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/阿伐麦布 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Various human cancer cells
5 µM
24 hours
Reduced cholesteryl ester storage, increased free cholesterol, led to apoptosis and inhibited proliferation.
ACS Nano. 2015 Mar 24;9(3):2420-32.
Glioblastoma cells
0 to 240 µM
24 or 48 hours
To determine the effect of avasimibe on cell proliferation, showing dose-dependent inhibition and increased apoptosis
Acta Pharmacol Sin. 2021 Jan;42(1):97-107.
B16F10 cells
1 µM
24, 48, or 72 hours
Enhanced cytotoxicity and proliferation of CD8+ T-cells were observed.
Nature. 2016 Mar 31;531(7596):651-5.
Avasimibe/阿伐麦布 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
B16F10 melanoma model
Intragastric administration
15 mg/kg
Every 2 days
Reduction in tumor size and improved survival rates were observed.
Nature. 2016 Mar 31;531(7596):651-5.
BALB/c-nu nude mice
U87 xenograft model
Intraperitoneal injection
15 or 30 mg/kg
Once per day for 18 days
To assess the antitumor effect, showing significant tumor size and weight reduction
Acta Pharmacol Sin. 2021 Jan;42(1):97-107.
Mice
PC3 and HCT116 tumor xenograft models
Intravenous injection
75 mg/kg (7.5 mg/kg avasimibe)
Daily for the first 5 days, followed by once every 4 days
Suppressed tumor growth and extended length of survival time.
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
搜索
