Acyl coenzyme A:Cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic drugs

被引:27
作者
Alegret, M
Llaverias, G
Silvestre, JS
机构
[1] Prous Sci SA, Dept Pharmacol, Barcelona 08025, Spain
[2] Univ Barcelona, Fac Farm, Dept Farmacol & Quim Terapeut, Unitat Farmacol, E-08007 Barcelona, Spain
来源
METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY | 2004年 / 26卷 / 07期
关键词
acyl coenzyme A : cholesterol acyltransferase (ACAT); ACAT inhibitors; animal models; clinical studies; experimental models;
D O I
10.1358/mf.2004.26.7.863738
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Acyl coenzyme A:cholesterol acyltransferase (ACAT) is the enzyme that catalyzes the conversion of intracellular cholesterol into cholesteryl esters. Two ACAT isoforms, termed ACAT1 and ACAT2, have been described. ACAT1 is ubiquitously found, with high expression levels in macrophages, adrenals, sebaceous glands and foam cells from human atherosclerotic lesions. In contrast, ACAT2 expression is restricted to the intestine and the liver of mice and non-human primates. The reaction catalyzed by ACAT is essential for intestinal cholesterol absorption, synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins, and intracellular storage of cholesterol. Therefore, ACAT inhibitors would theoretically reduce plasma cholesterol levels by blocking cholesterol absorption from the diet and by reducing hepatic VLDL synthesis. Moreover, ACAT inhibition could limit the accumulation of cholesteryl esters in the cytoplasm of macrophages, thus reducing the formation of foam cells. In view of these attractive possibilities, a great deal of molecules with ACAT inhibitory properties have been synthesized in the last 20 years. However, only a few of them have reached clinical studies, mainly due to unexpected side effects. On the other hand, most of the compounds assayed in humans have not shown substantial hypolipidemic efficacy. The present article focuses on the current knowledge of the pharmacology of ACAT inhibitors, and, specifically, on the different pharmacological approaches used to evaluate these compounds as hypolipidemic and antiatherosclerotic agents. (C) 2004 Prous Science. All rights reserved.
引用
收藏
页码:563 / 586
页数:24
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