title: The glycogen synthase kinase inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) is a partial agonist of the aryl hydrocarbon receptor.
abstract: Kinase inhibitors are frequently used tools in signal transduction research. 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a potent inhibitor of glycogen synthase kinase 3beta (GSK3beta), is frequently used to activate beta-catenin signaling by mimicking the action of Wnt molecules. beta-Catenin is a crucial player in the regulation of hepatic drug metabolism. Thus, it is of particular importance to know whether the tools used to study the effects of beta-catenin signaling may affect the respective drug-metabolizing target enzymes in an unwanted manner. In this study, we show that SB216763 is able to induce cytochrome P450 1a1 (Cyp1a1) expression in a dose-dependent manner in mouse hepatoma cells. Moreover, SB216763 is able to inhibit Cyp1a1 induction by the prototype aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachloro-p-dibenzodioxin. Cyp1a1 induction by SB216763 is independent of GSK3beta and the beta-catenin pathway. Instead, SB216763 induces Cyp1a1 by activation of AhR-mediated transcription. The present results suggest that SB216763 acts as a partial agonist of the AhR.
authors.affiliation: University of Tübingen, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Wilhelmstrasse 56, 72074 Tübingen, Germany. albert.braeuning@uni-tuebingen.de
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Albrecht
authors.initials: A
authors.lastname: Buchmann
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D004790:Enzyme Induction; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles; D008301:Maleimides; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; C484722:Ahr protein, mouse; C497397:Arnt protein, mouse; C495267:CTNNB1 protein, mouse; C417521:SB 216763; C000605507:Gsk3b protein, mouse