The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids[3]. SR-12813 inhibits cholesterol biosynthesis in Hep G2 cells via an enhanced degradation of HMG-CoA reductase. After 7 days plasma cholesterol was decreased by 15% in the 10 mg/kg/day group and by 19% in the 25 mg/kg/day group[4]. SR-12813 inhibited incorporation of tritiated water into cholesterol with an IC50 of 1.2 mM but had no effect on fatty acid synthesis. Furthermore, SR-12813 reduced cellular HMG-CoA reductase activity with an IC50 of 0.85 mM. The inhibition of HMG-CoA reductase activity was rapid with a T1/2 of 10 min. After a 16-h incubation with SR-12813, mRNA levels of HMG-CoA reductase and low density lipoprotein (LDL) receptor were increased. The increased expression of LDL receptor translated into a higher LDL uptake, which can explain the primary hypocholesterolemic effect of SR-12813 in vivo[5]. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well-established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P-gp expression by 1.8-, 6-, and 2-fold, respectively, with no effect observed for MRP1 expression[6]. Preactivation of hPXR by SR12813 in MDA-MB-231 cells led to an increased resistance to Taxol at concentrations of 20 and 50 nM[7].
SR12813 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MCF-7 cells
MCF-7 cells
Pretreatment led to increased resistance to tamoxifen
Cancer Biol Ther. 2009 Jul;8(13):1265-72.
MDA-MB-231 cells
MDA-MB-231 cells
Pretreatment led to increased resistance to Taxol
Cancer Biol Ther. 2009 Jul;8(13):1265-72.
HEK293 cells
HEK293 cells
To study the effect of SR12813 on PXR mutants, results showed that the C307A mutant restored SR12813-induced DNA binding.
JCI Insight. 2024 Jan 23;9(2):e172632.
HepG2 cells
HepG2 cells
To investigate the effect of SR12813 on PXR transactivation capacity, results showed that GSNO significantly decreased SR12813-induced PXR reporter activity.
JCI Insight. 2024 Jan 23;9(2):e172632.
LS174T-hPXR cells
LS174T-hPXR cells
To investigate the effect of SR12813 on the proliferation of LS174T-hPXR cells. The results showed that SR12813 significantly promoted cell proliferation, which was inhibited by the PXR antagonist SPA70
Cells. 2020 Jul 8;9(7):1641.
22RV1-hPXR cells
22RV1-hPXR cells
To investigate the activation of hPXR by SR12813. The results showed that SR12813 significantly activated hPXR, increasing luciferase expression
Cells. 2020 Jul 8;9(7):1641.
HepG2-hPXR cells
HepG2-hPXR cells
To investigate the activation of hPXR by SR12813. The results showed that SR12813 significantly activated hPXR, increasing luciferase expression
Cells. 2020 Jul 8;9(7):1641.
LS174T-hPXR cells
LS174T-hPXR cells
To investigate the activation of hPXR by SR12813. The results showed that SR12813 significantly activated hPXR, increasing luciferase expression
Cells. 2020 Jul 8;9(7):1641.
HG5LN GAL4-hPXR cells
HG5LN GAL4-hPXR cells
To investigate the activation of hPXR by SR12813. The results showed that SR12813 significantly activated hPXR, increasing luciferase expression by about 5-fold
Cells. 2020 Jul 8;9(7):1641.
THP-1-Blue NFκB cells
THP-1-Blue NFκB cells
To evaluate the effect of SR12813 on LPS-induced NFκB signaling, results showed that SR12813 inhibited NFκB signaling.
J Pharmacol Exp Ther. 2016 Oct;359(1):91-101.
Caco-2 cells
Caco-2 cells
To evaluate the protective effect of SR12813 on TNFα/IFNγ-induced intestinal epithelial barrier dysfunction, results showed that SR12813 pretreatment significantly reduced FITC-dextran flux, indicating barrier protection.
J Pharmacol Exp Ther. 2016 Oct;359(1):91-101.
hCMEC/D3 cells
hCMEC/D3 cells
Used as a positive regulator of P-gp to upregulate P-gp abundance
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