DIFFERING EFFECTS OF PROBUCOL AND VITAMIN-E ON THE OXIDATION OF LIPOPROTEINS, CEROID ACCUMULATION AND PROTEIN-UPTAKE BY MACROPHAGES

Studies using I-125-low density lipoprotein (I-125-LDL) show that prob ucol (10 mu M) and alpha-tocopherol (100 mu M) inhibit protein degrada tion in LDL exposed to Cu (II) in vitro. The inhibitory effect of alph a-tocopherol on protein fragmentation exceeded that of probucol. On th e other hand, probucol was more able to inhibit lipid peroxidation. Th e subsequent uptake of Cu (II)-oxidised I-125-LDL by murine peritoneal macrophages (MPM) was virtually unaffected by the presence of probuco l during LDL oxidation. The same was not true for alpha-tocopherol whi ch led to lower levels of I-125-LDL uptake by MPM. Thus, it appears th at although the antioxidant activity of probucol exceeds that of alpha -tocopherol for lipid oxidation, the reverse is true for protein degra dation and, perhaps more significantly, for subsequent macrophage upta ke. Further studies used artificial lipoproteins composed of cholester yl linoleate or cholesteryl arachidonate complexed with bovine serum a lbumin. Culture of these artificial lipoproteins with MPM resulted in protein uptake, protein degradation, cholesterol oxidation to cholest- 5-en-3 beta,7 beta-diol and the intracellular accumulation of ceroid i n MPM. The presence of a-tocopherol (0-100 mu M) inhibited all of thes e processes. Probucol (0-10 mu M) inhibited ceroid accumulation and ch olesterol oxidation to the same degree as alpha-tocopherol(0-100 mu M) but had no effect upon protein degradation and protein uptake. Contro l studies of lipoproteins incubated without cells showed that protein degradation by cell-independent processes was also inhibited by alpha- tocopherol, but not by probucol. These observations are discussed in t he context of the role of lipoprotein oxidation in atherogenesis.