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Toxicol Sci. 2014 Aug 1;140(2):259-70. doi: 10.1093/toxsci/kfu099. Epub 2014 May 25.

Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR.

Author information

1
University of Tuebingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstr. 56, 72074 Tuebingen, Germany albert.braeuning@uni-tuebingen.de.
2
University of Tuebingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstr. 56, 72074 Tuebingen, Germany.
3
CXR Biosciences, 2 James Lyndsay Place, Dundee Technopole, Dundee DD1 5JJ, Scotland, UK.
4
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.

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.

KEYWORDS:

HCC; constitutive androstane receptor; liver tumor; nongenotoxic carcinogen; pregnane X receptor

PMID:
24863967
DOI:
10.1093/toxsci/kfu099
[Indexed for MEDLINE]

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