title: Regulation of dioxin receptor function by different beta-carboline alkaloids.
abstract: The dioxin receptor, also known as arylhydrocarbon receptor (AhR), is a ligand-activated transcription factor that mediates the toxicity of dioxins and related environmental contaminants. In addition, there is a growing list of natural compounds, mainly plant polyphenols that can modulate AhR function and downstream signaling with quite unknown consequences for cellular function. We investigate the potential of four different beta-carboline alkaloids to stimulate AhR signaling in human hepatoma cells and keratinocytes. Three test substances, namely rutaecarpine, annomontine and xestomanzamine A, increase AhR-driven reporter gene activity as well as expression of two AhR target genes in a dose-dependent and time-dependent manner. Additionally, the three test alkaloids stimulate cytochrome P450 (CYP) 1 enzyme activity without showing any antagonistic effects regarding benzo(a)pyrene-stimulated CYP1 activation. The AhR-activating property of the beta-carbolines is completely abrogated in AhR-deficient cells providing evidence that rutaecarpine, annomontine and xestomanzamine A are natural stimulators of the human AhR. The toxicological relevance of beta-carboline-mediated AhR activation is discussed.
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-Universität Düsseldorf gGmbH, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany. haarmann@uni-duesseldorf.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
authors.forename: Jandirk
authors.initials: J
authors.lastname: Sendker
authors.forename: Christine
authors.initials: C
authors.lastname: Götz
authors.forename: Nathalie
authors.initials: N
authors.lastname: Krug
authors.forename: Hanno
authors.initials: H
authors.lastname: Bothe
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
authors.forename: Josef
authors.initials: J
authors.lastname: Abel
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000633:toxicity*; D002243:Carbolines / Q000737:chemistry / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D011799:Quinazolines / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D052999:Quinazolinones
chemical_list: D000470:Alkaloids; D002243:Carbolines; D019363:Cytochrome P-450 CYP1A1; D026121:Indole Alkaloids; D011743:Pyrimidines; D011799:Quinazolines; D018336:Receptors, Aryl Hydrocarbon; C508838:annomontine; C028632:rutecarpine; D052999:Quinazolinones