title: Inhibitory effects of N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), an acyl-CoA:cholesterol O-acyltransferase inhibitor, on cholesterol esterification in the intestine and liver.
abstract: The effects of an acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor, N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), on cholesterol esterification in the intestine and liver were investigated in vitro and in vivo. YIC-C8-434 inhibited the formation of cholesteryl [(3)H]oleate from [(3)H]oleic acid and cholesterol both in human colon adenocarcinoma Caco2 cells and in human hepatoma HepG2 cells with IC(50) values of 0.38 and 0.49 microM, respectively. However, it did not influence the incorporation of [(3)H]oleic acid into triacylglycerols and phospholipids. Oral administration of YIC-C8-434 at a dose of 8.3 mg/kg/d inhibited [(14)C]cholesterol absorption by 17% (p<0.01) in rats. YIC-C8-434 also significantly reduced the secretion of very low-density lipoprotein (VLDL) cholesterol from the liver into the plasma at an oral dose of 100 mg/kg/d after an intravenous injection of Triton WR-1339. These results suggest that oral administration of YIC-C8-434 reduces intestinal cholesterol absorption and hepatic VLDL cholesterol secretion by direct inhibition of ACAT in the intestinal epithelium and hepatocytes, respectively. However, the inhibitory action of YIC-C8-434 on cholesterol absorption rather than hepatic cholesterol secretion may play a more important role in its hypocholesterolemic activity, because the effective dose for the former was 12-fold lower than that for the latter.
authors.affiliation: Yakult Central Institute for Microbiological Research, Tokyo, Japan. kenji-ooishi@yakult.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohishi
authors.forename: Haruji
authors.initials: H
authors.lastname: Sawada
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Wakae
authors.initials: W
authors.lastname: Yokoi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatano
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Aiyama
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Watanabe
authors.forename: Teruo
authors.initials: T
authors.lastname: Yokokura
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002788:Cholesterol Esters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002934:Cinnamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C440193:(N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine); D002788:Cholesterol Esters; D002934:Cinnamates; D010879:Piperazines; D002785:Sterol O-Acyltransferase