Harnett K M, Walsh C T, Zhang L H
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Massachusetts.
J Pharmacol Exp Ther. 1989 Nov;251(2):502-9.
Bay o 2752 [N,N'-(1, 11-undecandiyl)bis(2,3-dihydro-2-methyl-1H-indole-1-carboxamide)] has been demonstrated in rats to inhibit intestinal cholesterol absorption. Studies were carried out in male Wistar rats to determine if the mechanism is inhibition of intestinal bile acid absorption or cholesterol esterification. Bay o 2752 did not alter intestinal bile acid absorption as measured by in vitro uptake of [14C]taurocholic acid into ileal everted sacs (0.01 and 1.0 mg/ml of Bay o 2752) or the biliary excretion of radioactivity after in vivo ileal perfusion of the bile acid and drug (1.0 mg/ml at 1.0 ml/min for 1 hr). Cholesterol esterification was determined by measurement of in vitro activity of acyl coenzyme A:cholesterol acyltransferase from hepatic microsomes and cholesterol ester hydrolase from pancreatic supernatant, and the in vivo lymphatic output of cholesteryl ester after intraduodenal cholesteryl infusion. Addition of Bay o 2752 (0.01-10 micrograms/ml) to hepatic microsomes produced a concentration-dependent decrease in acyl coenzyme A:cholesterol acyltransferase activity with an IC50 of 0.95 micrograms/ml. Cholesterol ester hydrolase activity was unaffected by the drug (1.0-100 micrograms/ml). Intraduodenal infusion of Bay o 2752 (10 mg/ml at 0.9 ml/hr for 8 hr) reduced markedly the flux of cholesterol from the intestinal lumen into the mesenteric lymph, especially the lymphatic output of the esterified form of both radioisotopically labeled and total cholesterol. These data suggest that Bay o 2752-induced reduction in intestinal cholesterol absorption results from its potent inhibitory effect on acyl coenzyme A:cholesterol acyltransferase activity.
Bay o 2752 [N,N'-（1,11-十一烷二基）双（2,3-二氢-2-甲基-1H-吲哚-1-甲酰胺）] 在大鼠中已被证明可抑制肠道胆固醇吸收。在雄性Wistar大鼠中进行了研究，以确定其作用机制是抑制肠道胆汁酸吸收还是胆固醇酯化。通过[14C]牛磺胆酸体外摄取到回肠外翻囊中（Bay o 2752浓度为0.01和1.0 mg/ml）或在体内回肠灌注胆汁酸和药物后（1.0 mg/ml，流速1.0 ml/min，持续1小时）放射性物质的胆汁排泄来测量，Bay o 2752未改变肠道胆汁酸吸收。通过测量肝微粒体中酰基辅酶A：胆固醇酰基转移酶和胰腺上清液中胆固醇酯水解酶的体外活性，以及十二指肠内注入胆固醇酯后胆固醇酯的体内淋巴输出量来确定胆固醇酯化。向肝微粒体中添加Bay o 2752（0.01 - 10微克/毫升）会导致酰基辅酶A：胆固醇酰基转移酶活性呈浓度依赖性降低，IC50为0.95微克/毫升。胆固醇酯水解酶活性不受该药物影响（1.0 - 100微克/毫升）。十二指肠内注入Bay o 2752（10 mg/ml，流速0.9 ml/hr，持续8小时）显著降低了胆固醇从肠腔进入肠系膜淋巴的通量，尤其是放射性标记胆固醇和总胆固醇酯化形式的淋巴输出量。这些数据表明，Bay o 2752诱导的肠道胆固醇吸收减少是由于其对酰基辅酶A：胆固醇酰基转移酶活性的强效抑制作用。
