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| Targets |
CAR; Bcl-2; TCPOBOP targets the mouse constitutive androstane receptor (CAR; NR1I3) as a potent and specific agonist. It directly binds to CAR, inducing nuclear translocation and activation of its target genes. In CAR wild-type mice, TCPOBOP treatment (3 mg/kg, i.p., daily for 3 days) induces the classical CAR target gene CYP2B10 by approximately 150-fold compared to vehicle-treated controls. This induction is absent in CAR knockout mice. [1][2]
In a reporter gene assay using Huh-7 cells transfected with mouse CAR, TCPOBOP (1 μM) significantly increased Mcl-1 promoter activity, and this effect was abrogated by mutating a putative CAR-binding site on the Mcl-1 promoter. [2] |
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| ln Vitro |
In Huh-7 human hepatoma cells transfected with mouse CAR, TCPOBOP (1 μmol/L) significantly increases Mcl-1 promoter activity in a CAR-dependent manner. This effect is mediated through a putative CAR-binding site (consensus direct repeat 4 sequence AGGTCACTTGAGGCCA at position 989-974) on the Mcl-1 promoter; point mutations of this binding site (changing GG to TT at residues 988/987 or 978/977) abrogate the TCPOBOP-induced increase in Mcl-1 promoter activity. [2]
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| ln Vivo |
TCPOBOP (3 mg/kg, i.p., daily for 3 days) induces hepatomegaly and hepatocyte proliferation in CAR wild-type mice. At 48 hours after TCPOBOP treatment, liver-to-body weight ratio increases 1.6-fold, and Ki67-positive hepatocytes are markedly increased. [1]
TCPOBOP provides CAR-dependent protection against Fas-mediated liver injury. In CAR wild-type mice pretreated with TCPOBOP (3 mg/kg, i.p., daily for 3 days) followed by Jo2 antibody (10 μg/mouse, i.p.), serum ALT levels are significantly reduced (from ~5000 U/L to ~2000 U/L), TUNEL-positive cells and activated caspase 3/7-positive cells are markedly decreased, and animal survival at 48 hours is improved by 47% compared to vehicle-treated controls. These protective effects are absent in CAR knockout mice. [2] TCPOBOP also protects against concanavalin A (ConA)-induced liver injury. In CAR wild-type mice pretreated with TCPOBOP (3 mg/kg, i.p., daily for 3 days) followed by ConA (25 mg/kg, i.v.), serum ALT levels are significantly reduced. In a chronic ConA model (8 mg/kg, i.v., weekly for 6 weeks with once-weekly TCPOBOP pretreatment), TCPOBOP reduces liver fibrosis as assessed by Sirius red staining and α-smooth muscle actin (αSMA) expression (approximately 2-fold reduction in αSMA mRNA). [2] TCPOBOP-induced hepatocyte proliferation and hepatomegaly are dramatically attenuated in mice with combined disruption of MET and EGFR signaling ([MET KO + EGFRi]), while CAR activation (nuclear translocation and CYP2B10 induction) remains unaltered. In [MET KO + EGFRi] mice, TCPOBOP fails to induce cyclin D1, FOXM1 (10-fold induction in controls vs. attenuated in [MET KO + EGFRi] at Day 1-2), and downstream cell cycle genes. [1] TCPOBOP(oral; 3 mg/kg; 1–5 days) significantly increases the liver weight to body weight ratio at 48 hours [1]. |
| Cell Assay |
Luciferase reporter gene assay: Huh-7 cells are cotransfected with 100 ng of mCAR expression vector (or empty vector), 10 ng of Renilla luciferase reporter plasmid, and 0.5 μg of firefly luciferase-based Mcl-1 promoter constructs (-140, -294, or -3893 bp). TCPOBOP (1 μmol/L) is added at the time of transfection. After 24 hours, cell lysates are assayed for firefly/Renilla luciferase activity using the Dual-Luciferase Reporter Assay System. Site-directed mutagenesis is performed to introduce point mutations into a putative CAR-binding site (AGGTCACCTTGAGGCCA at 989-974) on the Mcl-1 promoter. [2]
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| Animal Protocol |
METfl/fl: Tam-Cre+/+ mice with a targeted deletion for exon 16 with MET KO[1]
3 mg/kg Oral; 1, 2, 5 days |
| Toxicity/Toxicokinetics |
TCPOBOP at 3 mg/kg (i.p. or oral) is well-tolerated in mice with no reported mortality or overt toxicity at this dose. In CAR wild-type mice, TCPOBOP induces hepatomegaly and hepatocyte proliferation (physiological hyperplasia) without liver injury, as evidenced by normal serum ALT levels. In contrast, in CAR knockout mice, TCPOBOP does not induce hepatomegaly or hepatocyte proliferation. [1][2]
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| References |
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| Additional Infomation |
Chemical structure: TCPOBOP is a CAR agonist that directly binds to CAR. [1][2]
Species specificity: TCPOBOP is a potent and specific agonist for mouse CAR but does not activate human CAR. It is a nongenotoxic hepatocarcinogen in mice. [1][2] Mechanism of CAR activation: Upon TCPOBOP binding, CAR translocates from the cytoplasm to the nucleus, heterodimerizes with retinoid X receptor (RXR), and activates target genes containing phenobarbital-responsive enhancer modules (PBREMs). [2] Differential effects on proliferation vs. detoxification: Combined disruption of MET and EGFR signaling ([MET KO + EGFRi]) attenuates TCPOBOP-induced hepatocyte proliferation and hepatomegaly without affecting CAR nuclear translocation or induction of detoxification genes (e.g., Cyp2b10), demonstrating that these two processes can be uncoupled. [1] Regulation of Bcl-2 proteins: TCPOBOP treatment depletes pro-apoptotic Bak and Bax and increases anti-apoptotic Mcl-1 expression in a CAR-dependent manner, contributing to cytoprotection against Fas-mediated apoptosis. Mcl-1 transgenic mice are protected from Jo2-induced liver injury. [2] |
| Molecular Formula |
C16H8N2O2CL4
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|---|---|
| Molecular Weight |
402.05892
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| Exact Mass |
399.934
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| Elemental Analysis |
C, 47.80; H, 2.01; Cl, 35.27; N, 6.97; O, 7.96
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| CAS # |
76150-91-9
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| Related CAS # |
76150-91-9
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| PubChem CID |
5382
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| Appearance |
White to off-white solid powder
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| Density |
1.518g/cm3
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| Boiling Point |
444.8ºC at 760 mmHg
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| Flash Point |
222.8ºC
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| Index of Refraction |
1.635
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| LogP |
6.674
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
362
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=C(C=CC(=C1)OC2=C(C=C(C=N2)Cl)Cl)OC3=C(C=C(C=N3)Cl)Cl
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| InChi Key |
BAFKRPOFIYPKBQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H8Cl4N2O2/c17-9-5-13(19)15(21-7-9)23-11-1-2-12(4-3-11)24-16-14(20)6-10(18)8-22-16/h1-8H
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| Chemical Name |
3,5-dichloro-2-[4-(3,5-dichloropyridin-2-yl)oxyphenoxy]pyridine
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| Synonyms |
TCPOBOP;
tcpobop; 76150-91-9; 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene; 1,4-BDPOB; 1,4-Bis(2-(3,5-dichloropyridyloxy))benzene;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 10~25 mg/mL (62.2~24.9 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.22 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4872 mL | 12.4360 mL | 24.8719 mL | |
| 5 mM | 0.4974 mL | 2.4872 mL | 4.9744 mL | |
| 10 mM | 0.2487 mL | 1.2436 mL | 2.4872 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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