Aryl hydrocarbon receptor ligands in cancer: friend and foe

Murray, Iain A.; Patterson, Andrew D.; Perdew, Gary H.

doi:10.1038/nrc3846

Cited by 669 publications

(543 citation statements)

References 165 publications

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“…Differences in the AhR agonist and antagonist activities of the tryptophan metabolites are due not only to the transformed versus nontransformed phenotype of CaCo2 and YAMC cells but also to their different human versus mouse origins. These results suggest that indole-3-aldehyde, indole, indole-3-acetate, and tryptamine are selective AhR modulators (Safe et al, 2013;Murray et al, 2014) based on the results observed in this study.…”

Section: Downloaded Fromsupporting

confidence: 82%

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

et al. 2015

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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 genedependent. 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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Section: Downloaded Fromsupporting

confidence: 82%

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

et al. 2015

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“…The involvement of AHR in inflammatory signaling and cell cycle progression suggests it may play a role in various stages of tumorigenesis (Gasiewicz et al, 2008;Safe et al, 2013;Murray et al, 2014). Evidence for this includes the high levels of constitutive receptor activity and nuclear localization observed in aggressive tumors and tumor cell lines (Yang et al, 2008;DiNatale et al, 2012;Richmond et al, 2014).…”

Section: The Physiologic Significance Of Ahrmentioning

confidence: 99%

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

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

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442

398

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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 ligandmediated 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.

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“…In the gut, secretion of IL22 by innate lymphoid and T H 17 cells can promote proliferation of the gut epithelial cells (Kumar et al, 2013). The AHR is a member of the basic helix-loop-helix Per-Arnt-Sim family (Kohle and Bock, 2009;Murray et al, 2014) that has been historically of interest because of its ability to regulate the expression levels of drug metabolizing enzymes and transporters. Genes typically upregulated by the AHR are cytochromes CYP1A1 and CYP1B1 (phase 1); GSTA1, GSTA2, and UDPglucuronosyltransferase UGT1A1 (phase 2); and multidrug resistance associated protein MRP3/ABCC3 (phase 3).…”

Section: Contribution Of the Gut Microbiota To Intestinal Immune Homementioning

confidence: 99%

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

Swanson

2015

Drug Metab Dispos

136

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The importance of the gut microbiome in determining not only overall health, but also in the metabolism of drugs and xenobiotics, is rapidly emerging. It is becoming increasingly clear that the gut microbiota can act in concert with the host cells to maintain intestinal homeostasis, cometabolize drugs and xenobiotics, and alter the expression levels of drug-metabolizing enzymes and transporters and the expression and activity levels of nuclear receptors. In this myriad of activities, the impact of the microbiota may be beneficial or detrimental to the host. Given that the interplay between the gut microbiota and host cells is likely subject to high interindividual variability, this work has tremendous implications for our ability to predict accurately a particular drug's pharmacokinetics and a given patient population's response to drugs. In this issue of Drug Metabolism and Disposition, a series of articles is presented that illustrate the progress and challenges that lie ahead as we unravel the intricacies associated with drug and xenobiotic metabolism by the gut microbiota. These articles highlight the underlying mechanisms that are involved and the use of in vivo and in vitro approaches that are currently available for elucidating the role of the gut microbiota in drug and xenobiotic metabolism. These articles also shed light on exciting new avenues of research that may be pursued as we consider the role of the gut microbiota as an endocrine organ, a component of the brain-gut axis, and whether the gut microbiota is an appropriate and amenable target for new drugs.

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Aryl hydrocarbon receptor ligands in cancer: friend and foe

Cited by 669 publications

References 165 publications

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

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

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

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

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