Etomoxir irreversibly binds to the catalytic site of carnitine palmitoyltransferase-1 (CPT-1) on the outer mitochondrial membrane, inhibiting its activity and reducing fatty acid transport into mitochondria. Besides acting as a CPT-1 inhibitor, Etomoxir also functions as a peroxisomal proliferator in the liver, promoting DNA synthesis and liver growth, which suggests it might also act as a PPARalpha agonist[1]. As a member of the oxirane carboxylic acid group, Etomoxir is recognized for its potential as a therapeutic for heart failure. Acute treatment with Etomoxir irreversibly inhibits CPT-1, leading to reduced mitochondrial fatty acid β-oxidation, accumulation of cytosolic fatty acids, and enhanced glucose oxidation. Extended exposure (24 hours) to Etomoxir affects the expression of various metabolic enzymes, indicating diverse metabolic impacts[2].
体内研究
Etomoxir inhibits free fatty acid (FFA) oxidation by targeting the key enzyme CPT1. This inhibition is linked to the suppression of the direct interaction between P53 and Bax, as well as FAO-mediated mitochondrial ROS generation, as demonstrated in studies involving db/db mice[3].
In experimental studies, rats injected with 20 mg/kg of Etomoxir daily for 8 days show a 44% decrease in cardiac CPT-I activity. This regimen does not affect blood glucose levels or general growth such as body mass or muscle mass in the hindlimbs, aligning with similar findings from other Etomoxir studies. Notably, Etomoxir treatment significantly increases both heart and liver mass by 11% in treated rats[4].
体外研究
Etomoxir irreversibly binds to the catalytic site of carnitine palmitoyltransferase-1 (CPT-1) on the outer mitochondrial membrane, inhibiting its activity and reducing fatty acid transport into mitochondria. Besides acting as a CPT-1 inhibitor, Etomoxir also functions as a peroxisomal proliferator in the liver, promoting DNA synthesis and liver growth, which suggests it might also act as a PPARalpha agonist[1].
As a member of the oxirane carboxylic acid group, Etomoxir is recognized for its potential as a therapeutic for heart failure. Acute treatment with Etomoxir irreversibly inhibits CPT-1, leading to reduced mitochondrial fatty acid β-oxidation, accumulation of cytosolic fatty acids, and enhanced glucose oxidation. Extended exposure (24 hours) to Etomoxir affects the expression of various metabolic enzymes, indicating diverse metabolic impacts[2].
Etomoxir/乙莫克舍 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HCTR cells
100 μM
7 days
To evaluate the effect of Etomoxir on the clone formation capacity of HCTR cells, the results showed that Etomoxir significantly reduced the clone formation of HCTR cells.
Adv Sci (Weinh). 2023 Nov;10(32):e2301939.
RAW264.7 cells
25 μM
24 h
Inhibition of CPT1 significantly increased the secretion of 12/15-LOX-derived oxylipins
Nat Commun. 2022 Jan 10;13(1):139.
peritoneal macrophages
25 μM
24 h
Etomoxir significantly increased the detected levels of several monohydroxy lipids and COX-2 products
Nat Commun. 2022 Jan 10;13(1):139.
brown adipocytes
10 µM
15 min
To test the effect of Etomoxir on the respiratory capacity of brown adipocytes, it was found that Etomoxir treatment significantly reduced oxygen consumption, indicating that fatty acid oxidation plays an important role in respiratory capacity.
Elife. 2020 Aug 14;9:e52558.
HeLa-LNM2 cells
100 μM
Inhibited CPT1A activity, reduced ATP levels and maximum respiration rate
Adv Sci (Weinh). 2024 Jun;11(21):e2308422.
SiHa-LNM2 cells
100 μM
Inhibited CPT1A activity, reduced ATP levels and maximum respiration rate
Adv Sci (Weinh). 2024 Jun;11(21):e2308422.
OT-I TRM cells
40 μM
15 min
Inhibited mitochondrial fatty acid β-oxidation, preventing the increase in OCR of OT-I TRM cells
Nature. 2017 Mar 9;543(7644):252-256.
Jurkat cells
20 μM
24 h
To test the effect of Etomoxir on the metabolism of Jurkat cells, results showed that Etomoxir significantly increased the level of propionyl-carnitine and decreased the level of butyryl-carnitine.
Anal Chem. 2023 Mar 7;95(9):4325-4334.
BSC40 cells
360 µM
16 h
To investigate the effect of Etomoxir on viral yield, results showed that Etomoxir significantly inhibited viral yield, and the inhibition was more pronounced in the absence of exogenous glucose.
PLoS Pathog. 2014 Mar 20;10(3):e1004021.
BMDM
4 μM
18 h
To test the effect of Etomoxir on fatty acid oxidation and oxidative phosphorylation in BMDM cells, results showed that Etomoxir treatment significantly reduced OCR, indicating inhibition of CPT1A-dependent fatty acid oxidation.
inflammation via extracellular vesicles. J Extracell Vesicles.
pDCs
200 μM
24 h
Etomoxir inhibited the CpGA-induced increase in basal OCR and SRC in pDCs, indicating that CpGA stimulation of pDCs results in enhanced OXPHOS largely due to increased FAO.
Immunity. 2016 Jun 21;44(6):1325-36.
Etomoxir/乙莫克舍 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Murine model of human leukemia
Intraperitoneal
50 mg/kg
Every other day for 3 weeks
Ranolazine in combination with ABT-737 or Ara-C significantly decreased tumor burden and prolonged survival
J Clin Invest. 2010 Jan;120(1):142-56
CB-17 SCID mice
HCT116 and HCTR xenograft models
Intraperitoneal injection
30 mg/kg
Days 12, 13, 14, 15, 18, 19, 20, 21
To evaluate the effect of Etomoxir on the volume of HCTR xenograft tumors, the results showed that Etomoxir significantly reduced the volume of HCTR xenograft tumors.
Adv Sci (Weinh). 2023 Nov;10(32):e2301939.
Mice
OVA and HDM-induced asthma models
Intraperitoneal injection
50 mg/kg
30 minutes after and 24 hours later
Etomoxir significantly reduced OVA-induced airway hyperresponsiveness, decreased the number of inflammatory cells, and reduced the production of cytokines and chemokines associated with asthma.
Clin Exp Allergy. 2017 Sep;47(9):1170-1184
C57BL/6 mice
LPS-induced peritonitis model
Intraperitoneal injection
100 μg
Single injection, samples collected after 6 hours
Etomoxir significantly increased the levels of many oxylipins during inflammation
Inhibited CPT1A activity, reducing the long-term survival of OT-I TRM cells
Nature. 2017 Mar 9;543(7644):252-256.
Mice
LCMV infection model
Intraperitoneal injection
20 mg/kg
Once before infection and once after infection
Etomoxir treatment significantly reduced plasma IFN-α levels at day 3 post-infection and significantly increased LCMV viral load in the liver and spleen, indicating that the induction of FAO is critical for optimal type 1 IFN production and viral control following infection in vivo.
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