The nuclear constitutive androstane receptor (CAR, NR1I3) plays significant roles in many hepatic functions, such as fatty acid oxidation, biotransformation, liver regeneration, as well as clearance of steroid hormones, cholesterol, and bilirubin. CAR has been proposed as a hypothetical target receptor for metabolic or liver disease therapy. Currently known prototype high-affinity human CAR agonists such as CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) have limited selectivity, activating the pregnane X receptor (PXR) receptor, a related receptor of the NR1I subfamily. We have discovered several derivatives of 3-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine that directly activate human CAR in nanomolar concentrations. While compound 39 regulates CAR target genes in humanized CAR mice as well as human hepatocytes, it does not activate other nuclear receptors and is nontoxic in cellular and genotoxic assays as well as in rodent toxicity studies. Our findings concerning potent human CAR agonists with in vivo activity reinforce the role of CAR as a possible therapeutic target.

• MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• konstitutivní androstanový receptor * agonisté   chemie   MeSH
• lidé MeSH
• myši MeSH
• pyridiny farmakologie   MeSH
• receptory cytoplazmatické a nukleární metabolismus   MeSH
• steroidní receptory * agonisté   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• konstitutivní androstanový receptor * MeSH
• pyridiny MeSH
• receptory cytoplazmatické a nukleární MeSH
• steroidní receptory * MeSH

Aberrant signaling through β-catenin is an important determinant of tumorigenesis in rodents as well as in humans. In mice, xenobiotic activators of the constitutive androstane receptor (CAR), a chemo-sensing nuclear receptor, promote liver tumor growth by means of a non-genotoxic mechanism and, under certain conditions, select for hepatocellular tumors which contain activated β-catenin. In normal hepatocytes, interactions of β-catenin and CAR have been demonstrated with respect to the induction of proliferation and drug metabolism-related gene expression. The molecular details of these interactions are still not well understood. Recently it has been hypothesized that CAR might activate β-catenin signaling, thus providing a possible explanation for some of the observed phenomena. Nonetheless, many aspects of the molecular interplay of the two regulators have still not been elucidated. This review briefly summarizes our current knowledge about the interplay of CAR and β-catenin. By taking into account data and observations obtained with different mouse models and employing different experimental approaches, it is shown that published data also contain substantial evidence that xenobiotic activators of CAR do not activate, or do even inhibit signaling through the β-catenin pathway. The review highlights new aspects of possible ways of interaction between the two signaling cascades and will help to stimulate scientific discussion about the crosstalk of β-catenin signaling and the nuclear receptor CAR.

• Klíčová slova
• Drug metabolism, Hepatocyte, Liver tumor promotion, Nuclear receptor, Wnt signaling,
• MeSH
• beta-katenin metabolismus   MeSH
• hodnocení rizik MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• konstitutivní androstanový receptor MeSH
• lidé MeSH
• nádorová transformace buněk chemicky indukované   metabolismus   patologie   MeSH
• nádory jater chemicky indukované   metabolismus   patologie   MeSH
• receptory cytoplazmatické a nukleární agonisté   metabolismus   MeSH
• rizikové faktory MeSH
• signální dráha Wnt * MeSH
• xenobiotika toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• beta-katenin MeSH
• konstitutivní androstanový receptor MeSH
• receptory cytoplazmatické a nukleární MeSH
• xenobiotika MeSH

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes.

• Klíčová slova
• CAR, cytochrome P450, gene regulation, metabolism, nuclear receptor,
• Publikační typ
• časopisecké články MeSH