title: The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis.
abstract: Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancers induced by common environmental chemicals. Much of the biologic activity of one such class of pollutants, polycyclic aromatic hydrocarbons (PAH), is mediated by the aryl hydrocarbon receptor/transcription factor (AhR). For example, the AhR regulates PAH immunotoxicity that manifests as pre-B cell apoptosis in models of B cell development. Because bioflavonoids block PAH-induced cell transformation and are structurally similar to AhR ligands, it was postulated that some of them would suppress PAH-induced, AhR-dependent immunotoxicity, possibly through a direct AhR blockade. This hypothesis was tested using a model of B cell development in which pre-B cells are cultured with and are dependent on bone marrow stromal or hepatic parenchymal cell monolayers. Of seven bioflavonoids screened, galangin (3,5,7-trihydroxyflavone) blocked PAH-induced but not C(2)-ceramide- or H(2)O(2)-induced pre-B cell apoptosis. Because galangin blocked AhR-dependent reporter gene expression, AhR complex-DNA binding, and AhR nuclear translocation, inhibition of a relatively early step in AhR signaling was implicated. This hypothesis was supported by the ability of galangin to bind the AhR and stabilize AhR-90-kDa heat shock protein complexes in the presence of AhR agonists. These studies demonstrate the utility of pre-B cell culture systems in identifying compounds capable of blocking PAH immunotoxicity, define at least one mechanism of galangin activity (i.e., repression of AhR activation), and motivate the use of this and similar dietary bioflavonoids as relatively nontoxic inhibitors of AhR agonist activity and as pharmacologic agents with which to dissect AhR signaling pathways.
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Quadri
authors.forename: A N
authors.initials: AN
authors.lastname: Qadri
authors.forename: M E
authors.initials: ME
authors.lastname: Hahn
authors.forename: K K
authors.initials: KK
authors.lastname: Mann
authors.forename: D H
authors.initials: DH
authors.lastname: Sherr
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D001665:Binding Sites; D001692:Biological Transport; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D019281:Dimerization; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014316:Tritium
chemical_list: C497397:Arnt protein, mouse; D002273:Carcinogens; D004268:DNA-Binding Proteins; D005419:Flavonoids; D018841:HSP90 Heat-Shock Proteins; D009153:Mutagens; D000072317:Polychlorinated Dibenzodioxins; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D014316:Tritium; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C037032:galangin; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA