The Ah Receptor: Adaptive Metabolism, Ligand Diversity, and the Xenokine Model

Abstract

The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins (“dioxins”), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

“…Members of the steroid hormone receptor subfamily were among the first NR’s identified, and the binding and effects of their endogenous hormonal ligands such as 17β-estradiol have been extensively investigated and form a conceptual basis for understanding hormone-hormone receptor action [ 3 ]. The aryl hydrocarbon receptor (AhR) is also an intracellular receptor that is a member of the basic-helix-loop-helix (bHLH) family of genes that exhibit a mode of action similar to that described for many NRs [ 4 , 5 , 6 ]. The cytosolic AhR is bound to several factors, including hsp90, AIP/XAP2 and p23, and treatment with an AhR ligand results in nuclear uptake of the bound receptor complex that forms a nuclear heterodimer with the AhR nuclear translocator (Arnt) protein.…”

“…The cytosolic AhR is bound to several factors, including hsp90, AIP/XAP2 and p23, and treatment with an AhR ligand results in nuclear uptake of the bound receptor complex that forms a nuclear heterodimer with the AhR nuclear translocator (Arnt) protein. This heterodimer interacts with cis-dioxin/xenobiotic response elements (DRE/XRE), which have a core GCGTG pentanucleotide sequence, and this results in recruitment of nuclear cofactors to activate or repress gene expression [ 4 , 5 , 6 ]. This pathway is similar to that described for several nuclear receptors such as peroxisome proliferator-activated receptors, and retinoic acid receptors, which form a heterodimer with the retinoid X receptor (RXR) [ 1 , 2 ].…”

The Cellular and Molecular Determinants of Naphthoquinone-Dependent Activation of the Aryl Hydrocarbon Receptor

“…Although 1,2-NQ and 1,4-NQ are structurally similar (Figure 1), differences in the position of the carbonyl groups have been shown to result in diverse The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates the expression of a wide variety of genes and it plays a pivotal role in a broad spectrum of biological, physiological and toxicological effects [14][15][16][17][18][19]. While the best studied high affinity ligands (agonists) for the AhR include polycyclic and halogenated aromatic hydrocarbons (PAHs and HAHs, respectively), the AhR can bind and be activated by structurally diverse ligands and cross species differences in AhR ligand specificity have been observed [15,[20][21][22][23][24]. Localized in the cytosol as part of a multiprotein complex, agonist binding to the AhR stimulates translocation of the AhR protein complex into the nucleus, where dimerization of the AhR with its binding partner, the aryl hydrocarbon nuclear translocator (ARNT), releases the ligand-bound AhR from its associated proteins and converts the AhR into its DNA binding form [15,24,25].…”

“…While the best studied high affinity ligands (agonists) for the AhR include polycyclic and halogenated aromatic hydrocarbons (PAHs and HAHs, respectively), the AhR can bind and be activated by structurally diverse ligands and cross species differences in AhR ligand specificity have been observed [15,[20][21][22][23][24]. Localized in the cytosol as part of a multiprotein complex, agonist binding to the AhR stimulates translocation of the AhR protein complex into the nucleus, where dimerization of the AhR with its binding partner, the aryl hydrocarbon nuclear translocator (ARNT), releases the ligand-bound AhR from its associated proteins and converts the AhR into its DNA binding form [15,24,25]. Binding of the ligand: AhR:ARNT complex to its specific DNA binding site, the dioxin response element (DRE), results in transcriptional activation of adjacent genes [15,21,[24][25][26].…”

“…Localized in the cytosol as part of a multiprotein complex, agonist binding to the AhR stimulates translocation of the AhR protein complex into the nucleus, where dimerization of the AhR with its binding partner, the aryl hydrocarbon nuclear translocator (ARNT), releases the ligand-bound AhR from its associated proteins and converts the AhR into its DNA binding form [15,24,25]. Binding of the ligand: AhR:ARNT complex to its specific DNA binding site, the dioxin response element (DRE), results in transcriptional activation of adjacent genes [15,21,[24][25][26]. Notably, while naphthalene (NA) (the precursor to both 1,2-NQ and 1,4-NQ) reportedly fails to bind to and/or activate the AhR, 1,4-dihydroxy-2-naphthoic acid and several related NA derivatives were shown to be able to act as AhR agonists/antagonists [27].…”