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Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator.

Elcombe CR, Peffer RC, Wolf DC, Bailey J, Bars R, Bell D, Cattley RC, Ferguson SS, Geter D, Goetz A, Goodman JI, Hester S, Jacobs A, Omiecinski CJ, Schoeny R, Xie W, Lake BG.

Crit Rev Toxicol. 2014 Jan;44(1):64-82. doi: 10.3109/10408444.2013.835786. Epub 2013 Nov 4. Review.


Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane x receptors.

Luisier R, Lempiäinen H, Scherbichler N, Braeuning A, Geissler M, Dubost V, Müller A, Scheer N, Chibout SD, Hara H, Picard F, Theil D, Couttet P, Vitobello A, Grenet O, Grasl-Kraupp B, Ellinger-Ziegelbauer H, Thomson JP, Meehan RR, Elcombe CR, Henderson CJ, Wolf CR, Schwarz M, Moulin P, Terranova R, Moggs JG.

Toxicol Sci. 2014 Jun;139(2):501-11. doi: 10.1093/toxsci/kfu038. Epub 2014 Apr 1.


Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo.

Ross J, Plummer SM, Rode A, Scheer N, Bower CC, Vogel O, Henderson CJ, Wolf CR, Elcombe CR.

Toxicol Sci. 2010 Aug;116(2):452-66. doi: 10.1093/toxsci/kfq118. Epub 2010 Apr 19.


Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation.

Deguchi Y, Yamada T, Hirose Y, Nagahori H, Kushida M, Sumida K, Sukata T, Tomigahara Y, Nishioka K, Uwagawa S, Kawamura S, Okuno Y.

Toxicol Sci. 2009 Mar;108(1):69-80. doi: 10.1093/toxsci/kfp006. Epub 2009 Jan 27.


Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes.

Hirose Y, Nagahori H, Yamada T, Deguchi Y, Tomigahara Y, Nishioka K, Uwagawa S, Kawamura S, Isobe N, Lake BG, Okuno Y.

Toxicology. 2009 Apr 5;258(1):64-9.


Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from increased expression of xenosensor nuclear receptors PPARα and CAR/PXR.

Elcombe CR, Elcombe BM, Foster JR, Chang SC, Ehresman DJ, Butenhoff JL.

Toxicology. 2012 Mar 11;293(1-3):16-29. doi: 10.1016/j.tox.2011.12.014. Epub 2012 Jan 8.


The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism.

Roques BB, Leghait J, Lacroix MZ, Lasserre F, Pineau T, Viguié C, Martin PG.

Biochem Pharmacol. 2013 Oct 1;86(7):997-1039. doi: 10.1016/j.bcp.2013.08.012. Epub 2013 Aug 17.


A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression.

Wang H, Faucette S, Sueyoshi T, Moore R, Ferguson S, Negishi M, LeCluyse EL.

J Biol Chem. 2003 Apr 18;278(16):14146-52. Epub 2003 Feb 5.


Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action.

Currie RA, Peffer RC, Goetz AK, Omiecinski CJ, Goodman JI.

Toxicology. 2014 Jul 3;321:80-8. doi: 10.1016/j.tox.2014.03.003. Epub 2014 Mar 24.


AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line.

Rencurel F, Stenhouse A, Hawley SA, Friedberg T, Hardie DG, Sutherland C, Wolf CR.

J Biol Chem. 2005 Feb 11;280(6):4367-73. Epub 2004 Nov 29.


Mode-of-action analysis for induction of rat liver tumors by pyrethrins: relevance to human cancer risk.

Osimitz TG, Lake BG.

Crit Rev Toxicol. 2009;39(6):501-11. doi: 10.1080/10408440902914014. Review.


Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor.

LeBaron MJ, Gollapudi BB, Terry C, Billington R, Rasoulpour RJ.

Crit Rev Toxicol. 2014 May;44 Suppl 2:15-24. doi: 10.3109/10408444.2014.910751. Review.


Sterol regulatory element binding protein 1 interacts with pregnane X receptor and constitutive androstane receptor and represses their target genes.

Roth A, Looser R, Kaufmann M, Meyer UA.

Pharmacogenet Genomics. 2008 Apr;18(4):325-37. doi: 10.1097/FPC.0b013e3282f706e0.


Mode of action analysis for pesticide-induced rodent liver tumours involving activation of the constitutive androstane receptor: relevance to human cancer risk.

Lake BG, Price RJ, Osimitz TG.

Pest Manag Sci. 2015 Jun;71(6):829-34. doi: 10.1002/ps.3854. Epub 2014 Nov 17.


Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways.

Kakehashi A, Hagiwara A, Imai N, Nagano K, Nishimaki F, Banton M, Wei M, Fukushima S, Wanibuchi H.

Toxicol Appl Pharmacol. 2013 Dec 1;273(2):390-400. doi: 10.1016/j.taap.2013.09.016. Epub 2013 Sep 30.


Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response.

Wei P, Zhang J, Dowhan DH, Han Y, Moore DD.

Pharmacogenomics J. 2002;2(2):117-26.


Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes.

Gährs M, Roos R, Andersson PL, Schrenk D.

Toxicol Appl Pharmacol. 2013 Oct 1;272(1):77-85. doi: 10.1016/j.taap.2013.05.034. Epub 2013 Jun 12.

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