Regulation of Cytochrome P450 Expression by Ras- and &amp;#946;-Catenin-Dependent Signaling

Braeuning, Albert

doi:10.2174/138920009787522160

Cited by 33 publications

(32 citation statements)

References 123 publications

(294 reference statements)

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“…The red module contains 75 genes and is positively correlated with the expression of 43 P450 genes as well as all P450 activity measures but not CYP2E1, CYP2A6, and CYP2B6. This module is not enriched for any particular functional pathways but notably contains genes involved in WNT/beta-catenin signaling such as TGFB3, SMO, FRAT1, and ACVR1B, as well as genes involved in the regulation of apoptosis including SOD2, IL4R, SKP2, IRS1, BAG3, GPER, and TLR2, confirming the literature observations of P450 regulation by beta-catenin-dependent signaling and the connection between apoptosis and P450s (Schrenk et al 2004;Loeppen et al 2005;Sekine et al 2006;Braeuning 2009). On the other hand, both the pink and the brown modules are negatively correlated with P450 activities and gene expressions, with the former associating with CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4M, and CYP3A4T enzyme activities and gene expression of 42 P450 genes, and the latter with 45 P450 genes and the activity measurements of all P450s except CYP2E1 and CYP2B6.…”

Section: Gene Coexpression Network Analysissupporting

confidence: 80%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

240

226

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Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

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Section: Gene Coexpression Network Analysissupporting

confidence: 80%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

240

226

View full text Add to dashboard Cite

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“…Several other kinase inhibitors also affect the process of AhR activation by direct interaction with the AhR or by more complex indirect mechanisms, as reviewed in Braeuning (2009). Because most of the kinase inhibitors available from commercial suppliers have never been tested for a possible interplay with xenobiotic sensors, one might overlook such nonkinase-related properties and attribute the observed effects to the respective kinase-dependent pathway.…”

mentioning

confidence: 99%

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

Braeuning¹,

Buchmann²

2009

Drug Metab Dispos

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ABSTRACT:Kinase inhibitors are frequently used tools in signal transduction research. 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a potent inhibitor of glycogen synthase kinase 3␤ (GSK3␤), is frequently used to activate ␤-catenin signaling by mimicking the action of Wnt molecules. ␤-Catenin is a crucial player in the regulation of hepatic drug metabolism. Thus, it is of particular importance to know whether the tools used to study the effects of ␤-catenin signaling may affect the respective drugmetabolizing target enzymes in an unwanted manner. In this study, we show that SB216763 is able to induce cytochrome P450 1a1 (Cyp1a1) expression in a dose-dependent manner in mouse hepatoma cells. Moreover, SB216763 is able to inhibit Cyp1a1 induction by the prototype aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachloro-p-dibenzodioxin. Cyp1a1 induction by SB216763 is independent of GSK3␤ and the ␤-catenin pathway. Instead, SB216763 induces Cyp1a1 by activation of AhR-mediated transcription. The present results suggest that SB216763 acts as a partial agonist of the AhR.A variety of cellular signal transduction pathways are regulated by phosphorylation/dephosphorylation events, and a huge number of small molecule kinase inhibitors has been developed allowing for the blockade or activation of distinct signaling cascades. Besides the fact that many kinase inhibitors-often acting in an ATP-competitive manner-do not provide satisfactory specificity toward only one single kinase (Davies et al., 2000;Bain et al., 2007), there are also several reports which demonstrate that some of these molecules can act through additional mechanisms that are different from kinase inhibition. An example of this difference is the interaction with nuclear receptors such as the xenobiotic sensor aryl hydrocarbon receptor (AhR), which is a crucial player in the expression of various drug-metabolizing enzymes. In the absence of a ligand, the AhR is complexed by heat shock proteins in the cytosol. Upon binding of a ligand, mostly a planar hydrophobic molecule, the AhR translocates to the nucleus, releases the chaperones, and dimerizes with the Arnt protein. The AhR/Arnt heterodimer then binds to so-called dioxin response elements (DREs) on the DNA and activates transcription of target genes such as cytochrome P450 1a1 (Cyp1a1). For a recent review on AhR-dependent signal transduction, see Beischlag et al. (2008).The widely used kinase inhibitors U0126, PD98059, and SP600125 are ligands and partial agonists of the AhR (Reiners et al., 1998;Joiakim et al., 2003;Andrieux et al., 2004;Dvorak et al., 2008).Several other kinase inhibitors also affect the process of AhR activation by direct interaction with the AhR or by more complex indirect mechanisms, as reviewed in Braeuning (2009). Because most of the kinase inhibitors available from commercial suppliers have never been tested for a possible interplay with xenobiotic sensors, one might overlook such nonkinase-related properties and attribute the observed eff...

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“…Among them are signaling pathways dependent on NF-κB, MAP kinases, and -catenin (Braeuning, 2009;Murray et al, 2010;Zordoky & El-Kadi, 2009). Glucocorticoid receptor and GATA4, Nrf2 and C/EBP transcription factors also play important role in the transcriptional regulation of cytochromes P450 (Dvorak & Pavek, 2010;Jover et al, 2009;Mwinyi et al, 2010a;Yokota et al, 2011).…”

Section: Regulation Of Cytochrome P450 Gene Expression By Other Signamentioning

confidence: 99%

“…MAPK activators: sorbitol and EGF (Epidermal Growth Factor) inhibit constitutive and induced expression of CYP isoforms, however anisomycin does not cause such an effect or shows a weak stimulation effect (Bachleda et al, 2009). MAP kinases catalyze the phosphorylation of the complexes formed with the participation of transcription factors, including nuclear receptors, cytoplasmic receptors of AhR type and members of the AP-1 family (c-Fos, c-Jun), and because of that, they may affect their ability to transactivate target gens (Braeuning, 2009;Murray et al, 2010). MAPK-dependent pathways are crucial for regulating proliferation and differentiation of cells and their response to stress factors, exposure to chemicals present in the environment, and radiation (Murray et al, 2010).…”

Section: Regulation Of Cytochrome P450 Gene Expression By Other Signamentioning

confidence: 99%

“…EGF/Ras/MAPK and WNT/ -catenin/TCF signaling pathways participate in the regulation of such gene expression (Braeuning, 2009;Braeuning & Schwarz, 2010a). A model of antagonistic relationship between these pathways has been proposed: Ras-dependent pathway promotes the expression of genes in periportal zone (so called zone 1), whereascatenin-dependent pathway promotes expression in pericentral zone (zone 3), of liver acinus (Braeuning, 2009). This applies not only to genes encoding CYP apoprotein, but also to genes involved in heme biosynthesis, which is the prosthetic group of these enzymes (Braeuning & Schwarz, 2010b).…”

Section: Regulation Of Cytochrome P450 Gene Expression By Other Signamentioning

confidence: 99%

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Transcription Factors Potentially Involved in Regulation of Cytochrome P450 Gene Expression

Czekaj¹,

Skowronek²

2012

Topics on Drug Metabolism

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Regulation of Cytochrome P450 Expression by Ras- and β-Catenin-Dependent Signaling

Cited by 33 publications

References 123 publications

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

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

Transcription Factors Potentially Involved in Regulation of Cytochrome P450 Gene Expression

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