Probucol is a
drug that lowers plasma
cholesterol in both humans and animals. In
low density lipoprotein (
LDL) receptor-deficient Watanabe rabbits,
probucol reduces the progression of
atherosclerosis. This effect may be attributed to the
antioxidant and/or the
cholesterol-lowering properties of the
drug. In the present report we studied the antiatherogenic effect of a
probucol analogue (
MDL 29,311) that possesses
antioxidant activity but that does not lower
cholesterol. Modified Watanabe rabbits (11-12 weeks of age) produced by crossing British Brown and Japanese Watanabe rabbits were fed normal chow (n = 8), chow containing 1%
probucol (n = 9), or chow containing 0.1% (n = 9), 0.5% (n = 8), or 1% (n = 6)
probucol analogue. After 70 days serum
cholesterol levels and the percent area of sudanophilic lesions in the thoracic region of aortas were determined. Total serum
cholesterol was significantly lowered (p less than 0.05) in the
probucol group (560 +/- 54 mg/dl) compared with that of controls receiving no
drug (731 +/- 67 mg/dl) but was not lowered in the analogue groups (722-802 mg/dl). The lesioned area (mean% +/- SEM) in the
probucol group (16 +/- 3) was significantly lower (p less than 0.01) than in the controls (52 +/- 8). There were 43 +/- 7%, 33 +/- 8%, and 35 +/- 5% of lesions for the 0.1%, 0.5%, and 1% analogue groups, respectively. After combining the data for the 0.5% and 1% analogue groups, the value (34%) was lower than that of the controls and almost reached significance (p = 0.066). The mean serum
drug concentration in the 1%
probucol group was 58 +/- 4 micrograms/ml compared with 13 +/- 2, 44 +/- 8, and 74 +/- 8 micrograms/ml for the 0.1%, 0.5%, and 1% analogue groups, respectively. Thus, the decreased effectiveness of the
probucol analogue in preventing
atherosclerosis could not be explained by a lack of bioavailability. LDLs isolated from rabbits treated with the
drug were resistant to Cu(2+)-induced lipid peroxidation, as determined by
thiobarbituric acid-reactive substances. The resistance within the analogue groups was dependent on the number of
antioxidant molecules per
LDL particle. However, there was no significant difference in atherosclerotic lesions between these two groups, suggesting, although not definitively, that the maximal antiatherogenic effect had been reached. Our data suggest that the
antioxidant activity of this class of compounds may play an important role in reducing
atherosclerosis, but not in reducing
cholesterol levels, and that hypocholesterolemic and possibly other activities of
probucol might further enhance its antiatherogenic activity.