Activation of the Ah receptor by tryptophan and tryptophan metabolites

Biochemistry. 1998 Aug 18;37(33):11508-15. doi: 10.1021/bi980087p.


The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of a variety of hydrophobic natural and synthetic chemicals, including the environmental contaminant 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). A variety of indole-containing chemicals, such as indole-3-carbinol, indolo[3, 2-b]carbazole, and UV photoproducts of tryptophan (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 AhR in vitro and in cells in culture. Although hydroxylated TRP metabolites were inactive, two metabolites, namely 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 also can stimulate AhR transformation and DNA binding and induce expression of an AhR-dependent reporter gene in cells. In addition to being an AhR ligand, TA is also a competitive substrate for cytochrome P4501A1, a well-characterized AhR- and TCDD-inducible gene product. Although these compounds are relatively weak ligands, compared to TCDD, they represent some of the first endogenous hydrophilic AhR agonists identified to date.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5-Methoxytryptamine / metabolism
  • 5-Methoxytryptamine / pharmacology
  • Animals
  • Binding, Competitive
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Cell Nucleus / metabolism
  • Cytochrome P-450 CYP1A1 / metabolism
  • DNA / metabolism
  • Gene Expression Regulation / drug effects
  • Guinea Pigs
  • Indoleacetic Acids / metabolism
  • Indoleacetic Acids / pharmacology
  • Male
  • Mice
  • Polychlorinated Dibenzodioxins / antagonists & inhibitors
  • Polychlorinated Dibenzodioxins / metabolism
  • Protein Binding / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Aryl Hydrocarbon / drug effects
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Substrate Specificity
  • Tryptophan / metabolism*
  • Tryptophan / pharmacology*
  • Tumor Cells, Cultured


  • Indoleacetic Acids
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • 5-Methoxytryptamine
  • indoleacetic acid
  • Tryptophan
  • DNA
  • Cytochrome P-450 CYP1A1