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.

Figure 1

Investigations of carcinogenic PAHs led to discovery of the Ah locus. Studies using BAP, DMBA, and 3-MC provided early evidence for the existence of the AHR (see text for references).

Figure 2

Further elucidation of the Ah locus arose from toxicity studies using the toxicant TCDD. TCDD, 2,3,7,8-TCDF (tetrachlorodibenzofuran), and PCB 77 (polychlorinated biphenyl) induce the same P450s and related enzymes as did BAP, DMBA, and 3-MC. TCDD has higher affinity for AHR and thus has greater potency, making TCDD a model inducer of AHR signaling (see text for details).

Figure 3

Mapping of AHR and ARNT functional domains and founding bHLH-PAS family members. The bHLH domain and N-terminus provide recognition of target DNA enhancers. The PAS domains control dimerization strength and selectivity, receptor repression, chaperone interactions, and ligand binding. Approximation of those domains for AHR are depicted as lines above. The C-terminus provides possible docking sites for coactivators.^{−,,,−,,,,,,,,,−} Also see text for further details.

Figure 4

Classic AHR signaling pathway. Prior to ligand binding, AHR remains in cytosol bound to HSP90, P23, and ARA9. When a ligand binds, a conformational change occurs, exposing the nuclear localization sequence (NLS) in AHR’s N-terminus. Presentation of NLS permits the translocation of AHR to the nucleus and subsequent dimerization with ARNT. The AHR–ARNT heterodimer recognizes and binds to AHREs in the genome and initiates transcription of select genes. This interaction can be inhibited by AHRR, CYP1 metabolism of ligands, and post-translational modification of the receptor.^{,,,,,,,−,−,,,,,,}

Figure 5

Dioxin-like compound concept and approach to measuring human exposure to mixtures. Toxic equivalency factors (TEFs) are weighted measures that reflect the relative potencies of pollutants of concern as compared to TCDD. Toxic equivalents (TEQs) are reported values used for risk characterization and management (see text for details). Left: Structures of the three classes of chlorinated DLCs. Right: Examples of three formally designated DLCs. To calculate TEQ, the mass of each chemical in a mixture is multiplied by its TEF and summed.^,,,,,,

Figure 6

The flat hydrophobic rectangle model of AHR ligands. Molecular and ball and stick models of some AHR ligands discussed in this review that conform to the FHR concept of ligand structure. The three-dimensional structures are only provided as approximations, as some subtle bending and puckering of structure may occur that is not predicted by common algorithms. Figure was generated with ChemDraw software.