Chiari A, Lovisolo P, Fogliatto G, Fancelli D, Ghiselli G
Pharmacia Farmitalia Carlo Erba, Cardiovascular Department, Nerviano, Italy.
Pharmacol Res. 1996 Mar;33(3):181-9. doi: 10.1006/phrs.1996.0025.
Rabbits fed a wheat starch casein diet develop hypercholesterolaemia characterized by the plasma elevation of low density lipoprotein (LDL) that is caused by oversecretion of apoB-100 containing lipoproteins by the liver and by the suppression of the EDTA-sensitive hepatic beta- very low density lipoprotein (VLDL)-LDL receptor. In this study, the effect of FCE 27677 ((-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-(4-dimethylaminoph eny l)-4,5-dimethyl-dioxolan-2-yl]methylurea) a novel potent systemic acylCoA:cholesterol acetyltransferase (ACAT, EC 2.3.1.26) inhibitor, has been evaluated. When New Zealand White rabbits were fed with casein for 4 weeks, LDL cholesterol increased from 14 +/- 3 mg/dl-1 to 77 +/- 6 mg/dl-1. By contrast the animals receiving FCE 27677 (10 mg kg-1 d-1) mixed with the casein diet maintained a normal LDL concentration (22 +/- 3 mg dl-1). This hypolipidaemic effect was also observed when rabbits previously made hypercholesterolaemic by being fed casein for 4 weeks were then treated for a month with FCE 27677. [125I]LDL plasma turnover studies and [125I]LDL binding studies to liver membranes were carried out with the purpose of investigating the mechanism of action of the drug. The LDL apoB-100 production rate in chow-fed, casein-fed, and casein-fed rabbits receiving FCE 27677, was respectively 10.5, 22.4, and 12.5 mg kg-1 d-1. The turnover rate of [125I]LDL in the animals receiving the drug was not, however, different from that in the rabbits fed the casein diet alone (2.381 vs 2.079 pools d-1). Both values were lower than that in chow-fed animals (3.271 pools d-1). FCE 27677 did not normalize the activity of the hepatic beta-VLDL-LDL EDTA-sensitive receptor which is suppressed by casein feeding. Altogether the results are consistent with the idea that FCE 27677 by acting through inhibition of the cholesterol esterification in the liver normalizes the LDL synthetic rate. ACAT inhibitors may be useful drugs for the treatment of human dyslipoproteinaemia secondary to derangement of the apoB-100 synthetic rate.
喂食小麦淀粉酪蛋白饮食的兔子会出现高胆固醇血症，其特征是血浆低密度脂蛋白（LDL）升高，这是由肝脏中含载脂蛋白B - 100的脂蛋白分泌过多以及对EDTA敏感的肝脏β - 极低密度脂蛋白（VLDL）-LDL受体受抑制所致。在本研究中，评估了新型强效全身酰基辅酶A：胆固醇乙酰转移酶（ACAT，EC 2.3.1.26）抑制剂FCE 27677（（-）N - [2,6 - 双（1 - 甲基乙基）苯基] - N'- [（4R，5R） - 2 - （4 - 二甲基氨基苯基）-4,5 - 二甲基 - 二氧戊环 - 2 - 基]甲基脲）的作用。当给新西兰白兔喂食酪蛋白4周时，LDL胆固醇从14±3mg/dl - 1增加到77±6mg/dl - 1。相比之下，接受与酪蛋白饮食混合的FCE 27677（10mg kg - 1 d - 1）的动物维持正常的LDL浓度（22±3mg dl - 1）。当先前通过喂食酪蛋白4周而患高胆固醇血症的兔子随后用FCE 27677治疗一个月时，也观察到了这种降血脂作用。为了研究该药物的作用机制，进行了[125I]LDL血浆周转率研究和[125I]LDL与肝细胞膜的结合研究。在喂食普通饲料、酪蛋白饲料以及接受FCE 27677的酪蛋白饲料喂养的兔子中，LDL载脂蛋白B - 100的产生率分别为10.5、22.4和12.5mg kg - 1 d - 1。然而，接受该药物的动物中[125I]LDL的周转率与仅喂食酪蛋白饮食的兔子的周转率没有差异（分别为2.381和2.079池/天）。这两个值均低于喂食普通饲料动物的值（3.271池/天）。FCE 27677并未使因喂食酪蛋白而受抑制的肝脏β - VLDL - LDL EDTA敏感受体的活性恢复正常。总体而言，结果与FCE 27677通过抑制肝脏中的胆固醇酯化作用使LDL合成率恢复正常这一观点一致。ACAT抑制剂可能是治疗继发于载脂蛋白B - 100合成率紊乱的人类脂蛋白异常血症的有用药物。
