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Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors

  • 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 (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), 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 absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ 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 CARʰ-PXRʰ 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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Metadaten
Author:Raphaëlle Luisier, Harri Lempiäinen, Nina Scherbichler, Albert Braeuning, Miriam Geissler, Valerie Dubost, Arne Müller, Nico ScheerORCiD, Salah-Dine Chibout, Hisanori Hara, Frank Picard, Diethilde Theil, Philippe Couttet, Antonio Vitobello, Olivier Grenet, Bettina Grasl-Kraupp, Heidrung Ellinger-Ziegelbauer, John P. Thomson, Richard R. Meehan, Clifford R. Elcombe, Colin J. Henderson, C. Roland Wolf, Michael Schwarz, Pierre Moulin, Remi Terranova, Jonathan G. Moggs
DOI:https://doi.org/https://doi.org/10.1093/toxsci/kfu038
ISSN:1094-2025
Parent Title (English):Toxicological Sciences
Publisher:Oxford University Press
Place of publication:Oxford
Document Type:Article
Language:English
Year of Completion:2014
Date of the Publication (Server):2019/03/12
Volume:139
Issue:2
First Page:501
Last Page:511
Link:https://doi.org/10.1093/toxsci/kfu038
Zugriffsart:weltweit
Institutes:FH Aachen / Fachbereich Chemie und Biotechnologie
collections:Verlag / Oxford University Press
Open Access / Hybrid