Interplay of β-Catenin with Xenobiotic-Sensing Receptors and its Role in Glutathione S-Transferase Expression

Albert      Braeuning

Abstract

The Wnt/β-catenin pathway plays an important role in liver homeostasis, as well as during prenatal liver development, liver regeneration, and hepatocarcinogenesis. The connection of hepatic β-catenin activation and expression of drug-metabolizing enzymes has been established in the past few years: on the whole, a generally positive-regulatory effect of β-catenin on the expression and inducibility of many enzymes involved in phase I and phase II of drug metabolism has been described by different groups. The mechanisms underlying these processes are still not fully understood. However, there is accumulating evidence for a complex interaction of β-catenin with different xenobiotic-sensing receptors, which act as transcription factors after ligand activation, for example the aryl hydrocarbon receptor or the constitutive androstane receptor. Among others, these crosstalk mechanisms might explain the manifold effects of β-catenin on hepatic drug metabolism. In this review, the current knowledge regarding the role of Wnt/β-catenin signaling in the regulation of hepatic expression of glutathione S-transferases is presented. In addition, the crosstalk of β-catenin signaling with nuclear receptors involved in the regulation of glutathione S-transferases will be discussed.

Keywords: Aryl hydrocarbon receptor, beta-catenin, constitutive androstane receptor, liver tumor, metabolic zonation, phase II, Wnt signaling, liver regeneration, carcinogenesis, β-catenin, drug metabolism