TY  - JOUR
A1  - Luisier, Raphaëlle
A1  - Lempiäinen, Harri
A1  - Scherbichler, Nina
A1  - Braeuning, Albert
A1  - Geissler, Miriam
A1  - Dubost, Valerie
A1  - Müller, Arne
A1  - Scheer, Nico
A1  - Chibout, Salah-Dine
A1  - Hara, Hisanori
A1  - Picard, Frank
A1  - Theil, Diethilde
A1  - Couttet, Philippe
A1  - Vitobello, Antonio
A1  - Grenet, Olivier
A1  - Grasl-Kraupp, Bettina
A1  - Ellinger-Ziegelbauer, Heidrung
A1  - Thomson, John P.
A1  - Meehan, Richard R.
A1  - Elcombe, Clifford R.
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
A1  - Schwarz, Michael
A1  - Moulin, Pierre
A1  - Terranova, Remi
A1  - Moggs, Jonathan G.
T1  - Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors
T2  - Toxicological Sciences
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 (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.
Y1  - 2014
UR  - https://opus.bibliothek.fh-aachen.de/opus4/frontdoor/index/index/docId/8846
SN  - 1094-2025
VL  - 139
IS  - 2
SP  - 501
EP  - 511
PB  - Oxford University Press
CY  - Oxford
ER  -