Aryl hydrocarbon receptor

The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, AH receptor, or dioxin receptor) is a

More recently, it has been discovered that AhR is activated (or deactivated) by a number of

The AhR

Research has focused on naturally occurring compounds with the hope of identifying an endogenous ligand. Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of tryptophan such as indigo dye and indirubin,^[18] tetrapyrroles such as bilirubin,^[19] the arachidonic acid metabolites lipoxin A4 and prostaglandin G,^[20] modified low-density lipoprotein^[21] and several dietary carotenoids.^[16] One assumption made in the search for an endogenous ligand is that the ligand will be a receptor agonist. However, work by Savouret et al. has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.^[22]

Carbidopa is a selective aryl hydrocarbon receptor modulator (SAhRM).^[23] Other SAhRMs include microbial-derived 1,4-dihydroxy-2-napthoic acid^[24] and plant-derived 3,3-diindolylmethane.^[25]

Indolocarbazole (ICZ) is one of the strongest non-halogenated agonists for AhR in vitro reported.^[26]

Ligand-independent AhR activity can be seen in mammalian AhR. The mammalian AhR needs no exogenous ligand-dependent activation to be functional, and this appears to be the case for its role in the regulation of the expression of some transforming growth factor-beta (TGF-b) isoforms. This is not to say that ligand-dependent AhR activation is not needed for the AhR to function in those cases, but that, if a ligand is needed, it is provided endogenously by the cells or tissues in question and its identity is unknown.^[27]

Signaling pathway

Cytosolic complex

Non-ligand bound AhR is retained in the

TGF-β cytokines are members of a signaling protein family that includes activin, Nodal subfamily, bone morphogenetic proteins, growth and differentiation factors, and Müllerian inhibitor subfamily. TGF-β signaling plays an important role in cell physiology and development by inhibiting cell proliferation, promoting apoptosis, inducing differentiation, and determining developmental fate in vertebrates and invertebrates.[44] TGF-β activators include proteases such as plasmin, cathepsins, and calpains. Thrombospondin 1, a glycoprotein that inhibits angiogenesis, and matrix metalloproteinase 2 (MMP-2). The extracellular matrix itself appears to play an important regulatory role in TGF-β signaling.^[45][46]

Receptor activation

Upon ligand binding to AhR, AIP is released resulting in exposure of the NLS, which is located in the bHLH region,^[47] leading to import into the nucleus.^[48] It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.^{[40][49][50][51]} The activated AhR/ARNT heterodimer complex is then capable of either directly or indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.^[40][50][52]

DNA binding (xenobiotic response element – XRE)

The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5'-GCGTG-3'

The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the AhR signaling pathway.[74]^[75][76] The search for other metabolizing genes induced by AhR ligands, due to the presence of DREs, has led to the identification of an "AhR gene battery" of Phase I and Phase II metabolizing enzymes consisting of CYP1A1, CYP1A2, CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1.^[77] Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates AhR is able to bind and facilitate their biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.^[78]

AhR activation seems to be also important for immunological responses and inhibiting inflammation

Toxic response

Extensions of the adaptive response are the toxic responses elicited by AhR activation. Toxicity results from two different ways of AhR signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP), a ligand for AhR, induces its own metabolism and bioactivation to a toxic metabolite via the induction of CYP1A1 and CYP1B1 in several tissues.^[82] The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "AhR gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.^[83] Microarray analysis has proved most beneficial in understanding and characterizing this response.^{[64][84][85][86]}

Xenobiotic metabolizing enzymes help with the metabolic process by transforming and the excretion of chemicals. The most potent inducer of CYP1A1 is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, TCDD induces a broad spectrum of biochemical and toxic effects, such as teratogenesis, immunosuppression and tumor promotion. Most, if not all, of the effects caused by TCDD and other PAHs are known to be mediated by AhR which has a high binding affinity to TCDD.^[44]

Protein-protein interactions

In addition to the protein interactions mentioned above, AhR has also been shown to

References