The liver metabolite S-422 of the hypolipidaemic drug benfluorex decreases cholesterol esterification in fibroblasts and monocyte-like cells.
The effects of S-422 (1-(3-trifluoromethylphenyl)-2-[N-(2-hydroxyethyl) amino] propane), an hepatic metabolite of the hypolipidaemic drug Benfluorex, on lipid metabolism have been investigated in two experimental models: in human fetal lung fibroblasts, for study of the apo B/E receptor-mediated regulation of cholesterol metabolism, and in murine J 774 monocyte-like cells, for study of the scavenger receptor-mediated induction of cholesteryl ester accumulation. In human fibroblasts S-422 increased low density lipoprotein (LDL) catabolism by about 20%, whereas it decreased oleic acid incorporation into triacylglycerols and cholesteryl esters by 25 and 35%, respectively. In J 774 cells, S-422 decreased acetylated LDL degradation and cholesteryl ester formation by about 35%. In both cell types, ACAT activity was significantly reduced by the drug, either after a 24 h pretreatment of the cultured cells, or after an in vitro 30 min preincubation of cell homogenates. The results suggest that S-422, and thus Benfluorex, might prevent the development of atherosclerotic plaques.
Mazière
J C
JC
Laboratoire de Biochimie, Faculté de Médecine Saint-Antoine, Paris, France.
Mazière
C
C
Auclair
M
M
Mora
L
L
Arnaud
O
O
D000214:Acyl Coenzyme A / Q000187:drug effects / Q000378:metabolism; D001053:Apolipoproteins / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002788:Cholesterol Esters / Q000096:biosynthesis / Q000378:metabolism; D004951:Esterification / Q000187:drug effects; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018110:Receptors, Lipoprotein
D000214:Acyl Coenzyme A; D001053:Apolipoproteins; D002788:Cholesterol Esters; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; C032531:apolipoprotein B,E receptor; D005277:Fenfluramine; D019301:Oleic Acid; C001584:benfluorex; C073864:1-(3-trifluoromethylphenyl)-2-(N-(2-hydroxyethyl)amino)propane; D002784:Cholesterol