Probucol selectively increases oxidation of atherogenic lipoproteins in cholesterol-fed mice and in Watanabe heritable hyperlipidemic rabbits

The anti-atherogenic and cholesterol-lowering drug probucol (0.5-1%) or quercetin (1%), a natural antioxidant, was given to cholesterol-fed (1.5%) mice for a period of 6 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for a period of 8 weeks to investigate the oxidative changes in plasma and lipoproteins. Oxidation was measured as the total amount of malondialdehyde (nmol MDA/g protein) by a very specific MDA-HPLC method. A large and significant increase in MDA was seen in LDL from probucol treated WHHL rabbits (1778.7 +/- 585.5 nmol/g vs. 394.4 +/- 144.5 nmol/g, P <0.001) and cholesterol-fed mice (579.7 +/- 47.3 nmol/g vs. 408.1 +/- 85.8 nmol/g, P <0.05) as compared to controls while LDL cholesterol was lowered (WHHL rabbits: P <0.05; mice: P <0.01). In WHHL rabbits VLDL oxidation was determined additionally, and also revealed a large increase in the probucol group (2102.7 +/- 1156.1 nmol/g vs. 455.0 +/- 207.8 nmol/g, P <0.01). In contrast, the oxidation of plasma and HDL from probucol treated animals was not statistically significantly increased, implying that probucol mediates a selective oxidation of atherogenic cholesterol-transporting lipoproteins. Quercetin treated animals did not show increased oxidation of LDL land VLDL in rabbits) and cholesterol levels were not decreased. Furthermore, no protective antioxidant effect of quercetin was seen. In conclusion, the results suggest that a prooxidant mechanism rather than antioxidative effects influences lipoprotein metabolism in these animals. It is hypothesized that the oxidation of lipoproteins might be a physiological mechanism performed by macrophages or other cells for uptake and degradation (by macrophages and liver) of excessive amounts of LDL or VLDL and that probucol oxidizes atherogenic lipoproteins and thereby leads to a decrease in cholesterol levels.