QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: dmd.108.026179v1 37/5/1138    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Braeuning, A. Articles by Schwarz, M. Search for Related Content PubMed PubMed Citation Articles by Braeuning, A. Articles by Schwarz, M.

Inducibility of Drug-Metabolizing Enzymes by Xenobiotics in Mice with Liver-Specific Knockout of Ctnnb1

Institute of Pharmacology und Toxicology, Department of Toxicology, University of Tübingen, Tübingen, Germany (A.B., M.S.); Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Cagliari, Italy (R.S.); and Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland (J.H.)

Basal as well as xenobiotic-induced expression of the main enzymes from phase I and phase II of drug metabolism is confined to the perivenous areas of the mammalian liver lobule. Whereas signal transduction pathways that govern xenobiotic-induced expression of these enzymes via ligand-activated transcription factors such as constitutive androstane receptor (CAR) or the aryl hydrocarbon receptor (AhR) have been intensively studied, the mechanisms regulating zone-specific basal expression of genes related to drug metabolism and preferential response of perivenous hepatocytes to xenobiotic inducers are still largely unknown. Recent publications by our and other groups point to an important role for the Wnt/β-catenin pathway in the maintenance of the perivenous hepatocyte gene expression profile including the main hepatic detoxification enzymes, and β-catenin signaling was recently implicated in the expression of several cytochrome P450 isoenzymes. To analyze, whether the β-catenin pathway would also affect inducible expression of drug-metabolizing enzymes, mice with liver-specific knockout of the Ctnnb1 gene (encoding β-catenin) were treated with different model inducers of xenobiotic metabolism. Knockout of β-catenin led to alterations in basal expression of most drug metabolism-related genes analyzed and resulted in strongly diminished responses to agonists of CAR-, AhR-, and nuclear factor erythroid-related factor 2-dependent transcription. Taken together, the data presented in this study indicate that β-catenin not only regulates basal expression of drug-metabolizing enzymes but also determines the magnitude and hepatic localization of response to xenobiotic inducers in vivo.

This article has been cited by other articles:

				A. Braeuning and A. Buchmann 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 Drug Metab. Dispos., August 1, 2009; 37(8): 1576 - 1580. [Abstract] [Full Text] [PDF]