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

Benjamin J. Moyer, Itzel Y. Rojas, Iain Alexander Murray, Seokwon Lee, Haley F. Hazlett, Gary H. Perdew, Craig R. Tomlinson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)74-80
Number of pages7
JournalToxicology and Applied Pharmacology
Volume323
DOIs
StatePublished - May 15 2017

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Aryl Hydrocarbon Receptors
Tryptophan
Assays
Clinical Trials
Cytochrome P-450 CYP1A1
Oncology
T-cells
Immune system
Enzyme Assays
Enzyme activity
Xenobiotics
Luciferases
Reporter Genes
Metabolism
Tumors
Cell Differentiation
Immune System
Neoplasms
Genes

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Moyer, Benjamin J. ; Rojas, Itzel Y. ; Murray, Iain Alexander ; Lee, Seokwon ; Hazlett, Haley F. ; Perdew, Gary H. ; Tomlinson, Craig R. / Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. In: Toxicology and Applied Pharmacology. 2017 ; Vol. 323. pp. 74-80.
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Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. / Moyer, Benjamin J.; Rojas, Itzel Y.; Murray, Iain Alexander; Lee, Seokwon; Hazlett, Haley F.; Perdew, Gary H.; Tomlinson, Craig R.

In: Toxicology and Applied Pharmacology, Vol. 323, 15.05.2017, p. 74-80.

Research output: Contribution to journalArticle

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