Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 11508-11515 |
| Number of pages | 8 |
| Journal | Biochemistry |
| Volume | 37 |
| Issue number | 33 |
| DOIs | |
| State | Published - Aug 18 1998 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Activation of the Ah receptor by tryptophan and tryptophan metabolites. / Heath-Pagliuso, Sharon; Rogers, William J.; Tullis, Kathryn; Seidel, Shawn D.; Cenijn, Peter H.; Brouwer, Abraham; Denison, Michael S.
In: Biochemistry, Vol. 37, No. 33, 18.08.1998, p. 11508-11515.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of the Ah receptor by tryptophan and tryptophan metabolites
AU - Heath-Pagliuso, Sharon
AU - Rogers, William J.
AU - Tullis, Kathryn
AU - Seidel, Shawn D.
AU - Cenijn, Peter H.
AU - Brouwer, Abraham
AU - Denison, Michael S.
PY - 1998/8/18
Y1 - 1998/8/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032544183&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032544183&partnerID=8YFLogxK
U2 - 10.1021/bi980087p
DO - 10.1021/bi980087p
M3 - Article
C2 - 9708986
AN - SCOPUS:0032544183
VL - 37
SP - 11508
EP - 11515
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 33
ER -