Inducibility of Drug-Metabolizing Enzymes by Xenobiotics in Mice with Liver-Specific Knockout ofCtnnb1

Abstract

ABSTRACT: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/␤-catenin pathway in the maintenance of the perivenous hepatocyte gene expression profile including the main hepatic detoxification enzymes, and ␤-catenin signaling was recently implicated in the expression of several cytochrome P450 isoenzymes. To analyze, whether the ␤-catenin pathway would also affect inducible expression of drug-metabolizing enzymes, mice with liverspecific knockout of the Ctnnb1 gene (encoding ␤-catenin) were treated with different model inducers of xenobiotic metabolism. Knockout of ␤-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 ␤-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.

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…Expectedly, expression of UGT1A6a and 1a6b were found to be decreased in these animals. The finding that AhR is a target of ß-catenin signaling has also been reported by others ( [27] for references).…”

The connection of β-catenin and phenobarbital in murine hepatocarcinogenesis: a critical discussion of Awuah et al., PLoS ONE 7(6):e39771, 2012

“…Similar observations were made with the PB-like tumor promoter PCB153 (Strathmann et al 2006). Furthermore, CAR and b-catenin interact in the regulation of enzyme induction and hepatocyte proliferation triggered by PB (Braeuning et al 2009;Braeuning et al 2011).…”

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

“…Primary hepatocytes from adult male C3H/He wild-type mice and from mice with a hepatocyte-specific knockout of the Ctnnb1 gene (referred to as "Ctnnb1 knockout mice" in Braeuning et al, 2009) were isolated by standard collagenase perfusion and maintained as recently described (Hailfinger et al, 2006). Mouse hepatoma cell lines Hepa1c1c7, Hepa4, Hepa12, and PW53I were grown in Dulbecco's modified Eagle's medium/F12 medium and analyzed for Ctnnb1 mutations as recently described (Aydinlik et al, 2001).…”

“…In addition, hepatic expression of several P450s and other enzymes linked to xenobiotic metabolism is altered in mice with liver-specific knockout of ␤-catenin (Sekine et al, 2006;Tan et al, 2006;Braeuning et al, 2009). For a recent review of ␤-catenin signaling and P450 expression, see Braeuning (2009).…”