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

Raphaelle Luisier, Harri Lempiäinen, Nina Scherbichler, Albert Braeuning, Miriam Geissler, Valerie Dubost, Arne Müller, Nico Scheer, Salah-Dine Chibout, Hisanori Hara, Frank Picard, Diethilde Theil, Philippe Couttet, Antonio Vitobello, Oliver Grenet, Bettina Grasl-Kraupp, Heidrun Ellinger-Ziegelbauer, John P. Thomson, Richard R. Meehan, Clifford R. ElcombeColin J. Henderson, C. Roland Wolf, Michael Schwarz, Pierre Moulin, Remi Terranova, Jonathan G. Moggs

    Research output: Contribution to journalArticle

    37 Citations (Scopus)

    Abstract

    The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR-PXR), double humanized CAR and PXR (CAR-PXR), and wild-type C57BL/6 mice.Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1)and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absentin CAR-PXR mouse livers and largely reversible in wild-type and CAR-PXR mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR-PXR mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
    Original languageEnglish
    Pages (from-to)501-511
    Number of pages11
    JournalToxicological Sciences
    Volume139
    Issue number2
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    Phenobarbital
    Liver
    Cell Cycle
    Cells
    Untranslated RNA
    Xenobiotics
    Genes
    Tissue
    constitutive androstane receptor
    pregnane X receptor
    androstane
    Nuclear Antigens
    Biomarkers
    Cytoplasmic and Nuclear Receptors
    DNA Replication
    Inbred C57BL Mouse
    Metabolism
    Hepatocytes
    Rodentia
    Up-Regulation

    Cite this

    Luisier, R., Lempiäinen, H., Scherbichler, N., Braeuning, A., Geissler, M., Dubost, V., ... Moggs, J. G. (2014). Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors. Toxicological Sciences, 139(2), 501-511. https://doi.org/10.1093/toxsci/kfu038
    Luisier, Raphaelle ; Lempiäinen, Harri ; Scherbichler, Nina ; Braeuning, Albert ; Geissler, Miriam ; Dubost, Valerie ; Müller, Arne ; Scheer, Nico ; Chibout, Salah-Dine ; Hara, Hisanori ; Picard, Frank ; Theil, Diethilde ; Couttet, Philippe ; Vitobello, Antonio ; Grenet, Oliver ; Grasl-Kraupp, Bettina ; Ellinger-Ziegelbauer, Heidrun ; Thomson, John P. ; Meehan, Richard R. ; Elcombe, Clifford R. ; Henderson, Colin J. ; Wolf, C. Roland ; Schwarz, Michael ; Moulin, Pierre ; Terranova, Remi ; Moggs, Jonathan G. / Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors. In: Toxicological Sciences. 2014 ; Vol. 139, No. 2. pp. 501-511.
    @article{be46ff87cac64495b79c3910e5dea6af,
    title = "Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors",
    abstract = "The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR-PXR), double humanized CAR and PXR (CAR-PXR), and wild-type C57BL/6 mice.Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1)and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absentin CAR-PXR mouse livers and largely reversible in wild-type and CAR-PXR mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR-PXR mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.",
    author = "Raphaelle Luisier and Harri Lempi{\"a}inen and Nina Scherbichler and Albert Braeuning and Miriam Geissler and Valerie Dubost and Arne M{\"u}ller and Nico Scheer and Salah-Dine Chibout and Hisanori Hara and Frank Picard and Diethilde Theil and Philippe Couttet and Antonio Vitobello and Oliver Grenet and Bettina Grasl-Kraupp and Heidrun Ellinger-Ziegelbauer and Thomson, {John P.} and Meehan, {Richard R.} and Elcombe, {Clifford R.} and Henderson, {Colin J.} and Wolf, {C. Roland} and Michael Schwarz and Pierre Moulin and Remi Terranova and Moggs, {Jonathan G.}",
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    doi = "10.1093/toxsci/kfu038",
    language = "English",
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    Luisier, R, Lempiäinen, H, Scherbichler, N, Braeuning, A, Geissler, M, Dubost, V, Müller, A, Scheer, N, Chibout, S-D, 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 2014, 'Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors', Toxicological Sciences, vol. 139, no. 2, pp. 501-511. https://doi.org/10.1093/toxsci/kfu038

    Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors. / Luisier, Raphaelle; Lempiäinen, Harri; Scherbichler, Nina; Braeuning, Albert; Geissler, Miriam; Dubost, Valerie; Müller, Arne; Scheer, Nico; Chibout, Salah-Dine; Hara, Hisanori; Picard, Frank; Theil, Diethilde; Couttet, Philippe; Vitobello, Antonio; Grenet, Oliver; Grasl-Kraupp, Bettina; Ellinger-Ziegelbauer, Heidrun; Thomson, John P.; Meehan, Richard R.; Elcombe, Clifford R.; Henderson, Colin J.; Wolf, C. Roland; Schwarz, Michael; Moulin, Pierre; Terranova, Remi (Lead / Corresponding author); Moggs, Jonathan G. (Lead / Corresponding author).

    In: Toxicological Sciences, Vol. 139, No. 2, 2014, p. 501-511.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors

    AU - Luisier, Raphaelle

    AU - Lempiäinen, Harri

    AU - Scherbichler, Nina

    AU - Braeuning, Albert

    AU - Geissler, Miriam

    AU - Dubost, Valerie

    AU - Müller, Arne

    AU - Scheer, Nico

    AU - Chibout, Salah-Dine

    AU - Hara, Hisanori

    AU - Picard, Frank

    AU - Theil, Diethilde

    AU - Couttet, Philippe

    AU - Vitobello, Antonio

    AU - Grenet, Oliver

    AU - Grasl-Kraupp, Bettina

    AU - Ellinger-Ziegelbauer, Heidrun

    AU - Thomson, John P.

    AU - Meehan, Richard R.

    AU - Elcombe, Clifford R.

    AU - Henderson, Colin J.

    AU - Wolf, C. Roland

    AU - Schwarz, Michael

    AU - Moulin, Pierre

    AU - Terranova, Remi

    AU - Moggs, Jonathan G.

    PY - 2014

    Y1 - 2014

    N2 - The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR-PXR), double humanized CAR and PXR (CAR-PXR), and wild-type C57BL/6 mice.Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1)and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absentin CAR-PXR mouse livers and largely reversible in wild-type and CAR-PXR mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR-PXR mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.

    AB - The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CAR-PXR), double humanized CAR and PXR (CAR-PXR), and wild-type C57BL/6 mice.Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1)and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absentin CAR-PXR mouse livers and largely reversible in wild-type and CAR-PXR mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CAR-PXR mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.

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