Aryl Hydrocarbon Receptors

Aryl hydrocarbon receptors (AHRs) are cytosolic transcription factors that exist bound to co-chaperones in the resting state (Hsp90, prostaglandin E synthase 3 and hepatitis B virus X-associated protein 2). Ligand binding causes the co-chaperones to dissociate, allowing AHR to translocate to the nucleus, dimerize with AHR nuclear translocator (ARNT) and alter transcription of target genes.
AHR is an evolutionary conserved receptor that has roles in cell proliferation and differentiation and induction of xenobiotic-metabolizing enzymes (for example CYP1A1). The human gene encoding the aryl hydrocarbon receptor has been localized to chromosome 7p15.

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An overview of Aryl hydrocarbon receptors

Aryl hydrocarbon receptor, belonging to the superfamily of basic helix loop helix/Per-Arnt-Sim proteins, was identified as a cytosolic receptor for polycyclic aromatic hydrocarbon. Structurally, the aryl hydrocarbon receptor consists of basic helix loop helix domain and Per-Arnt-Sim domain, which are responsible for DNA binding and ligand binding. The sequence of aryl hydrocarbon receptor is composed of 848 amino acids and a molecular of 90 kDa. The aryl hydrocarbon receptor is expressed in vertebrate cells and plays key regulatory roles in normal physiology, like immune, inflammatory responses, and atherogenesis. Besides, aryl hydrocarbon receptor mediates function in responses to environmental toxicity.

Antagonists of Aryl hydrocarbon receptors

Accumulating evidence shows that cigarette smoke could induce the activation of aryl hydrocarbon receptor in atherosclerosis. The antagonists of aryl hydrocarbon receptors are mainly planar phenolic compounds, including α-naphthoflavone, 7,8-benzoflavone, 3-methoxy-4-nitroflavone, 6,2,4-trimethoxyflavone, CH-223191, and resveratrol. However, some antagonists are not available for aryl hydrocarbon receptors despite of their antagonist properties. For example, α-naphthoflavone may produce submaximal effects and cytotoxicity. As a selective aryl hydrocarbon receptor antagonist, CH-2233191 exerts function only when agonists trigger the aryl hydrocarbon receptor. Since many aryl hydrocarbon receptor antagonists exhibit pharmacological limitations, researchers try to develop novel antagonists provided with ideal pharmacological features. Santostefano synthesized phenolic compounds with electron-rich substituents exhibiting pure antagonist activity for aryl hydrocarbon receptor.

Aryl hydrocarbon receptors and diseases

As mentioned above, the aryl hydrocarbon receptor plays a crucial role in pathogenesis of several diseases. The progression of atherosclerosis is related to aryl hydrocarbon receptor activation. The aryl hydrocarbon receptor also functions as a modulator of T cell differentiation through specific ligands and the cytokine milieu. Thus, the deficiency of aryl hydrocarbon receptor can prevent collagen-induced arthritis development. Undoubtedly, there is a cumulative request by both researchers and clinicians for the deeper understanding of aryl hydrocarbon receptor and antagonists with high potency and selectivity.


Pernomian, L. & Da, S. C. Current basis for discovery and development of aryl hydrocarbon receptor antagonists for experimental and therapeutic use in atherosclerosis. European Journal of Pharmacology 764, 118-123 (2015).

Kawajiri, K. & Fujiikuriyama, Y. The aryl hydrocarbon receptor: a multifunctional chemical sensor for hostdefense and homeostatic maintenance. Experimental Animals 66, 75-89 (2017).