Effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on esterification of cholesterol and basolateral secretion of cholesteryl ester in Caco-2 cells

• Published in: Nihon yakurigaku zasshi Vol. 110; no. 6; p. 357
• Main Authors: Kusunoki, J, Aragane, K, Kitamine, T, Yamaura, T, Ohnishi, H
• Format: Journal Article
• Language: Japanese
• Published: Japan 1997
• Subjects: Anilides - pharmacology; Anticholesteremic Agents - pharmacology; Caco-2 Cells; Cholesterol - metabolism; Cholesterol Esters - metabolism; Clofibrate - pharmacology; Cyclohexanes - pharmacology; Dioxanes - pharmacology; Esterification; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Intestinal Mucosa - enzymology; Phenylurea Compounds - pharmacology; Pravastatin - pharmacology; Probucol - pharmacology; Simvastatin - pharmacology; Sterol O-Acyltransferase - antagonists & inhibitors
• ISSN: 0015-5691; 1347-8397
• DOI: 10.1254/fpj.110.357

The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.