Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice
Open accessAbstract
The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that displays interspecies differences with the human and mouse AHR C-terminal region sequences sharing only 58% amino acid sequence identity. Compared with the mouse AHR (mAHR), the human AHR (hAHR) displays approximately 10-fold lower relative affinity for prototypical AHR ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, which has been attributed to the amino acid residue valine 381 (alanine 375 in the mAHR) in the ligand binding domain of the hAHR. We investigated whether the 10-fold difference in ligand-binding affinity between the mAHR and hAHR would be observed with a diverse range of AHR ligands. To test this hypothesis, ligand binding assays were performed using the photo-affinity ligand 2-azido-3-[(125)I]iodo-7,8-dibromodibenzo-p-dioxin and liver cytosol isolated from hepatocyte-specific transgenic hAHR mice and C57BL/6J mice. It is noteworthy that competitive ligand-binding assays revealed that, compared with the mAHR, the hAHR has a higher relative affinity for certain compounds, including indirubin [(2Z)-2,3-biindole-2,3 (1'H,1'H)-dione and quercetin (2-(3,4dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one]. Electrophoretic mobility shift assays revealed that indirubin was more efficient at transforming the hAHR compared with the mAHR. Indirubin was also a more potent inducer of Cyp1a1 expression in transgenic hAHR mouse hepatocytes compared with C57BL/6J mouse hepatocytes. These observations suggest that indirubin is a potent hAHR ligand that is able to selectively bind to and activate the hAHR. These discoveries imply that there may be a significant degree of structural divergence between mAHR and hAHR ligands and highlights the importance of the hAHR transgenic mouse as a model to study the hAHR in vivo.
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Substantial differences among species in AHR ligand binding specificity, selectivity, and response have been observed, but the structural determinants behind them remain unknown.
“While significant interspecies differences in AHR ligand binding specificity, selectivity and response have been observed, the structural determinants responsible have not been determined and homology models of the AHR ligand-binding domain (LBD) are available for only a few species.”
From Comparative Analysis of Homology Models of the Ah Receptor Ligand Binding Domain: Verification of Structure–Function Predictions by Site-Directed Mutagenesis of a Nonfunctional Receptor (2013) · cites this paper as [26]
The ligand-binding results report different affinities and responses for human and mouse AHR. The Discussion says the residues critical to high-affinity human AHR binding of indirubin require further investigation, but the Abstract attributes the known human–mouse difference in TCDD affinity to Val381; the claim overstates how little is known about the structural determinants. (LLM, conf=0.88)
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- Authors
- Flaveny, C. A., Murray, I. A., Chiaro, C. R., & Perdew, G. H.
- Affiliations
- Pennsylvania State University (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 75
- Issue
- 6
- Pages
- 1412-1420
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC2684888
- OpenAlex
- W2136650702
- Cited by
- 124
- References
- 26
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 13 · 2017: 11 · 2016: 8 · 2015: 8 · 2014: 4 · 2013: 5 · 2012: 8
- FWCI
- 8.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dow Chemical Company
- National Institutes of Health (1c06rr014520-01a1, ES04869)
- National Institute of Environmental Health Sciences (ES04869)
- National Center for Research Resources (1C06-RR14520)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- aryl hydrocarbon receptor, ligand selectivity, ligand binding affinity, indirubin, quercetin, CYP1A1 expression, gene expression regulation, hepatocytes, 2,3,7,8-tetrachlorodibenzo-p-dioxin, species differences
- MeSH terms
- Animals, Benzimidazoles, Binding, Competitive, Chlorocebus aethiops, Dioxins, Gene Expression Regulation, Humans, Indoles, Iodine Radioisotopes, Ligands, Mice, Inbred C57BL, Mice, Transgenic, Quercetin, Radioligand Assay, Receptors, Aryl Hydrocarbon, Cytochrome P-450 CYP1A1, COS Cells, Photoaffinity Labels, Hepatocytes, Models, Animal, Mice, In Vitro Techniques
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