation of LDL. Treatment of cholic acid/cholesterol-fed rats with CGP 28 81 (50 mg/kg per day, orally for 5 days) inhibited ex vivo Cu2+-induced oxi dation (TBARS) of the very low density lipoproteins (VLDL) + LDL lipoprotei n fraction by 93% versus vehicle controls (P < 0.0001), and prolonged the l ag phase for Cu2+-induced diene formation by 3.4-fold over vehicle-treated controls. Five days of orally administered CGP 2881 reduced plasma total ch olesterol and LDL cholesterol levels to 55 and 54% of vehicle-treated contr ols, respectively (P < 0.05). In contrast, probucol had no appreciable effe ct on plasma total cholesterol or LDL cholesterol levels, unless administer ed for longer than 5 days. Treatment of hypercholesterolemic rabbits with 5 0 mg/kg per day orally for 5-12 days delayed the lag phase of diene formati on during LDL oxidation by 4.3-fold over controls. However, the relative an tioxidant potencies of CGP 2881 and probucol seen with oral administration to hypercholesterolemic rabbits were reversed when the compounds were given intravenously. In addition, the effects of these antioxidants were potenti ated when given to normocholesterolemic rabbits compared to hypercholestero lemic animals. These data establish that CGP 2881 demonstrates hypolipidemi c activity and is a substantially more potent antioxidant than probucol (in vitro and ex vivo). CGP 2881 may be useful as a new antioxidant tool in th e effort to better understand the atherogenicity of oxidized LDL (oxLDL). ( C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved.