Structural and Functional Diversification of AHRs during Metazoan Evolution

Hahn, Mark E.; Karchner, Sibel I.

doi:10.1002/9781118140574.ch27

Cited by 10 publications

(13 citation statements)

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“…Commonly studied mammals like mice and humans harbor only the AHR1 gene, having apparently lost AHR2, and knockout of the single AHR in mice abrogates toxicity of AHR agonists 11, 69–71 . However, surveys of recently completed genome projects suggest that AHR2 is retained in diverse mammalian species, including platypus, opossum, and cow 68 . The role of the corresponding gene products in xenobiotic toxicity, development, and physiology is not yet characterized.…”

Section: Discussionmentioning

confidence: 99%

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Shoots

Fraccalvieri

Franks

et al. 2015

Environ. Sci. Technol.

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Structural features of the aryl hydrocarbon receptor (AHR) can underlie species- and population-specific differences in its affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These differences often explain variations in TCDD toxicity. Frogs are relatively insensitive to dioxin, and Xenopus AHRs bind TCDD with low affinity. Weak TCDD binding results from the combination of three residues in the ligand-binding domain: A354 and A370, and N325. Here we sought to determine whether this mechanism of weak TCDD binding is shared by other amphibian AHRs. We isolated an AHR cDNA from the Mexican axolotl (Ambystoma mexicanum). The encoded polypeptide contains identical residues at positions that confer low TCDD affinity to X. laevis AHRs (A364, A380, and N335), and homology modeling predicts they protrude into the binding cavity. Axolotl AHR bound one-tenth the TCDD of mouse AHR in velocity sedimentation analysis, and in transactivation assays, the EC50 for TCDD was 23 nM, similar to X. laevis AHR1β (27 nM) and greater than AHR containing the mouse ligand-binding domain (0.08 nM). Sequence, modeled structure, and function indicate that axolotl AHR binds TCDD weakly, predicting that A. mexicanum lacks sensitivity to TCDD toxicity. We hypothesize that this characteristic of axolotl and Xenopus AHRs arose in a common ancestor of the Caudata and Anura.

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Section: Discussionmentioning

confidence: 99%

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Shoots

Fraccalvieri

Franks

et al. 2015

Environ. Sci. Technol.

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“…Beyond the established model systems, a broader elucidation of the evolutionary history of the AHR, and of the bHLH-PAS (basic helix-loop-helix Per-Arnt-Sim) family to which it belongs, can provide a foundation for understanding shared and novel features of AHR biology, foster insight into toxic mechanisms, and support extrapolation and prediction of responses to chemicals among species [17,18]. To understand AHR evolution, we look at modern representatives of early-diverging groups.…”

Section: Introductionmentioning

confidence: 99%

Diversity as opportunity: Insights from 600 million years of AHR evolution

Hahn

Karchner

Merson

2017

Current Opinion in Toxicology

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111

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The aryl hydrocarbon receptor (AHR) was for many years of interest only to pharmacologists and toxicologists. However, this protein has fundamental roles in biology that are being revealed through studies in diverse animal species. The AHR is an ancient protein. AHR homologs exist in most major groups of modern bilaterian animals, including deuterostomes (chordates, hemichordates, echinoderms) and the two major clades of protostome invertebrates [ecdysozoans (e.g. arthropods and nematodes) and lophotrochozoans (e.g. molluscs and annelids)]. AHR homologs also have been identified in cnidarians such as the sea anemone Nematostella and in the genome of Trichoplax, a placozoan. Bilaterians, cnidarians, and placozoans form the clade Eumetazoa, whose last common ancestor lived approximately 600 million years ago (MYA). The presence of AHR homologs in modern representatives of all these groups indicates that the original eumetazoan animal possessed an AHR homolog. Studies in invertebrates and vertebrates reveal parallel functions of AHR in the development and function of sensory neural systems, suggesting that these may be ancestral roles. Vertebrate animals are characterized by the expansion and diversification of AHRs, via gene and genome duplications, from the ancestral protoAHR into at least five classes of AHR-like proteins: AHR, AHR1, AHR2, AHR3, and AHRR. The evolution of multiple AHRs in vertebrates coincided with the acquisition of high-affinity binding of halogenated and polynuclear aromatic hydrocarbons and the emergence of adaptive functions involving regulation of xenobiotic-metabolizing enzymes and roles in adaptive immunity. The existence of multiple AHRs may have facilitated subfunction partitioning and specialization of specific AHR types in some taxa. Additional research in diverse model and non-model species will continue to enrich our understanding of AHR and its pleiotropic roles in biology and toxicology.

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“…It regulates the activity of various genes in different cell types across all vertebrates, and is well known and extensively studied as the mediator of toxicity induced by a class of environmental contaminants called dioxins [polychlorinated dibe nzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCBs); reviewed, for example, in (Hahn andKarchner 2011, Mandal 2005)]. More recently, evidence about the importance of the AHR in numerous physiological phenomena has started to emerge, thus revealing its potential as a target for novel pharmacological therapies in several fields.…”

Section: Introductionmentioning

confidence: 99%

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Mahiout

Lindén

Esteban

et al. 2017

Toxicology and Applied Pharmacology

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The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

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Structural and Functional Diversification of AHRs during Metazoan Evolution

Cited by 10 publications

References 145 publications

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Diversity as opportunity: Insights from 600 million years of AHR evolution

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

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