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

Albert Braeuning (Lead / Corresponding author), Alina Gavrilov, Susan Brown, C Roland Wolf, Colin J Henderson, Michael Schwarz

    Research output: Contribution to journalArticle

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    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 ß-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.
    Original languageEnglish
    Pages (from-to)259-70
    Number of pages12
    JournalToxicological Sciences
    Volume140
    Issue number2
    Early online date25 May 2014
    DOIs
    Publication statusPublished - 1 Aug 2014

    Fingerprint

    Phenobarbital
    Transgenic Mice
    Tumors
    Liver
    Neoplasms
    Carcinogens
    Liver Cell Adenoma
    constitutive androstane receptor
    pregnane X receptor
    Diethylnitrosamine
    Catenins
    Liver Neoplasms
    Cytoplasmic and Nuclear Receptors
    Tumor Burden
    Rodentia
    Epilepsy
    Chemical activation
    Injections

    Keywords

    • live tumor
    • nongenotoxic carcinogen
    • HCC
    • constitutive androstane receptor
    • pregnane X receptor

    Cite this

    Braeuning, Albert ; Gavrilov, Alina ; Brown, Susan ; Wolf, C Roland ; Henderson, Colin J ; Schwarz, Michael. / Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR. In: Toxicological Sciences. 2014 ; Vol. 140, No. 2. pp. 259-70.
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    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 {\ss}-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.",
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    author = "Albert Braeuning and Alina Gavrilov and Susan Brown and Wolf, {C Roland} and Henderson, {Colin J} and Michael Schwarz",
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    Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR. / Braeuning, Albert (Lead / Corresponding author); Gavrilov, Alina; Brown, Susan; Wolf, C Roland; Henderson, Colin J; Schwarz, Michael.

    In: Toxicological Sciences, Vol. 140, No. 2, 01.08.2014, p. 259-70.

    Research output: Contribution to journalArticle

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    T1 - Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR

    AU - Braeuning, Albert

    AU - Gavrilov, Alina

    AU - Brown, Susan

    AU - Wolf, C Roland

    AU - Henderson, Colin J

    AU - Schwarz, Michael

    N1 - This work was supported by the Innovative Medicine Initiative Joint Undertaking (IMI JU) [grant agreement number 115001 (MARCAR project)]. CRW gratefully acknowledges Programme Grant support from Cancer Research UK, C4639/A10822.

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    N2 - 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 ß-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.

    AB - 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 ß-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.

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