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

• Published in: Drug metabolism and disposition Vol. 43; no. 10; pp. 1536 - 1543
• Main Authors: Cheng, Yating, Jin, Un-Ho, Allred, Clint D, Jayaraman, Arul, Chapkin, Robert S, Safe, Stephen
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01-10-2015
• Subjects: Age Factors; Animals; Caco-2 Cells; Colon - cytology; Colon - drug effects; Colon - metabolism; Dose-Response Relationship, Drug; Humans; Mice; Polychlorinated Dibenzodioxins - pharmacology; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - metabolism; Special Section on Drug Metabolism and the Microbiome; Tryptophan - metabolism
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.115.063677

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.