Coordinate Regulation of Cytochrome P450 1A1 Expression in Mouse Liver by the Aryl Hydrocarbon Receptor and the β-Catenin Pathway

• Published in: Toxicological sciences 2011-07, Vol.122 (1), p.16-25
• Main Authors: Braeuning, Albert, Köhle, Christoph, Buchmann, Albrecht, Schwarz, Michael
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Blotting, Western; Cells, Cultured; Chromatin Immunoprecipitation; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Gene Expression Regulation; Hepatocytes - enzymology; Isoenzymes - genetics; Isoenzymes - metabolism; Liver - cytology; Liver - metabolism; Male; Mice; Mice, Inbred C3H; Mice, Knockout; Mice, Transgenic; Plasmids; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction; TCF Transcription Factors - genetics; TCF Transcription Factors - metabolism; Transcriptional Activation; Wnt Signaling Pathway
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfr080

The expression of cytochrome P450 (CYP) 1a1 and other drug-metabolizing enzymes is controlled by the aryl hydrocarbon receptor (AhR), which is activated by dioxin-type inducers leading to transcriptional induction of target genes. Here, we show that a second level of transcriptional control exists in hepatocytes, which is tightly linked to the Wnt/β-catenin/T-cell factor (TCF) signaling pathway. In transgenic mice, hepatic expression of CYP1A (and other CYP isoforms) is stimulated by the expression of mutationally activated β-cateninS33Y in the absence of AhR-activating compounds but repressed after knockout of β-catenin. These effects were further analyzed in vitro, and the stimulatory role of β-catenin was ascribed to a TCF-binding site within the CYP1A1 promoter. Moreover, β-catenin signaling acted cooperatively with AhR agonists via AhR-binding sites on the DNA during the induction of Cyp1a1 in vivo and in vitro. Activation of β-catenin enhanced the transactivation potential of ligand-activated AhR at its DNA-binding sites without altering the total amount of DNA-bound AhR. Coimmunoprecipitation demonstrated a physical interaction between AhR and β-catenin. Furthermore, the present results suggest that transcriptional induction of the AhR by β-catenin does not play a major role in β-catenin-dependent regulation of Cyp1a1 expression and that inhibition of β-catenin signaling by ligand-activated AhR, as recently observed in the intestine does not occur in mouse liver. In conclusion, signaling through β-catenin activates basal CYP1A1 expression and augments CYP1A1 induction by AhR ligands through enhancement of the transactivation potential of the AhR.