Avasimibe is an ACAT inhibitor with IC50 of 3.3 μM, it also inhibits human P450 isoenzymes CYP2C9, CYP1A2 and CYP2C19 with IC50 of 2.9/13.9 and 26.5 μM, respectively.
Acyl-CoA:cholesterol acyltransferases (ACAT) are intracellular enzymes that catalyze the synthesis of cholesterol esters. Avasimibe is an inhibitor for both ACAT1 and ACAT2 with IC50 values of 24 and 9.2 μM, respectively[3]. In human hepatic microsomes, avasimibe inhibits the activity of three human P450 isoenzymes, CYP2C9, CYP2C19, and CYP1A, with IC50 values of 2.88 ± 0.14, 26.5 ± 2.8, and 13.9 ± 5.0 μM, respectively. Avasimibe between 0.05 and 10 μM dose-dependently induced CY2C9 activity in primary cultures of human hepatocytes. For CYP2B6, avasimibe from 0.5 to 10 μM increased the enzyme activity at a concentration-dependent manner[4]. Incubation of THP-1 cells with 0.2 μM avasimibe during the process of lipid loading for 48 hours resulted in the 70% reduction of cellular cholesteryl ester content. In HepG2 cells administered with 10 nM to 10 μM avasimibe for 24 h, the secretion of apo B 100 was dose-dependently decreased. An overnight incubation with 10 μM avasimibe also suppressed the synthesis of apo B in HepG2 cells. For apo E*3-Leiden mice, the supplementation of avasimibe (0.01%, » a daily dose of 10 mg/kg) in the diet decreased the plasma total cholesterol concentration by 56% compared to mice fed with high fat/high cholesterol diet alone.
作用机制
Avasimibe is an oral inhibitor for ACAT that suppresses lipid accumulation in macrophages, thereby impeding the development of atherosclerotic lesions[5].
Avasimibe 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
HepG2 cells
Function assay
Inhibition of ACAT in human HepG2 cells, IC50=0.479 μM
19167888
rat macrophages
Function assay
24 h
Inhibition of ACAT in rat macrophages assessed as incorporation of extracellular [3H]-oleic acid-BSA complex into the intracellular cholesteryl ester after 24 hrs, IC50=0.479 μM
19464189
THP1 cells
Function assay
Inhibition of ACAT-mediated esterified cholesterol accumulation in human THP1 cells exposed to acetyl-LDL during differentiation assessed as effect on foam cell formation, IC50=1.5 μM
Inhibition of ACAT in human HepG2 cells, IC50=0.479 μM
19167888
rat macrophages
Function assay
24 h
Inhibition of ACAT in rat macrophages assessed as incorporation of extracellular [3H]-oleic acid-BSA complex into the intracellular cholesteryl ester after 24 hrs, IC50=0.479 μM
19464189
THP1 cells
Function assay
Inhibition of ACAT-mediated esterified cholesterol accumulation in human THP1 cells exposed to acetyl-LDL during differentiation assessed as effect on foam cell formation, IC50=1.5 μM
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