Effect of probucol on macrophages, leading to regression of xanthomas and atheromatous vascular lesions.
To explain the strong effect of probucol on xanthomas, the drug's effect on lipid storage in macrophages in the presence of denatured low-density lipoprotein (LDL) was studied. Two macrophage cell lines, UE-12 and THP-1, were used. Those cells stored lipids and became foam cells when they were incubated with acetylated LDL (acetyl-LDL). When probucol was added into the medium either in ethanolic solution or in the form bound to LDL, the storage of cholesterol and other lipids and the development of macrophages into foam cells were greatly suppressed. Two functions of probucol should be considered: (1) It inhibited the uptake of acetyl-LDL by macrophages; and (2) it enhanced the release of cholesterol from these cells. Cells were first incubated with probucol. After the cells were washed with fresh medium, the radiolabeled acetyl-LDL was added to the medium and the degradation of acetyl-LDL was measured. Increasing the concentration of probucol led to a decrease in degradation of acetyl-LDL by macrophages. Probucol also suppressed the uptake of albumin. Macrophages were incubated with acetyl-LDL, washed once, then incubated with or without probucol and high-density lipoprotein (HDL). Addition of HDL caused a rapid decrease in cholesterol content in the cells, and this phenomenon was enhanced by probucol for both kinds of cells. The secretion of apolipoprotein E was also stimulated by the addition of probucol. These 2 sets of experimental results suggest that probucol prevents lipid storage in macrophages by both suppressing the uptake and stimulating the release of cholesterol and other lipids into or from the macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
Yamamoto
A
A
Department of Etiology and Pathophysiology, National Cardiovascular Center Research Institute, Osaka, Japan.
Hara
H
H
Takaichi
S
S
Wakasugi
J
J
Tomikawa
M
M
D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003864:Depression, Chemical; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D014973:Xanthomatosis / Q000188:drug therapy* / Q000378:metabolism
D008077:Lipoproteins, LDL; D010636:Phenols; C032629:acetyl-LDL; D002784:Cholesterol; D011341:Probucol