Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor

• Published in: Toxicology and applied pharmacology 2017-05, Vol.323, p.74-80
• Main Authors: Moyer, Benjamin J., Rojas, Itzel Y., Murray, Iain A., Lee, Seokwon, Hazlett, Haley F., Perdew, Gary H., Tomlinson, Craig R.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; AHR agonists; Animals; Aryl Hydrocarbon Receptor; Basic Helix-Loop-Helix Transcription Factors - agonists; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; BEARS; Cancer; CELL DIFFERENTIATION; CLINICAL TRIALS; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - genetics; DIOXIN; DMSO; DRUGS; ENZYME ACTIVITY; Enzyme Induction; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; GENES; Genes, Reporter; Hep G2 Cells; Humans; HYDROXY COMPOUNDS; IDO inhibitors; IDO1; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; KYNURENINE; LIGANDS; LUCIFERASE; MEDICAL SURVEILLANCE; METABOLISM; MICE; NEOPLASMS; PHOSPHATES; QUINOLINES; RECEPTORS; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Risk Assessment; SUBSTRATES; Transcription, Genetic; Transfection; TRYPTOPHAN; XENOBIOTICS
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2017.03.012

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes. •Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors are in cancer clinical trials.•Some IDO1 inhibitors also potently activate AHR signaling.•The dual role of the IDO1 inhibitors may explain some past paradoxical findings.•AHR induction studies must be included in assessing clinical suitability.