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. 2015 Oct;43(10):1536-43.
doi: 10.1124/dmd.115.063677. Epub 2015 Apr 14.

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

Yating Cheng  1 , Un-Ho Jin  1 , Clint D Allred  1 , Arul Jayaraman  1 , Robert S Chapkin  1 , Stephen Safe  2
Affiliations

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

Yating Cheng et al. Drug Metab Dispos. 2015 Oct.

Abstract

The tryptophan microbiota metabolites indole-3-acetate, indole-3-aldehyde, indole, and tryptamine are aryl hydrocarbon receptor (AhR) ligands, and in this study we investigated their AhR agonist and antagonist activities in nontransformed young adult mouse colonocyte (YAMC) cells. Using Cyp1a1 mRNA as an Ah-responsive end point, we observed that the tryptophan metabolites were weak AhR agonists and partial antagonists in YAMC cells, and the pattern of activity was different from that previously observed in CaCo2 colon cancer cells. However, expansion of the end points to other Ah-responsive genes including the Cyp1b1, the AhR repressor (Ahrr), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiParp) revealed a highly complex pattern of AhR agonist/antagonist activities that were both ligand- and gene-dependent. For example, the magnitude of induction of Cyp1b1 mRNA was similar for TCDD, tryptamine, and indole-3-acetate, whereas lower induction was observed for indole and indole-3-aldehyde was inactive. These results suggest that the tryptophan metabolites identified in microbiota are selective AhR modulators.

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Figures

Fig. 1.
Fig. 1.
Tryptophan metabolites and TCDD as inducers of Cyp1a1 in YAMC cells. YAMC cells were treated for 24 hours with (A) tryptophan metabolites, (B) TCDD, (C) tryptophan metabolites plus CH, or (D) TCDD plus CH. Expression of Cyp1a1 mRNA was determined by real-time PCR. Results are expressed as mean ± S.E. for three replicate determinations, and significant (P < 0.05) induction (*) (A and B) or inhibition by CH (**) (C and D) is indicated.
Fig. 2.
Fig. 2.
Tryptophan metabolites as AhR antagonists. YAMC cells were treated with tryptophan metabolites, TCDD, and their combination, and the effects on (A) Cyp1a1 mRNA and (B) CYP1A1/AhR proteins were determined by real-time PCR and Western blot analysis. (C) YAMC cells were treated with 10 nM TCDD, 50 μM tryptamine, or their combination for 2 and 24 hours and real-time PCR was used to determine interactions of the AhR with the Cyp1a1 promoter (containing XRE) in a ChIP assay. (D) YAMC cells were treated with dimethylsulfoxide or 10 nM TCDD for 24 hours and also cotreated with 50 μM tryptamine after 18, 20, 22, and 23 hours, and Cyp1a1 mRNA was determined by real-time PCR. The results (A and D) are expressed as mean ± S.E. (three replicates), and significant (P < 0.05) inhibition is indicated (**).
Fig. 3.
Fig. 3.
Induction of Cyp1b1. YAMC cells were treated with TCDD (alone), indole-3-aldehyde (A), indole (B), indole-3-acetate (C), and tryptamine (D) alone and in combination with TCDD for 24 hours, and Cyp1b1 was determined by real-time PCR. Results are expressed as mean ± S.E. (three replicates), and significant (P < 0.05) induction (*) or inhibition (**) of TCDD-induced Cyp1b1 is indicated.
Fig. 4.
Fig. 4.
Induction of Ahrr. YAMC cells were treated with TCDD (alone), indole-3-aldehyde (A), indole (B), indole-3-acetate (C), or tryptamine (D) alone and in combination with TCDD for 24 hours, and Cyp1b1 was determined by real-time PCR. Results are expressed as mean ± S.E. (three replicates), and significant (P < 0.05) induction (*) or inhibition (**) of TCDD-induced Ahrr is indicated.
Fig. 5.
Fig. 5.
Induction of TiParp. YAMC cells were treated with TCDD (alone), indole-3-aldehyde (A), indole (B), indole-3-acetate (C), or tryptamine (D) alone and in combination with TCDD for 24 hours, and TiParp was determined by real-time PCR. Results are expressed as mean ± S.E. (three replicates), and significant (P < 0.05) induction (*) or inhibition (**) of TCDD-induced TiParp is indicated.
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