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

Stephen Safe,Arul Jayaraman,Un-Ho Jin,Hyejin Park,Robert S Chapkin

doi:10.3390/ijms21186654

Stephen Safe, Arul Jayaraman + Show 3 more

Open Access

https://doi.org/10.3390/ijms21186654

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Abstract

The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.

Highlights

Intracellular receptors such as the nuclear receptor (NR) superfamily play important roles in maintaining cellular homeostasis and in pathophysiology [1,2]
The aryl hydrocarbon receptor (AhR) is an intracellular receptor that is a member of the basic-helix-loop-helix 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

Summary

Introduction

Intracellular receptors such as the nuclear receptor (NR) superfamily play important roles in maintaining cellular homeostasis and in pathophysiology [1,2]. The cytosolic AhR is bound to several factors, including hsp, 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]. Several endogenous ligands that bind the AhR have subsequently been identified, and these include 6-formyl (3,2-b) carbazole (FICZ), 2-(1 -H-indole-3-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE), tryptophan metabolites such as kynurenine and other gut microbial products, and leukotrienes [15,16,17,18,19,20] These compounds exhibit some tissue-specific modulation of AhR action; their role as major endogenous AhR ligands is unresolved. This review will focus on the conceptual similarities between NRs and the AhR in terms of the development of selective receptor modulators (SRMs) and their potential clinical applications in treating adverse health conditions

AhR Functions and Potential for Drug Targeting

Findings

Classification of AhR Ligands—SahRMs or Not?