ACTIVATION OF THE AH RECEPTOR BY TRYPTOPHAN AND TRYPTOPHAN-METABOLITES

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptio n factor that mediates many of the biological and toxicological action s of a variety of hydrophobic natural and synthetic chemicals, includi ng the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD, dioxin). A variety of indole-containing chemicals, such as indol e-3-carbinol, indolo[3,2-b]carbazole, and UV photoproducts of tryptoph an (TRP), have previously been identified as Ligands for AhR. Here we have examined the ability of endogenous metabolites of tryptophan (TRP ) to bind to and activate AI-LR in vitro and in cells in culture. Alth ough hydroxylated TRP metabolites were inactive, two metabolites, name ly tryptamine (TA) and indole acetic acid (IAA), were shown to be AhR agonists. Not only do TA and IAA bind competitively to AhR, but they a lso can stimulate AhR transformation and DNA binding and induce expres sion of an AhR-dependent reporter gene in cells. In addition to being an AhR ligand, TA is also a competitive substrate for cytochrome P4501 A1, a well-characterized AhR- and TCDD-inducible gene product. Althoug h these compounds are relatively weak ligands, compared to TCDD, they represent some of the first endogenous hydrophilic AhR agonists identi fied to date.