HYPOLIPIDEMIC DRUGS REDUCE LIPOPROTEIN SUSCEPTIBILITY TO UNDERGO LIPID-PEROXIDATION - INVITRO AND EXVIVO STUDIES

Oxidized LDL, which has been discovered in vivo in areas of proximity to the atherosclerotic lesion, has been shown to enhance macrophage cholesterol accumulation. We studied the anti-oxidant potential of pravastatin, bezafibrate and cholestyramine in 18 patients with hypercholesterolemia. In addition, we examined the electrophoretic mobility and the uptake of LDL by macrophages before and after drug therapy. Pravastatin lowered plasma levels of LDL cholesterol by 57%, cholestyramine by 27% and bezafibrate by 25%. Pravastatin and bezafibrate also altered the composition of LDL as evidenced by the reduction of its cholesterol/apo B100 ratio. Pravastatin and bezafibrate reduced plasma triglyceride levels by 45% and 25%, respectively, whereas cholestyramine raised plasma triglyceride concentrations by 28%. LDL propensity for in vitro oxidation was analyzed following lipoprotein incubation with 10-mu-M copper ions and determination of LDL malondialdehyde (MDA), peroxides (PD) and conjugated dienes (CD) content. All drugs inhibited the susceptibility to in vitro oxidation of LDL isolated after drug therapy in comparison to LDL isolated before commencing drug therapy. Pravastatin reduced MDA content by 22%, PD by 18% and CD by 20%. Cholestyramine reduced LDL content of MDA by 41%, PD by 25% and CD by 63%. Bezafibrate reduced MDA by 41%, PD by 38% and CD by 45%. LDL vitamin E content was reduced after treatment with bezafibrate, pravastatin and cholestyramine by 49%, 36% and 8%, respectively. The electrophoretic mobility of LDL after all drug therapies was reduced in comparison to LDL obtained before therapy. Macrophage uptake of LDL assessed by either the cellular cholesterol esterification rate or by lipoprotein degradation was not affected by drug therapy. There was no effect on LDL oxidizability following in vitro oxidation of LDL in the presence of pravastatin or bezafibrate. These findings demonstrated that pravastatin, bezafibrate and cholestyramine reduced the propensity for LDL to undergo lipid peroxidation as a result of their hypolipidemic effect and of some alteration in LDL composition.