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Aryl Hydrocarbon Receptor-Mediated Carcinogenesis and Modulation by Dietary Xenobiotic and Natural Ligands

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Bioactive Compounds and Cancer

Part of the book series: Nutrition and Health ((NH))

Key Points

1. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the helix-loop-helix/PAS family. Many compounds interact with the AhR including xenobiotic (“xeno” = foreign) polycyclic aromatic hydrocarbons (PAH) and dioxins, endogenous ligands, and natural bioactive compounds. The activation of the AhR leads to increased expression of Phase I enzymes at xenobiotic responsive elements (XRE) and production of chemically reactive species known to induce cancer. Conversely, activation of the AhR leads to decreased expression of the tumor-suppressor genes p16 and BRCA-1.

2. Data from both animal and human studies suggest that the persistent activation of the AhR may be a risk factor and promote various types of cancer. In particular, PAH appear to preferentially induce mammary tumors in preclinical models. Natural modulators of the AhR include the phytoalexin resveratrol, the indole compounds indole-3-carbinol (I3C) and its condensation product 3,3′-diindolylmethane (DIM), several flavonoids, and catechins.

3. Data from cell culture and animal studies suggest that at relatively low concentration (∼10 μM), DIM may exert antagonistic protective effects, whereas at higher levels (∼100 μM), it may exert agonistic effects and activate the expression of P450. Animal studies reported that the compound I3C may also promote tumor development. The therapeutic properties of these compounds may be influenced by various factors including cell context, timing of exposure, concentration, and relative binding affinity for the AhR.

4. Both the bioavailability and pharmacokinetics of AhR ligands from phytochemicals may influence the therapeutic values of preventative strategies based on AhR antagonists.

5. Although further investigations are necessary to assess the potential benefits of AhR-based strategies against cancer, it is suggested that several phytochemicals may exert protective effects and reduce the risk of toxicity and cancer through competitive transformation of the AhR.

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Acknowledgments

This research has been supported by grants from the Arizona Biomedical Research Commission (100116, 8015), the Susan G. Komen Breast Cancer Foundation (BCTR0707643), the US Department Breast Cancer Research Program (DAMD17-00-1-0130), the National Institute of Environmental Health Sciences, National Institutes of Health (ES009966), and Training Grant in Toxicology and Toxicogenomics (T32 ES-07091-24).

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Authors and Affiliations

  1. Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA

    Donato F. Romagnolo PHD, MS, Stephanie C. Degner PHD & Ornella Selmin PHD

  2. Department of Veterinary Science and Microbiology, The University of Arizona, Tucson, AZ, USA

    Stephanie C. Degner PHD

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  1. Donato F. Romagnolo PHD, MS
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  2. Stephanie C. Degner PHD
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  1. Nutritional Science Research Group, Division of Cancer Prevention, National Institutes of Health, Executive Boulevard 6130, Rockville, 20892, Maryland, USA

    John A. Milner

  2. Nutritional and Cancer Biology, BIO5 Institute and Center for Toxicology, The University of Arizona, Tucson, 85721-0038, Arizona, USA

    Donato F. Romagnolo

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Romagnolo, D.F., Degner, S.C., Selmin, O. (2010). Aryl Hydrocarbon Receptor-Mediated Carcinogenesis and Modulation by Dietary Xenobiotic and Natural Ligands. In: Milner, J., Romagnolo, D. (eds) Bioactive Compounds and Cancer. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-627-6_32

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