The Search for Endogenous Activators of the Aryl Hydrocarbon Receptor

Abstract

The primary design of this perspective is to describe the major ligand classes of the aryl hydrocarbon receptor (AHR). A grander objective is to provide models that may help define the physiological activator or "endogenous ligand" of the AHR. We present evidence supporting a developmental role for the AHR and propose mechanisms by which an endogenous ligand and consequent AHR activation might be important during normal physiology and development. From this vista, we survey the known xenobiotic, endogenous, dietary, and "unconventional" activators of the AHR, including, when possible, information about their induction potency, receptor binding affinity, and potential for exposure. In light of the essential function of the AHR in embryonic development, we discuss the candidacy of each of these compounds as physiologically important activators.

Transcriptional regulatory networks in Th17 cell differentiation

“…dioxin, a polycyclic aromatic hydrocarbon xenobiotic compound), is a ligand-dependent transcription factor that is structurally distinct from the nuclear receptor superfamily. Upon binding to a ligand (such as dioxin or FICZ, a UV photoproduct of tryptophan), cytosolic AhR translocates into the nucleus, heterodimerizes with its partner aryl hydrocarbon receptor nuclear translocator (ARNT), and turns on transcription of its target genes [54]. The findings of the involvement of AhR in Th17 cell differentiation suggest a potential link between environmental pollution and inflammation.…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…In addition to xenobiotic aryl hydrocarbons and dioxins, a variety of endogenous ligands are presently discussed together with non-ligand activators [8]. Ligand-binding leads to nuclear translocation of the cytosolic AhR where it associates with its partner protein Arnt and binds to XREs (xenobiotic response elements) containing the core DNA sequence TnGCGTG.…”

“…A significant amount of bilirubin is produced every day (250-400 mg in adult humans) which is cleared in the liver by the above CARregulated XME system. Interestingly, bilirubin is an activator of CAR [78] and of AhR ( [8], for references). In support of the role of these LATFs in bilirubin catabolism, 10 phenobarbital-type inducers in human primary hepatocyte cultures [79].…”

“…This discovery also stimulated identification of the responsible ligand-activated transcription factors (LATFs): AhR [7,8], CAR and PXR [9][10][11]. In addition, treatment of rats with fibrates led to their characterization as peroxisome proliferators [12], CYP4 family inducers [5], and identification of PPARα as the responsible LATF [13].…”

Development and characterization of monoclonal antibodies against human aryl hydrocarbon receptor

“…Functional domains of AhR are classified to a bHLH region, two PAS domains (A and B) and a transcription activation domain (TAD). The aryl hydrocarbon receptor can be activated by exogenous chemicals, such as halogenated aromatic hydrocarbons, non-halogenated polycyclic aromatic hydrocarbons, and other dioxin-like chemicals (DLCs), as well as endogenous compounds, such as 6-formylindolo-[3,2-b]-carbazole, bilirubin and lipoxinA4 (Denison and Nagy, 2003;Nguyen and Bradfield, 2007). The activation of AhR by these compounds leads to regulation of the expression of a battery of genes resulting in diverse biological and toxicological effects, including dermal, hepatic, cardiac and immunotoxic response, wasting syndrome, reproductive and developmental toxicities (Beischlag et al, 2008;Flaveny et al, 2010;Birnbaum and Tuomisto, 2000;Bock, 1994).…”