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(KO)-PXR(KO)), double humanized CAR and PXR (CAR(h)-PXR(h)), and wild-type C57BL/6 mice. Wild-type and CAR(h)-PXR(h) 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 CAR(KO)-PXR(KO) mouse livers and largely reversible in wild-type and CAR(h)-PXR(h) 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(h)-PXR(h) mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
authors.affiliation: Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Luisier
authors.forename: Harri
authors.initials: H
authors.lastname: Lempiäinen
authors.forename: Nina
authors.initials: N
authors.lastname: Scherbichler
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Miriam
authors.initials: M
authors.lastname: Geissler
authors.forename: Valerie
authors.initials: V
authors.lastname: Dubost
authors.forename: Arne
authors.initials: A
authors.lastname: Müller
authors.forename: Nico
authors.initials: N
authors.lastname: Scheer
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.forename: Hisanori
authors.initials: H
authors.lastname: Hara
authors.forename: Frank
authors.initials: F
authors.lastname: Picard
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.forename: Philippe
authors.initials: P
authors.lastname: Couttet
authors.forename: Antonio
authors.initials: A
authors.lastname: Vitobello
authors.forename: Olivier
authors.initials: O
authors.lastname: Grenet
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Elcombe
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.forename: Rémi
authors.initials: R
authors.lastname: Terranova
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010634:Phenobarbital / Q000493:pharmacokinetics / Q000633:toxicity*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D059467:Transcriptome / Q000187:drug effects*; D015262:Xenobiotics / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D010634:Phenobarbital
keywords: CAR; PXR; cancer risk assessment; humanized mice; liver; nongenotoxic carcinogenesis; phenobarbital; proliferation; transcription