title: Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR.
abstract: The nuclear receptors CAR (constitutive androstane receptor) and possibly PXR (pregnane X receptor) mediate the hepatic effects of phenobarbital (PB) and similar-acting compounds. Although PB is a potent nongenotoxic tumor promoter in rodent liver, epidemiological data from epilepsy patients treated with phenobarbital do not show a specific role of PB in human liver cancer risk. That points to species differences in the susceptibility to tumor promotion by PB, which might be attributed to divergent functions of the PB receptors CAR and PXR in mice and humans. In the present study, male transgenic mice expressing human CAR and PXR were used to detect possible differences between wild-type (WT) and humanized mice in their response to CAR activation in a tumor initiation/promotion experiment with a single injection of the tumor initiator N-nitrosodiethylamine preceding chronic PB treatment for 10 months. Analysis of liver tumor burden revealed that PB strongly promoted the outgrowth of hepatocellular adenoma driven by activated β-catenin in WT mice, whereas the tumor-promoting effect of PB was much less pronounced in the humanized group. In conclusion, the present findings demonstrate that human CAR and PXR support tumor promotion by PB in mouse liver, but to a significantly lesser extent than the WT murine receptors.
authors.affiliation: University of Tuebingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstr. 56, 72074 Tuebingen, Germany albert.braeuning@uni-tuebingen.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.affiliation: University of Tuebingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstr. 56, 72074 Tuebingen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Gavrilov
authors.affiliation: CXR Biosciences, 2 James Lyndsay Place, Dundee Technopole, Dundee DD1 5JJ, Scotland, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Brown
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, University of Dundee, James Arrott Drive, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK.
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, University of Dundee, James Arrott Drive, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.affiliation: University of Tuebingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstr. 56, 72074 Tuebingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D000090702:Constitutive Androstane Receptor; D018736:DNA Adducts; D017931:DNA Primers; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000378:metabolism / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics*
chemical_list: D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D018736:DNA Adducts; D017931:DNA Primers; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D010634:Phenobarbital
keywords: HCC; constitutive androstane receptor; liver tumor; nongenotoxic carcinogen; pregnane X receptor