title: Cooperation of structurally different aryl hydrocarbon receptor agonists and β-catenin in the regulation of CYP1A expression.
abstract: The ligand-activated nuclear receptor AhR (aryl hydrocarbon receptor) mediates the response of hepatocytes to various exogenous compounds. AhR is classically activated by planar, aromatic hydrocarbons, but also by other, structurally rather unrelated compounds. Recent data show that the canonical Wnt/β-catenin signaling pathway is also involved in the regulation of hepatic zonal gene expression and drug metabolism in mammalian liver. Previous studies indicate that the loss of β-catenin in hepatocytes diminishes the response to the AhR agonists 3-methylcholanthrene (3MC) in vivo and to 2,3,7,8-tetrachlorodibenzo-[p]-dioxin in vitro. The knockout of β-catenin also impairs the zonal pattern of AhR target gene induction by 3MC. However, it is presently unknown whether the chemical nature of the AhR agonist influences the AhR/β-catenin interaction. Moreover, no information is available about the dose-response curves of AhR activation in the absence or presence of Wnt/β-catenin signaling. In the present study, we have analyzed AhR-dependent responses to different concentrations of structurally unrelated AhR agonists in vivo and in vitro. The results demonstrate that β-catenin is essential to obtain the maximum AhR response. Moreover, using transgenic mouse models which allow for the ablation of β-catenin at different age of mice, we demonstrate that the presence of β-catenin, not postnatal developmental effects in β-catenin-deficient livers, is responsible for the observed interplay of β-catenin and the AhR.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Dept. of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vaas
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Dept. of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Kreft
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Dept. of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Dept. of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany. Electronic address: albert.braeuning@uni-tuebingen.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D065694:Cytochrome P-450 CYP1A2 Inducers / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D018345:Mice, Knockout; D015394:Molecular Structure; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065694:Cytochrome P-450 CYP1A2 Inducers; D008024:Ligands; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051176:beta Catenin; C484722:Ahr protein, mouse; C495267:CTNNB1 protein, mouse
keywords: Cytochrome P450; Dioxin receptor; Liver zonation; Perivenous hepatocyte; TCDD; Wnt signaling