Cooperation of structurally different aryl hydrocarbon receptor agonists and β-catenin in the regulation of CYP1A expression

Activating and Inhibitory Functions of WNT/β-Catenin in the Induction of Cytochromes P450 by Nuclear Receptors in HepaRG Cells

“…A similar connection between b-catenin and the murine Cyp2e1 (Braeuning et al, 2009;Gougelet et al, 2014) and Cyp1a1/Cyp1a2 mRNAs (Braeuning et al, 2009(Braeuning et al, , 2011bVaas et al, 2014) has also been reported. Interestingly, the basal level of the mouse homolog of the human CYP2B6 gene, Cyp2b10, was upregulated in Ctnnb1 knockout mice (Braeuning et al, 2009;Ganzenberg et al, 2013), thereby confirming our findings on increased basal expression of CYP2B6 after siRNA-mediated b-catenin knockdown.…”

“…Synergistic activation of target gene expression by b-catenin and the nuclear receptors AhR and CAR has been previously studied in mice as well as in murine cell lines (Braeuning et al, 2009(Braeuning et al, , 2011aGanzenberg et al, 2013;Vaas et al, 2014). Data presented in this article show, for the first time, synergistic effects of the WNT/b-catenin pathway and the receptors AhR, CAR, and PXR in human liver cells.…”

“…The WNT/b-catenin signaling pathway, traditionally well known as a regulator of embryonic development, tissue homeostasis, and carcinogenesis, was recently identified as an important endogenous regulator of hepatic drug metabolism in mouse liver, where the activity of this particular pathway determines hepatic zonation of cytochrome P450 (P450) expression (Loeppen et al, 2005;Hailfinger et al, 2006;Sekine et al, 2006;Braeuning and Schwarz, 2010;Braeuning et al, 2011a;Schreiber et al, 2011) and is also critically involved in the regulation of P450 transcription in response to exposure to xenobiotic agonists of a number of nuclear receptors (Braeuning et al, 2009;Ganzenberg et al, 2013;Vaas et al, 2014). Lipid-and xenobiotic-sensing nuclear receptors pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (CAR, NR1I3), and aryl hydrocarbon receptor (AhR), together with the liverenriched transcription factor peroxisome proliferator-activated receptor (PPAR) a (NR1C1) form networks of transcription factors that coordinately regulate hepatic expression of the majority of drug-metabolizing P450s, phase II enzymes, and transporters in response to xenobiotic exposure (Handschin and Meyer, 2005;Pascussi et al, 2008;Pelkonen et al, 2008;Thomas et al, 2013).…”

Firefly luciferase inhibition: a widely neglected problem

“…Certain flavonoids, for example, the kinase inhibitor PD98,059 (2′-amino-3′-methoxyflavone) and the widely used aryl hydrocarbon receptor agonist β-naphthoflavone, also inhibit firefly luciferase at concentrations far below what is routinely used for in vitro assays (Auld et al 2008;Vaas et al 2014;Wang 2002).It is quite difficult to find a paper in the literature where the possibility of luciferase enzyme inhibition has been explicitly taken into account by the authors. This does, however, not necessarily mean that all luciferase reporter assays conducted with cells treated with substances such as resveratrol must have yielded inconclusive results (nor do problems with a luciferase reporter assay invalidate the findings obtained with other experimental approaches which are presented in the same paper).…”

“…Certain flavonoids, for example, the kinase inhibitor PD98,059 (2′-amino-3′-methoxyflavone) and the widely used aryl hydrocarbon receptor agonist β-naphthoflavone, also inhibit firefly luciferase at concentrations far below what is routinely used for in vitro assays (Auld et al 2008;Vaas et al 2014;Wang 2002).…”