Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligand-mediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.

Fig. 1.

Canonical pathway of AHR-mediated transcription after binding.

Fig. 2.

Gastric acid condensation of indole-3-carbinol lead to the production of high-affinity AHR ligands.

Fig. 3.

Microbial synthesis of AHR ligands and host metabolism of indole.

Fig. 4.

Endogenous tryptophan metabolism through the kynurenine pathway generates AHR ligands.

Fig. 5.

Summary of endogenous pathways of AHR ligand synthesis. (1) Microbial production of indole, (2) microbial/host indole metabolism to generate AHR ligands, (3) tryptophan UV photo-oxidation to form 6-formylindolo[3,2-b]carbazole (FICZ), (4) endogenous tryptophan metabolism via the kynurenine pathway, and (5) diet-derived ligand synthesis are all pathways of AHR ligand synthesis that mediate (6) AHR activation and transcription of target genes interleukin-6 (IL6), cytochrome P450 1A1 (CYP1A1), vascular endothelial growth factor A (VEGFA), prostaglandin G/H synthase 2 (PTGS2), interleukin-22 (IL22), and cytochrome P450 1B1 (CYP1B1).