Phenobarbital and TCPOBOP effects on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Peter Juvan
PROVIDER: E-GEOD-12529 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Transcriptional activation of PPARalpha by phenobarbital in the absence of CAR and PXR.
Tamasi Viola V Juvan Peter P Beer Markus M Rozman Damjana D Meyer Urs A UA
Molecular pharmaceutics 20090901 5
The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital on gene transcription. To investigate the relative contribution of these nuclear receptors to the expression of specific genes we studied the effect of phenobarbital in livers of wild type, CAR(-/-), PXR(-/-) and CAR/PXR(-/-) knockout mice. Spotted Steroltalk v1 cDNA arrays were applied containing probes for genes involved in drug metabolism, sterol biosynthesis, steroi ...[more]
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Project description:The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital (PB) on gene transcription. To investigate the relative role of CAR and PXR in the induction response, cDNA arrays were generated containing 120 genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PB for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments unexpectedly revealed that if CAR and PXR are deleted, PB increases the expression of several other nuclear receptors and genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 100mg/kg phenobarbital or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the phenobarbital treated ones and hybridized to Sterolgene V1 arrays.
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2008-08-23 | E-GEOD-12509 | biostudies-arrayexpress
Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program âSteroltalkâ (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 40mg/kg PCN or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the PCN treated ones and hybridized to Steroltalk V2 arrays.
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2010-10-08 | E-GEOD-13688 | biostudies-arrayexpress
Project description: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 hepatocarcino- genesis. 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 tran- scriptional 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 ob- served with peak expression occurring between 1 and 7 days PB ex- posure. 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 subse- quent 4-week recovery period. Furthermore, PB-mediated upregu- lation of the noncoding RNA Meg3, which has recently been associ- ated 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. 13-week oral (drinking water) investigative phenobarbital study in male C57BL/6 wild type, CAR/PXR knockout and humanized CAR/PXR mice with a 4 week recovery period
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