Toxic mechanisms and metabolism of endogenous and exogenous AhR ligands

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Arylhydrocarbon Receptor (AhR) recognizes wide variety of chemicals as its ligand. It is widely known that many persistent organic pollutants (POPs) such as polychlorinated dibenzo-dioxins (PCDDs), polychlorinated dibenzo-furans (PCDFs), polychlorinated biphenyls (PCBs) and polyaromatic hydrocarbons (PAHs) are AhR ligands. It is also known that some natural indole compounds, such as indole[3,2-b]carbazole (ICZ), 3,3'-diindolylmethane (DIM), 6-folmylindolo [3,2-b]carbazole (FICZ) show strong AhR ligand activity. Our group also has found one of the strongest AhR ligand, indirubin. In this study, we detected and identified the new AhR ligands in the environment and in food. We identified several AhR ligands in the effluent from dye works and a municipal waste water treatment plant. Those AhR lingads were dyes which are widely used. We showed AhR ligand activity in several commercially obtained anthraquinone dyes. We also found that there were several AhR ligands in coffee extract.We compared the activity of several natural AhR ligands, DIM,ICZ,FICZ and indirubin. ICZ,FICZ and indirubin all showed very strong activity. However, the activity was vanished when they were incubated with CYP1A1 or CYP1A2,which are the monooxigenases induced via AhR signaling. The difference of toxicity between these natural ligands and dioxins may be due to their metabolic propaties.