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Chemical Compound Review

tcpobop     3,5-dichloro-2-[4-(3,5- dichloropyridin-2...

Synonyms: Lopac-T-1443, CHEMBL488803, SureCN240269, CCRIS 3521, AG-H-03806, ...
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Disease relevance of tcpobop


Psychiatry related information on tcpobop

  • Only P4502a-4/5 and associated mRNA displayed a biphasic time-response after TCPOBOP induction: a transient increase occurring 3-8 hr after administration with a subsequent decline at 24 hr before the maximal induction at 72 hr [5].

High impact information on tcpobop

  • Here we show that the nuclear receptor CAR mediates the response evoked by a class of xenobiotics known as the 'phenobarbital-like inducers'. The strong activation of Cyp2b10 gene expression by phenobarbital, or by the more potent TCPOBOP, is absent in mice lacking the CAR gene [6].
  • Treatment with TCPOBOP or PB decreased the levels of phosphoenolpyruvate carboxykinase 1 mRNA in mice but not in Car(-/-) mice [7].
  • Both its ability to target CYP genes and its activation by TCPOBOP demonstrate that CAR is a novel xenobiotic receptor that may contribute to the metabolic response to such compounds [8].
  • Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice [1].
  • Further studies evaluated TCPOBOP-induced gene expression in CAR-/- mice, by microarray expression profiling and Northern blot [9].

Chemical compound and disease context of tcpobop


Biological context of tcpobop

  • However, CAR transactivation is increased in the presence of 1,4-bis[2-(3, 5-dichloropyridyloxy)]benzene (TCPOBOP), the most potent known member of the phenobarbital-like class of CYP-inducing agents [8].
  • We compared mouse immediate-early gene expression changes after PH with those induced by 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene (TCPOBOP), a tumor-promoting liver mitogen [11].
  • To directly test the role of cyclin D1 in the progression of the cell cycle, we have examined the proliferative response of hepatocytes to the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in mice with homozygous disruption of the cyclin D1 gene [12].
  • To examine the structure-activity relationship, 31 congeners of TCPOBOP were synthesized and tested for their potency to induce hepatic aminopyrine N-demethylase activity in B6D2F1/J mice [13].
  • The more favorable enthalpic contribution for TCPOBOP-bound CAR-RXR indicates that preformation of the binding site improves the complementarity of the coactivator-receptor interaction [14].

Anatomical context of tcpobop

  • We show that treatment of 12-month-old CD-1 mice with the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) caused an increase in hepatocyte proliferation similar to that seen in young (8-week-old) mice [15].
  • Our results showed no difference in the proliferative response of the liver between the wild type and the knock-out mice following treatment with the mitogens 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or the peroxisome proliferator, ciprofibrate, suggesting that TNF or IL-6 may not play a major role in this type of proliferation [16].
  • Interestingly however, TCPOBOP, when given subsequent to NDEA, caused a significant increase in nasal cavity tumors in F344 rats [17].
  • Thus TCPOBOP at maximal CYP2B induction doses exhibits a strong promoting activity for both liver and thyroid of rats [10].
  • The effects of an oral treatment with 3 mg/kg body weight of TCPOBOP were scored in the bone marrow cells and in the liver cells of B6C3F1 hybrid mice [4].

Associations of tcpobop with other chemical compounds


Gene context of tcpobop

  • Activation of the PBREM by TCPOBOP generated a 10-fold induction of CYP2B6 mRNA in HepG2 cells stably expressing mouse CAR (Ym17) [20].
  • TCPOBOP, a CAR agonist that increases the interaction of CAR with coactivators, potentiated CAR inhibition of HNF-4 transactivation [21].
  • Gel shift assay indicated that TCPOBOP-induced hepatocyte proliferation is not associated with activation of STAT3 transcription factor, a major target of IL-6 and other growth factors/cytokines [16].
  • Increased expression of c-fos, c-jun and LRF-1 is not required for in vivo priming of hepatocytes by the mitogen TCPOBOP [22].
  • The CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) induced Mrp2, -3, -4, -6, and -7 mRNA expression [23].

Analytical, diagnostic and therapeutic context of tcpobop

  • We have previously demonstrated that hepatocyte proliferation induced by the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) is independent of changes in cytokines, immediate early genes, and transcription factors that are considered to be necessary for regeneration of the liver after partial hepatectomy (PH) or necrosis [2].
  • However, both DNA affinity and chromatin immunoprecipitation assays showed a significant increase in CAR association with the OARE after co-treatment with TCPOBOP and OA, indicating the indirect binding of CAR to the OARE [20].
  • The result of Western-blot analysis showed that PB and TPD increased CYP2B protein content in rat liver, PB and TCPOBOP - in mouse liver [24].


  1. Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. Baskin-Bey, E.S., Huang, W., Ishimura, N., Isomoto, H., Bronk, S.F., Braley, K., Craig, R.W., Moore, D.D., Gores, G.J. Hepatology (2006) [Pubmed]
  2. Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis[2-(3,5-Dichloropyridyloxy)] benzene. Ledda-Columbano, G.M., Pibiri, M., Loi, R., Perra, A., Shinozuka, H., Columbano, A. Am. J. Pathol. (2000) [Pubmed]
  3. Promoting effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene in mouse hepatocarcinogenesis. Dragani, T.A., Manenti, G., Galliani, G., Della Porta, G. Carcinogenesis (1985) [Pubmed]
  4. Clastogenic effects induced in mice and rats by 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene, a phenobarbital-like enzyme inducer and liver tumour promoter. Rossi, A.M., Zaccaro, L., Rosselli, F., Quattrone, C. Carcinogenesis (1988) [Pubmed]
  5. Distinct induction profiles of three phenobarbital-responsive mouse liver cytochrome P450 isozymes. Honkakoski, P., Auriola, S., Lang, M.A. Biochem. Pharmacol. (1992) [Pubmed]
  6. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., Moore, D.D. Nature (2000) [Pubmed]
  7. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Kodama, S., Koike, C., Negishi, M., Yamamoto, Y. Mol. Cell. Biol. (2004) [Pubmed]
  8. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Tzameli, I., Pissios, P., Schuetz, E.G., Moore, D.D. Mol. Cell. Biol. (2000) [Pubmed]
  9. Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Columbano, A., Ledda-Columbano, G.M., Pibiri, M., Cossu, C., Menegazzi, M., Moore, D.D., Huang, W., Tian, J., Locker, J. Hepatology (2005) [Pubmed]
  10. Enhancement of thyroid and hepatocarcinogenesis by 1,4-bis[2-(3,5- dichloropyridyloxy)]benzene in rats at doses that cause maximal induction of CYP2B. Diwan, B.A., Henneman, J.R., Rice, J.M., Nims, R.W. Carcinogenesis (1996) [Pubmed]
  11. A common set of immediate-early response genes in liver regeneration and hyperplasia. Locker, J., Tian, J., Carver, R., Concas, D., Cossu, C., Ledda-Columbano, G.M., Columbano, A. Hepatology (2003) [Pubmed]
  12. Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli. Ledda-Columbano, G.M., Pibiri, M., Concas, D., Cossu, C., Tripodi, M., Columbano, A. Hepatology (2002) [Pubmed]
  13. Structure-activity relationship of bispyridyloxybenzene for induction of mouse hepatic aminopyrine N-demethylase activity. Chemical, biological, and X-ray crystallographic studies. Kende, A.S., Ebetino, F.H., Drendel, W.B., Sundaralingam, M., Glover, E., Poland, A. Mol. Pharmacol. (1985) [Pubmed]
  14. Thermodynamic characterization of the interaction between CAR-RXR and SRC-1 peptide by isothermal titration calorimetry. Wright, E., Vincent, J., Fernandez, E.J. Biochemistry (2007) [Pubmed]
  15. Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP. Ledda-Columbano, G.M., Pibiri, M., Cossu, C., Molotzu, F., Locker, J., Columbano, A. Hepatology (2004) [Pubmed]
  16. In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway. Ledda-Columbano, G.M., Curto, M., Piga, R., Zedda, A.I., Menegazzi, M., Sartori, C., Shinozuka, H., Bluethmann, H., Poli, V., Ciliberto, G., Columbano, A. Oncogene (1998) [Pubmed]
  17. Tumor-promoting and hepatocarcinogenic effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in DBA/2NCr and C57BL/6NCr mice and an apparent promoting effect on nasal cavity tumors but not on hepatocellular tumors in F344/NCr rats initiated with N-nitrosodiethylamine. Diwan, B.A., Lubet, R.A., Ward, J.M., Hrabie, J.A., Rice, J.M. Carcinogenesis (1992) [Pubmed]
  18. Mechanism-based inhibition of mouse P4502b-10 by selected arylalkynes. Beebe, L.E., Roberts, E.S., Fornwald, L.W., Hollenberg, P.F., Alworth, W.L. Biochem. Pharmacol. (1996) [Pubmed]
  19. Retinoic acids repress constitutive active receptor-mediated induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene of the CYP2B10 gene in mouse primary hepatocytes. Kakizaki, S., Karami, S., Negishi, M. Drug Metab. Dispos. (2002) [Pubmed]
  20. Novel CAR-mediated mechanism for synergistic activation of two distinct elements within the human cytochrome P450 2B6 gene in HepG2 cells. Swales, K., Kakizaki, S., Yamamoto, Y., Inoue, K., Kobayashi, K., Negishi, M. J. Biol. Chem. (2005) [Pubmed]
  21. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. Miao, J., Fang, S., Bae, Y., Kemper, J.K. J. Biol. Chem. (2006) [Pubmed]
  22. Increased expression of c-fos, c-jun and LRF-1 is not required for in vivo priming of hepatocytes by the mitogen TCPOBOP. Columbano, A., Ledda-Columbano, G.M., Pibiri, M., Piga, R., Shinozuka, H., De Luca, V., Cerignoli, F., Tripodi, M. Oncogene (1997) [Pubmed]
  23. Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver. Maher, J.M., Cheng, X., Slitt, A.L., Dieter, M.Z., Klaassen, C.D. Drug Metab. Dispos. (2005) [Pubmed]
  24. Comparative study of CYP2B induction in the liver of rats and mice by different compounds. Pustylnyak, V.O., Lebedev, A.N., Gulyaeva, L.F., Lyakhovich, V.V., Slynko, N.M. Life Sci. (2007) [Pubmed]
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