Differing effects of probucol and vitamin E on the oxidation of lipoproteins, ceroid accumulation and protein uptake by macrophages.
Studies using 125I-low density lipoprotein (125I-LDL) show that probucol (10 microM) and alpha-tocopherol (100 microM) inhibit protein degradation in LDL exposed to Cu (II) in vitro. The inhibitory effect of alpha-tocopherol on protein fragmentation exceeded that of probucol. On the other hand, probucol was more able to inhibit lipid peroxidation. The subsequent uptake of Cu (II)-oxidised 125I-LDL by murine peritoneal macrophages (MPM) was virtually unaffected by the presence of probucol during LDL oxidation. The same was not true for alpha-tocopherol which led to lower levels of 125I-LDL uptake by MPM. Thus, it appears that although the antioxidant activity of probucol exceeds that of alpha-tocopherol for lipid oxidation, the reverse is true for protein degradation and, perhaps more significantly, for subsequent macrophage uptake. Further studies used artificial lipoproteins composed of cholesteryl linoleate or cholesteryl arachidonate complexed with bovine serum albumin. 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 in MPM. The presence of alpha-tocopherol (0-100 microM) inhibited all of these processes. Probucol (0-10 microM) inhibited ceroid accumulation and cholesterol oxidation to the same degree as alpha-tocopherol (0-100 microM) but had no effect upon protein degradation and protein uptake. Control 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 the context of the role of lipoprotein oxidation in atherogenesis.
Department of Pathology, University of Cambridge, UK.
J V
JV
Hunt
M A
MA
Bottoms
S E
SE
Taylor
V
V
Lyell
M J
MJ
Mitchinson
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002566:Ceroid / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D011341:Probucol / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D014810:Vitamin E / Q000378:metabolism*
D002566:Ceroid; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D014810:Vitamin E; D012710:Serum Albumin, Bovine; D011341:Probucol