title: [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].
abstract: 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.
authors.affiliation: Pharmaceuticals Research Laboratories, Fujirebio, Inc., Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kusunoki
authors.forename: K
authors.initials: K
authors.lastname: Aragane
authors.forename: T
authors.initials: T
authors.lastname: Kitamine
authors.forename: T
authors.initials: T
authors.lastname: Yamaura
authors.forename: H
authors.initials: H
authors.lastname: Ohnishi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D004951:Esterification; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000201:enzymology; D010671:Phenylurea Compounds / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000813:Anilides; D000924:Anticholesteremic Agents; D002788:Cholesterol Esters; D003510:Cyclohexanes; D004146:Dioxanes; C094918:F 1394; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010671:Phenylurea Compounds; C069304:PD 128042; C050492:CL 277082; D002784:Cholesterol; D019821:Simvastatin; D002785:Sterol O-Acyltransferase; D002994:Clofibrate; D017035:Pravastatin; D011341:Probucol