Evidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity

Abstract

The concept of selective receptor modulators has been established for the nuclear steroid hormone receptors. Such selective modulators have been used therapeutically with great success in the treatment of cancer. However, this concept has not been examined with regard to the aryl hydrocarbon receptor (AHR) because of the latent toxicity commonly associated with AHR activation. AHR-mediated toxicity is primarily derived from AHR binding to its dioxin response element (DRE) and driving expression of CYP1 family members, which have the capacity to metabolize procarcinogens to genotoxic carcinogens. Recent evidence using a non-DRE binding AHR mutant has established the DRE-independent suppression of inflammatory markers by the AHR. We wished to determine whether such DRE-independent repression with wild-type AHR could be dissociated from canonical DRE-dependent transactivation in a ligand-dependent manner and, in doing so, prove the concept of a selective AHR modulator (SAhRM). Here, we identify the selective estrogen receptor (ER) modulator Way-169916 as a dually selective modulator, binding both ER and AHR. Inflammatory gene expression associated with the cytokine-inducible acute-phase response (e.g., SAA1 and CRP) are diminished by Way-169916 in an AHR-dependent manner. Furthermore, activation of AHR by Way-169916 fails to stimulate canonical DREdriven AHR-mediated CYP1A1 expression, thus eliminating the potential for AHR-mediated genotoxic stress. Such anti-inflammatory activity in the absence of DRE-mediated expression fulfills the major criteria of an SAhRM, which suggests that selective modulation of AHR is possible and renders the AHR a therapeutically viable drug target for the amelioration of inflammatory disease.

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

“…The AHR is a ligand-activated receptor that not only plays a role in mediating the toxicity of TCDD and related compounds but is also a potential target for the treatment of several diseases including autoimmune diseases, various inflammatory conditions, and cancer (McDougal et al, 2001;Quintana et al, 2008Quintana et al, , 2010Zhang et al, 2009Zhang et al, , 2012DiNatale et al, 2010bDiNatale et al, , 2011Murray et al, 2010;O'Donnell et al, 2010;Kiss et al, 2011;Li et al, 2011;Opitz et al, 2011;Singh et al, 2011). Depending on the tissue or cell, AHR agonists or antagonists may be required, and there is also evidence that the effects of various AHR-active compounds are structure-dependent.…”

“…However, MCDF did not inhibit TCDD-induced antiestrogenic effects in the rodent uterus or human breast cancer cells but acted as an AHR agonist (Astroff and Safe, 1991;Zacharewski et al, 1992), and subsequent studies showed that MCDF also inhibited ERpositive and ER-negative breast cancer cell and tumor growth (McDougal et al, 2001;Zhang et al, 2009Zhang et al, , 2012. Thus, MCDF was one of the first compounds characterized as a selective AHR modulator (SAhRM) that exhibits tissue-selective AHR agonist or antagonist activities (Astroff and Safe, 1991;Zacharewski et al, 1992;McDougal et al, 2001;Zhang et al, 2009Zhang et al, , 2012, and several other AHR antagonists and SAhRMs have been identified (Boitano et al, 2010;Murray et al, 2010Murray et al, , 2011Zhao et al, 2010;Smith et al, 2011).…”

Aryl Hydrocarbon Receptor Control of Adaptive Immunity

“…Although AhR complexes clearly interact with the canonical AhR binding site , recent data indicate noncanonical recognition sequences as well (Huang and Elferink, 2012), suggesting the likelihood that the AhR controls transcription of significantly more genes than previously appreciated. It is striking that several AhR protein interactions are only triggered by specific AhR ligands (Boronat et al, 2007;Zhang et al, 2008;Murray et al, 2010), suggesting that some transcriptional partners of AhR are recruited in a ligand-specific manner.…”

Suppression of Cytokine-Mediated Complement Factor Gene Expression through Selective Activation of the Ah Receptor with 3′,4′-Dimethoxy-α-naphthoflavone

“…The recent characterization of an anti-inflammatory SAhRM, which represents a novel subset of AHR ligands with the capacity to dissociate non-DRE dependent antiinflammatory action of AHR from potentially undesirable DRE-mediated transactivation points to the amelioration of inflammatory conditions through pharmacological modulation of AHR (Murray et al, 2010c). The modulation of AHR and resultant beneficial effects has also been demonstrated with AHR agonists such as TCDD in diminishing inflammatory parameters associated with a genetic model of diabetes ).…”