Food flavonoid aryl hydrocarbon receptor-mediated agonistic/antagonistic/synergic activities in human and rat reporter gene assays

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor mediating the
adverse effects of dioxins and polycyclic aromatic hydrocarbons (PAHs). In this study, we
investigated the genetic-, time-, dose-, species- and tissue-dependent AhR-mediated agonistic/
antagonistic activities of three food flavonoids: quercetin, chrysin and genistein.
To that end, four stably transfected cell lines were used in cell-based luciferase reporter
gene assays: three lines were transformed with the ptKLuc vector harbouring four dioxinresponsive
elements (DREs) upstream of the thymidine kinase promoter and the luciferase
gene (HepG2-Luc, T-47D-Luc and H4IIE-ULg). The fourth is a patented cell line transformed
with a different construct: H4IIE DR-CALUX®. Both H4IIE cells were compared for their
genetic construction. Human hepatoma (HepG2-Luc) and human breast tumour (T-47D-Luc)
cells were compared for tissue-dependent effects. Rat hepatoma (H4IIE-ULg) and human
hepatoma (HepG2-Luc) cellswere compared for species-dependent activities.We concluded
that quercetin, chrysin and genistein act in a time-, dose-, species- and tissue-specific way.
For example, genistein displayed agonistic activities when exposed to rat hepatoma cells
during 6h but not after 24 h. Flavonoids displayed agonistic/antagonistic activities in human
breast tumour cells, depending on the exposure time, while in human hepatoma cells, only
antagonistic activities of flavonoids were measured. In addition, we report, in all the cells, a
synergy between an isoflavone and two food contaminants; the 2,3,7,8-tetrachlorodibenzop-
dioxin and 3-methylcholanthrene, a PAH. In rat cells, this synergy occurred when cells
were exposed to flavonoids and contaminant for 6h, while it was observed in human cells
only after 24 h.