Search results for "CONSTITUTIVE ANDROSTANE RECEPTOR"
showing 10 items of 14 documents
The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and co…
2004
Induction of cytochrome P450 3A (CYP3A) by xenobiotics may lead to clinically relevant drug interactions. In contrast with other CYP3A family members, studies on the inducibility of CYP3A5 indicate conflicting results. We report the induction of CYP3A5 mRNA in 13 of 16 hepatocyte preparations exposed to rifampin. Furthermore, induction of CYP3A5 mRNA was observed in intestinal biopsies in three of eight probands following exposure to the antibiotic. The highest absolute levels of CYP3A5 transcripts were found following rifampin treatment in hepatocytes and intestines from carriers of CYP3A5*1 alleles. Elucidation of the mechanism involved in CYP3A5 induction revealed that constitutively act…
Effects of typical inducers on olfactory xenobiotic-metabolizing enzyme, transporter, and transcription factor expression in rats.
2010
International audience; Several xenobiotic-metabolizing enzymes (XMEs) have been identified in the olfactory mucosa (OM) of mammals. However, the molecular mechanisms underlying the regulation of these enzymes have been little explored. In particular, information on the expression of the transcriptional factors in this tissue is quite limited. The aim of the present study was to examine the impact of five typical inducers, Aroclor 1254, 3-methylcholanthrene, dexamethasone, phenobarbital, and ethoxyquin, on the activities and mRNA expression of several XMEs in the OM and in the liver of rats. We also evaluated the effects of these treatments on the mRNA expression of transcription factors an…
Coordinated induction of drug transporters and phase I and II metabolism in human liver slices
2008
Although regulation of phase I drug metabolism in human liver is relatively well studied, the regulation of phase II enzymes and of drug transporters is incompletely characterized. Therefore, we used human liver slices to investigate the PXR, CAR and AhR-mediated induction of drug transporters and phase I and II metabolic enzymes. Precision-cut human liver slices were incubated for 5 or 24 h with prototypical inducers: phenobarbital (PB) (50 mu M) for CAR, beta-naphthoflavone (BNF) (25 mu M) for AhR, and rifampicin (RIF) (10 mu M) for PXR, and gene expression of the phase I enzymes CYP1A1, 1A2, 3A4, 3A5, 2136, 2A6, the phase II enzymes UGT1A1 and 1A6, and the transporters MRP2, MDR1, BSEP, …
CCAAT/Enhancer-binding Protein α (C/EBPα) and Hepatocyte Nuclear Factor 4α (HNF4α) Synergistically Cooperate with Constitutive Androstane Receptor to…
2010
The transcription of tissue-specific and inducible genes is usually subject to the dynamic control of multiple activators. Dedifferentiated hepatic cell lines lose the expression of tissue-specific activators and many characteristic hepatic genes, such as drug-metabolizing cytochrome P450. Here we demonstrate that by combining adenoviral vectors for CCAAT/enhancer-binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), and constitutive androstane receptor, the CYP2B6 expression and inducibility by CITCO are restored in human hepatoma HepG2 cells at levels similar to those in cultured human hepatocytes. Moreover, several other phase I and II genes are simultaneously activated, whic…
Evolutionary History and Functional Characterization of the Amphibian Xenosensor CAR
2011
AbstractThe xenosensing constitutive androstane receptor (CAR) is widely considered to have arisen in early mammals via duplication of the pregnane X receptor (PXR). We report that CAR emerged together with PXR and the vitamin D receptor from an ancestral NR1I gene already in early vertebrates, as a result of whole-genome duplications. CAR genes were subsequently lost from the fish lineage, but they are conserved in all taxa of land vertebrates. This contrasts with PXR, which is found in most fish species, whereas it is lost from Sauropsida (reptiles and birds) and plays a role unrelated to xenosensing in Xenopus. This role is fulfilled in Xenopus by CAR, which exhibits low basal activity a…
Structural and Functional Similarity of Amphibian Constitutive Androstane Receptor with Mammalian Pregnane X Receptor
2016
The nuclear receptors and xenosensors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) induce the expression of xenobiotic metabolizing enzymes and transporters, which also affects various endobiotics. While human and mouse CAR feature a high basal activity and low induction upon ligand exposure, we recently identified two constitutive androstane receptors in Xenopus laevis (xlCARá and â) that possess PXR-like characteristics such as low basal activity and activation in response to structurally diverse compounds. Using a set of complementary computational and biochemical approaches we provide evidence for xlCARá being the structural and functional counterpa…
Orphan nuclear receptor binding site in the human inducible nitric oxide synthase promoter mediates responsiveness to steroid and xenobiotic ligands
2002
Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are members of the nuclear receptor superfamily that regulate target gene transcription in a ligand-dependent manner. CAR and PXR have a rather broad, overlapping set of ligands that range from natural steroids to xenobiotics and also recognize similar DNA binding sites, referred to as response elements (REs), primarily in promoter regions of cytochrome P450 (CYP) genes. In this study, a CAR and PXR RE, composed of a direct repeat of two GGTTCA motifs in a distance of 4 nucleotides (DR4), was identified in the promoter of the human inducible nitric oxide (NO) synthase (iNOS) gene, which is the first nuclear receptor bindin…
Etude du rôle du récepteur nucléaire CAR, Constitutive Androstane Receptor, dans le métabolisme des lipides et la susceptibilité à l'athérosclérose
2011
The Constitutive Androstane Receptor (CAR) belongs to the subfamily of nuclear receptors NR1. Initially described as an orphan receptor, CAR is activated by a large number of exogenous molecules and acts as a xenosensor. The activation of CAR by these ligands stimulates transcription of phase I, II and III enzymes required for the detoxification and elimination of xenobiotics. Furthermore CAR is also involved in the metabolism of endogenous molecules such as bile acids, bilirubin or thyroid hormones. CAR has recently been the subject of numerous independent studies that have highlighted his involvement in major metabolic pathways including gluconeogenesis, lipogenesis and lipoprotein metabo…
Xanthohumol ameliorates Diet-Induced Liver Dysfunction via Farnesoid X Receptor-Dependent and Independent Signaling
2020
The farnesoid X receptor (FXR) plays a critical role in the regulation of lipid and bile acid (BA) homeostasis. Hepatic FXR loss results in lipid and BA accumulation, and progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH). This study aimed to evaluate the effects of xanthohumol (XN), a hop-derived compound mitigating metabolic syndrome, on liver damage induced by diet and FXR deficiency in mice. Wild-type (WT) and liver-specific FXR-null mice (FXRLiver−/−) were fed a high-fat diet (HFD) containing XN or the vehicle formation followed by histological characterization, lipid, BA and gene profiling. HFD supplemented with XN resulted in amelioration of hepatic steatosis a…
Constitutive androstane receptor activation stimulates faecal bile acid excretion and reverse cholesterol transport in mice.
2010
The constitutive androstane receptor (CAR) is a nuclear receptor expressed in the liver and involved in xenobiotic metabolism. The aim of this study was to assess whether pharmacological CAR activation could affect neutral sterol and bile acid elimination under conditions of cholesterol overload.Wild type, Car-/-, ApoE-/-, and low-density lipoprotein receptor (Ldlr)-/- mice fed a western-type diet were treated with the CAR agonist TCPOBOP.CAR activation was associated with a decrease in faecal cholesterol output related to the repression of the Abcg5/g8 cholesterol transporters. In contrast, TCPOBOP treatment induced a marked increase (up to three fold, p0.01) in the elimination of faecal b…