beta-Catenin as a multilayer modulator of zonal cytochrome P450 expression in mouse liver.
The liver is the major organ for metabolism of drugs and other xenobiotics. Expression of many drug-metabolizing enzymes is not equally distributed throughout the liver: under normal conditions, many of them, including the most relevant members of the cytochrome P450 superfamily, are exclusively expressed in a hepatocyte subpopulation located near branches of the efferent central vein. Activation of different ligand-dependent transcription factors by exogenous compounds stimulates high expression of certain cytochrome P450 isoforms. This process also occurs preferentially in perivenous hepatocytes. The mechanisms, however, which determine the zone-specificity of basal and xenobiotic-induced expression of cytochrome P450 enzymes, have remained largely unknown for decades. Very recently, signaling through the Wnt/beta-catenin pathway has been implicated in the regulation of zonal gene expression in mouse liver. In this review, current knowledge of cytochrome P450 regulation by beta-catenin-dependent transcription is summarized and underlying molecular mechanisms are discussed.
Braeuning
Albert
A
Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany.
Schwarz
Michael
M
Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D003577:Cytochrome P-450 Enzyme System