Activation of the Ah receptor by tryptophan and tryptophan metabolites.
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.
Department of Environmental Toxicology, University of California, Davis 95616-8588, USA.
S
S
Heath-Pagliuso
W J
WJ
Rogers
K
K
Tullis
S D
SD
Seidel
P H
PH
Cenijn
A
A
Brouwer
M S
MS
Denison
D008735:5-Methoxytryptamine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D007210:Indoleacetic Acids / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014364:Tryptophan / Q000378:metabolism* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007210:Indoleacetic Acids; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D008735:5-Methoxytryptamine; C030737:indoleacetic acid; D014364:Tryptophan; D004247:DNA; D019363:Cytochrome P-450 CYP1A1