Antioxidant activity of probucol and its analogues in hypercholesterolemic Watanabe rabbits.

Probucol (1) and probucol analogues with the substitutions at the disulfide-linked carbon (2, 3) and an additional substitution at a tert-butyl of each phenolic ring (4) were tested for their ability to lower total serum cholesterol and prevent aortic atherosclerosis in modified Watanabe heritable hyperlipidemic (WHHL) rabbits and to inhibit Cu2(+)-induced lipid peroxidation of isolated plasma low-density lipoproteins (LDL). After 84 days of feeding 1% of each compound in rabbit chow, probucol was effective in lowering serum cholesterol, whereas 2-4 were not. The concentration of drug in serum and LDL was 2 greater than 1 greater than 3 greater than 4. Probucol and analogues prevented Cu2(+)-induced oxidation of LDL in vitro to an extent that directly related to their concentrations in LDL. The decrease in lipid oxidation was directly correlated with the inhibition of both oxidized-LDL-induced cholesteryl ester synthesis in cultured macrophages and to the inhibition of aortic atherosclerosis in vivo. These results show that the antioxidant activity of probucol and analogues is directly related to their concentration in LDL, which may explain their pharmacological activity in reducing atherosclerosis.