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标题：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
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作者：Kenji Ohishi ; Haruji Sawada ; Yasuto Yoshida 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2003
卷号：26
期号：8
页码：1125-1128
DOI：10.1248/bpb.26.1125
出版社：The Pharmaceutical Society of Japan
摘要：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 [³H]oleate from [³H]oleic acid and cholesterol both in human colon adenocarcinoma Caco2 cells and in human hepatoma HepG2 cells with IC₅₀ values of 0.38 and 0.49 μ M , respectively. However, it did not influence the incorporation of [³H]oleic acid into triacylglycerols and phospholipids. Oral administration of YIC-C8-434 at a dose of 8.3 mg/kg/d inhibited [¹⁴C]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.
关键词：YIC-C8-434;intestinal cholesterol absorption;hepatic cholesterol secretion;cholesterol esterification;acyl-CoA:cholesterol O-acyltransferase inhibitor