The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis

Bioflavonoids are plant compounds touted for their potential to treat or pr event several diseases including cancers induced by common environmental ch emicals. Much of the biologic activity of one such class of pollutants, pol ycyclic aromatic hydrocarbons (PAH), is mediated by the aryl hydrocarbon re ceptor/transcription factor (AhR). For example, the AhR regulates PAH immun otoxicity that manifests as pre-B cell apoptosis in models of B cell develo pment. Because bioflavonoids block PAH-induced cell transformation and are structurally similar to AhR ligands, it was postulated that some of them wo uld suppress PAH-induced, AhR-dependent immunotoxicity, possibly through a direct AhR blockade. This hypothesis was tested using a model of B cell dev elopment in which pre-B cells are cultured with and are dependent on bone m arrow stromal or hepatic parenchymal cell monolayers. Of seven bioflavonoid s screened, galangin (3,5,7-trihydroxyflavone) blocked PAH-induced but not C-2-ceramide- or H2O2-induced pre-B cell apoptosis. Because galangin blocke d AhR-dependent reporter gene expression, AhR complex-DNA binding, and AhR nuclear translocation, inhibition of a relatively early step in AhR signali ng 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 t he presence of AhR agonists. These studies demonstrate the utility of pre-B cell culture systems in identifying compounds capable of blocking PAH immu notoxicity, define at least one mechanism of galangin activity (i.e., repre ssion 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.