AHR Ligands: Promiscuity in Binding and Diversity in Response

The AH Receptor in Biology and Toxicology

Volumn , Issue , 2011, Pages 63-79

  Degroot, Danica ^a   He, Guochun ^a   Fraccalvieri, Domenico ^b   Bonati, Laura ^b   Pandini, Allesandro ^c   Denison, Michael S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF MILANO BICOCCA   (Italy)

^c NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

Author keywords

AHR ligands, promiscuity; AHR, endogenous responses; Novel AHR agonists antagonists

Indexed keywords

EID: 84873838885     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118140574.ch4     Document Type: Chapter

References (164)

1. Poland, A. and Knutson, J. C. (1982). 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annual Review of Pharmacology and Toxicology, 22, 517-542.
2. Safe, S. (1990). Polychlorinated biphenyls (PCBs), dibenzo-pdioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Critical Review in Toxicology, 21, 51-88.
3. Hankinson, O. (1995). The aryl hydrocarbon receptor complex. Annual Review of Pharmacology and Toxicology, 35, 307-340.
4. Ma, Q. (2001). Induction of CYP1A1. The AhR/DRE paradigm: transcription, receptor regulation, and expanding biological roles. Current Drug Metabolism, 2, 149-164.
5. Kewley, R. J., Whitelaw, M. L., and Chapman-Smith, A. (2004). The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. International Journal of Biochemistry and Cell Biology, 36, 189-204.
6. Beischlag, T. V., Luis Morales, J., Hollingshead, B. D., and Perdew, G. H. (2008). The aryl hydrocarbon receptor complex and the control of gene expression. Critical Review in Eurkaryotic Gene Expression, 18, 207-250.
7. Bradshaw, T. D. and Bell, D. R. (2009). Relevance of the aryl hydrocarbon receptor (AhR) for clinical toxicology. Clinical Toxicology, 47, 632-642.
8. Furness, S. G. and Whelan, F. (2009). The pleiotropy of dioxin toxicity-xenobiotic misappropriation of the aryl hydrocarbon receptor's alternative physiological roles. Pharmacological Therapeutics, 124, 336-354.
9. McIntosh, B. E., Hogenesch, J. B., and Bradfield, C. A. (2010). Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annual Review of Physiology, 72, 625-645.
10. Chen, H.-S. and Perdew, G. H. (1994). Subunit composition of the heteromeric cytosolic aryl hydrocarbon receptor complex. Journal of Biological Chemistry, 269, 27554-27558.
11. Meyer, B. K., Pray-Grant, M. G., Vanden Heuvel, J. P., and Perdew, G. H. (1998). Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Molecular and Cellular Biology, 18, 978-988.
12. Kazlauskas, A., Poellinger, L., and Pongratz, I. (1999). Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (aryl hydrocarbon) receptor. Journal of Biological Chemistry, 274, 13519-13524.
13. Ikuta, T., Eguchi, H., Tachibana, T., Yoneda, Y., and Kawajiri, K. (1998). Nuclear localization and export signals of the human aryl hydrocarbon receptor. Journal of Biological Chemistry, 273, 2895-2904.
14. Soshilov, A. A. and Denison, M. S. (2008). Role of the Per/ Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor. Journal of Biological Chemistry, 283, 32995-33005.
15. Hord, N. G. and Perdew, G. H. (1994). Physiochemical and immunochemical analysis of aryl hydrocarbon receptor nuclear translocator: characterization of two monoclonal antibodies to the aryl hydrocarbon receptor nuclear translocator. Molecular Pharmacology, 46, 618-624.
16. Pollenz, R. S., Sattler, C. A., and Poland, A. (1994). The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. Molecular Pharmacology, 45, 428-438.
17. Denison, M. S., Fisher, J. M., and Whitlock, J. P., Jr. (1988). The DNA recognition site for the dioxin-Ah receptor complex: nucleotide sequence and functional analysis. Journal of Biological Chemistry, 263, 17721-17724.
18. Carlson, D. B. and Perdew, G. H. (2002). A dynamic role for the Ah receptor in cell signaling? Insights from a diverse group of Ah receptor interacting proteins. Journal of Biochemical and Molecular Toxicology, 16, 317-325.
19. Hankinson, O. (2005). Role of coactivators in transcriptional activation by the aryl hydrocarbon receptor. Archives of Biochemistry and Biophysics, 433, 379-386.
20. Poland, A., Glover, E., and Kende, A. S. (1976). Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-pdioxin by hepatic cytosol: evidence that the binding species is the receptor for induction of aryl hydrocarbon hydroxylase. Journal of Biological Chemistry, 251, 4936-4946.
21. Denison, M. S., Seidel, S. D., Rogers, W. J., Ziccardi, M., Winter, G. M., and Heath-Pagliuso, S. (1998). Natural and synthetic ligands for the Ah receptor. In Molecular Biology Approaches to Toxicology (Puga, A. andWallace, K. B.,Eds). Taylor & Francis, Philadelphia, pp. 393-410.
22. Denison, M. S. and Nagy, S. R. (2003). Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual Review of Pharmacology and Toxicology, 43, 309-334.
23. Nguyen, L. P. and Bradfield, C. A. (2008). The search for endogenous activators of the aryl hydrocarbon receptor. Chemical Research in Toxicology, 21, 102-106.
24. Seidel, S. D., Li, V.,Winter, G. M., Rogers,W. J., Martinez, E. I., and Denison, M. S. (2000). Ah receptor-based chemical screening bioassays: application and limitations for the detection of Ah receptor agonists. Toxicological Sciences, 55, 107-115.
25. Denison, M. S., Zhao, B., Baston, D. S., Clark, G. C., Murata, H.,and Han, D.-H. (2004). Recombinant cell bioassay systems for the detection and relative quantitation of halogenated dioxins and related chemicals. Talanta, 63, 1123-1133.
26. Nagy, S. R., Liu, G., Lam, K., and Denison, M. S. (2002). Identification of novel Ah receptor agonists using a highthroughput green fluorescent protein-based recombinant cell bioassay. Biochemistry, 41, 861-868.
27. Denison, M. S., Pandini, A., Nagy, S. R., Baldwin, E. P., and Bonati, L. (2002). Ligand binding and activation of the Ah receptor. Chemico-Biological Interactions, 141, 3-24.
28. Bonati, L., Fraschini, E., Lasagni, M., Modoni, E. P., and Pitea, D. (1995). A hypothesis on the mechanism of PCDD biological activity based on molecular electrostatic potential modeling. Part 2. Journal of Molecular Structure (Theochem), 340, 83-95.
29. Zhao, Y. Y., Tao, F. M., and Zeng, E. Y. (2008). Theoretical study of the quantitative structure-activity relationships for the toxicity of dibenzo-p-dioxins. Chemosphere, 73, 86-91.
30. Diao, J., Li, Y., Shi, S., Sun, Y., and Sun, Y. (2010). QSAR models for predicting toxicity of polychlorinated dibenzo-pdioxins and dibenzofurans using quantum chemical descriptors. Bulletin of Environmental Contamination and Toxicology, 85, 109-115.
31. Petko, P. I., Rowlands, J. C., Budinsky, R., Zhao, B., Denison, M. S., and Mekenyan, O. (2010). Mechanism based common reactivity pattern (COREPA) modeling of AhR binding affinity. SAR QSAR in Environmental Research, 21, 187-214.
32. Schladach, C. N., Riby, J., and Bjeldanes, L. F. (1999). Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry, 38, 7594-7600.
33. Seidel, S. D., Winters, G. M., Rogers, W. J., Ziccardi, M. H., Li, V., Keser, B., and Denison, M. S. (2001). Activation of the Ah receptor signaling pathway by prostaglandins. Journal of Biochemical and Molecular Toxicology, 15, 187-196.
34. Chiaro, C. R., Patel, R. D., and Perdew, G. H, (2008). 12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid [12(R)-HETE], an arachidonic acid derivative, is an activator of the aryl hydrocarbon receptor. Molecular Pharamacology, 74, 1649-1656.
35. Chiaro, C. R., Morales, J. L., Prabhu, K. S., and Perdew, G. H. (2008). Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. Biochemistry, 47, 8445-8455.
36. McMillan, B. J. and Bradfield, C. A. (2007). The aryl hydrocarbon receptor is activated by modified low-density lipoprotein. Proceedings of the National Academy of Sciences of the United States of America, 104, 1412-1417.
37. DiNatale, B. C., Murray, I. A., Schroeder, J. C., Flaveny, C. A., Lahoti, T. S., Laurenzana, E. M., Omiecinski, C. J., and Perdew, G. H. (2010). Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicological Sciences, 115, 89-97.
38. Mezrich, J. D., Fechnew, J. H., Zhang, X., Johnson, B. P., Burlingham,W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. Journal of Immunology, 185, 3190-3198.
39. Bjeldanes, L. F., Kim, J.-L., Grose, K. R, Bartholomew, J. C., and Bradfield, C. A. (1991). Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proceedings of the National Academy of Sciences of the United States of America, 88, 9543-9547.
40. Rannug, A., Rannug, U., Rosenkranz, H. S., Winqvist, L., Westerholm, R., Agurell, E, and Grafstrom, A.-K. (1987). Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. Journal of Biological Chemistry, 262, 15422-15427.
41. Knockaert, M., Blondel, M., Bach, S., Leost, M., Elbi, C., Hager, G. L., Nagy, S. R., Han, D., Denison, M., French, M., Ryan, X. P., Magiatis, P., Polychronopoulos, P., Greengard, P., Skaltsounis, L., and Meijer, L. (2004). Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins. Oncogene, 23, 4400-4412.
42. Backlund, M. and Ingelman-Sundberg, M. (2004). Different structural requirements of the ligand binding domain of the aryl hydrocarbon receptor for high-and low-affinity ligand binding and receptor activation. Molecular Pharmacology, 65, 416-425.
43. Goryo, K., Suzuki, A., Del Carpio, C. A., Siizaki, K., Kuriyama, E., Mikami, Y., Kinoshita, K., Yasumoto, K., Rannug, A., Miyamoto, A., Fujii-Kuriyama,Y., and Sogawa, K. (2007). Identification of amino aid residues in the Ah receptor involved in ligand binding. Biochemical Biophysical Research Communications, 354, 396-402.
44. Whelan, F., Hao, N., Furness, S. G., Whitelaw, M. L., and Chapman-Smith, A. (2010). Amino acid substitutions in the aryl hydrocarbon receptor (AhR) ligand binding domain reveal YH439 as a atypical AhR activator. Molecular Pharmacology, 77, 1037-1046.
45. Noy, N. (2007). Ligand specificity of nuclear hormone receptors: sifting through promiscuity. Biochemistry, 46, 13461-13467.
46. Ngan, C. H., Beglov, D., Rudnitskaya, A. N., Kozakov, D., Waxman, D. J., and Vajda, S. (2009). The structural basis of pregnane X receptor binding promiscuity. Biochemistry, 48, 11572-11581.
47. Carver, L. A., Jackiw, V., and Bradfield, C. A. (1994). The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system. Journal of Biological Chemistry, 269, 30109-30112.
48. Pongratz, I., Mason, G. G. F., and Poellinger, L. (1992). Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Journal of Biological Chemistry, 267, 13728-13734.
49. Petrulius, J. R., Hord, N. G., and Perdew, G. H. (2000). Subcellular location of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2. Journal of Biological Chemistry, 275, 37448-37453.
50. LaPres, J. J., Glover, E., Dunham, E. E., Bunger, M. K., and Bradfield, C. A. (2000). ARA9 modifies agonist signaling through an increase in cytosolic aryl hydrocarbon receptor. Journal of Biological Chemistry, 275, 6153-6159.
51. McGuire, J., Okamoto, K., Whitelaw, M. L., Tanaka, H., and Poellinger, L. (2001). Definition of a dioxin receptor mutant that is a constitutive activator of transcription: delineation of overlapping repression and ligand binding functions within the PAS domain. Journal of Biological Chemistry, 276, 41841-41849.
52. Coumailleau, P., Poellinger, L., Gustafsson, J.-A., and Whitelaw, M. L. (1995). Definition of a minimal domain of the dioxin receptor that is associated with hsp90 and maintains wild type ligand binding affinity and specificity. Journal of Biological Chemistry, 270, 25291-25300.
53. Ema, M., Ohe, N., Suzuki, M., Mimura, J., Sogawa, K., Ikawa, S., and Fujii-Kuriyama,Y. (1994). Dioxin binding activities of polymorphic forms of mouse and human aryl hydrocarbon receptors. Journal of Biological Chemistry, 269, 27337-27343.
54. Poland, A., Palen, D., and Glover, E. (1994). Analysis of the four alleles of the murine aryl hydrocarbon receptor. Molecular Pharmacology, 46, 915-921.
55. Rowlands, J. C. and Gustafsson, J.-A. (1997). Aryl hydrocarbon receptor-mediated signal transduction. Critical Reviews in Toxicology, 27, 109-134.
56. Borgstahl, G. E., Williams, D. R., and Getzoff, E. D. (1995). 1.4Å structure of photoactive yellow protein, a cytosolic photoreceptor: unusual fold, active site, and chromophore. Biochemistry, 34, 6278-6287.
57. Dux, P., Rubinstenn, G.,Vuister,G.W., Boelens, R., Mulder, F. A., Hard, K., Hoff, W. D., Kroon, A. R., Crielaard, W., Hellingwerf, K. J., and Kaptein, R. (1998). Solution structure and backbone dynamics of the photoactive yellow protein. Biochemistry, 37, 12689-12699.
58. Cabral, J. H. M., Lee, A., Cohen, S. L., Chait, B. T., Li, M., and Mackinnon, R. (1998). Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell, 95, 649-655.
59. Gong, W., Hao, B., Mansy, S. S., Gonzalez, G., Gilles-Gonzalez, M. A., and Chan, M. K. (1998). Structure of a biological oxygen sensor: a new mechanism for hemedriven signal transduction. Proceedings of the National Academy of Sciences of the United States of America, 95, 15177-15182.
60. Procopio, M., Lahm, A., Tramontano, A., Bonati, L., and Pitea, D. (2002). A model for recognition of polychlorinated dibenzo-p-dioxins by the aryl hydrocarbon receptor. European Journal of Biochemistry, 269, 13-18.
61. Murray, I. A., Reen, R. K., Leathery, N., Ramadoss, P., Bonati, L., Gonzalez, F. J., Peters, J. M., and Perdew, G. H. (2005). Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. Archives of Biochemistry and Biophysics, 442, 59-71.
62. Crosson, S. and Moffat, K. (2001). Structure of a flavinbinding plant photoreceptor domain: insights into light-mediated signal transduction. Proceedings of the National Academy of Sciences of the United States of America, 98, 2995-3000.
63. Amezcua, C., Harper, S., Rutter, J., and Gardner, K. (2002). Structure and interactions of PAS kinase N-terminal PAS domain: model for intramolecular kinase regulation. Structure, 10, 1349-1361.
64. Erbel, P. J., Card, P. B., Karakuzu, O., Bruick, R. K., and Gardner, K. H. (2003). Structural basis for PAS domain heterodimerization in the basic helix-loop-helix/PAS transcription factor hypoxia-inducible factor. Proceedings of the National Academy of Sciences of the United States of America, 100, 15504-15509.
65. Razeto, A., Ramakrishnan, V., Litterst, C. M., Giller, K., Griesinger, C., Carlomagno, T., Lakomek, N., Heimburg, T., Lodrini, M., Pfitzner, E., and Becker, S. (2004). Structure of the NCoA-1/Src-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. Journal of Molecular Biology, 336, 319-329.
66. Yildiz, O., Doi, M., Yujnovsky, I., Cardone, L., Berndt, A., Hennig, S., Schulze, S., Urbanke, C., Sassone-Corsi, P., and Wolf, E. (2005). Crystal structure and interactions of the PAS repeat region of the Drosophila clock protein PERIOD. Molecular Cell, 17, 69-82.
67. Card, P. B., Erbel, P. J., and Gardner, K. H. (2005). Structural basis of ARNT PAS-B dimerization: use of a common betasheet interface for hetero-and homodimerization. Journal of Molecular Biology, 353, 664-678.
68. Erbel, P. J., Card, P. B., Karakuzu, O., Bruick, R. K., and Gardner, K. H. (2003). Structural basis for PAS domain heterodimerization in the basic helix-loop-helix-PAS transcription factor hypoxia-inducible factor. Proceedings of the National Academy of Sciences of the United States of America, 100, 15504-15509.
69. Kewley, R. J., Whitelaw, M. L., and Chapman-Smith, A. (2004). The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. International Journal of Biochemistry and Cellular Biology, 36, 189-204.
70. Pandini, A., Denison, M. S., Song, Y., Soshilov, A., and Bonati, L. (2007). Structural and functional characterization of the AhR ligand binding domain by homology modeling and mutational analysis. Biochemistry, 23, 696-708.
71. Pandini, A., Soshilov, A. A., Song,Y., Zhao, J., Bonati, L., and Denison, M. S. (2009). Detection of the TCDD binding fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis. Biochemistry, 48, 5972-5983.
72. Bisson, W. H., Koch, D. C., O'Donnell, E. F., Khalil, S. M., Kerkvliet, N. I., Tanguay, R. L., Abagyan, R., and Kolluri, S. K. (2009). Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands. Journal of Medicinal Chemistry, 52, 5635-5641.
73. Murray, I. A., Flaveny, C. A., Chiaro, C. R., Sharma, A. K., Tanos, R. S., Schroeder, J. C., Amin, S. G., Bisson, W. H., Kolluri, S. K., and Perdew, G. H. (2010). Suppression of cytokine-mediatedcomplement factor gene expression through selective activation of the Ah receptor with 30,40-dimethoxya-naphthoflavone. Molecular Pharmacology, 79, 508-519.
74. Wu, B., Zhang, Y., Kong, J., Zhang, X., and Cheng, S. (2009). In silico prediction of nuclear hormone receptors for organic pollutants by homology modeling and molecular docking. Toxicology Letters, 191, 69-73.
75. Olivero-Verbel, J., Cabaras-Montalvo, M., and Ortega-Uniga, C. (2010). Theoretical targets for TCDD: a bioinformatical approach. Chemosphere, 80, 1160-1166.
76. Jogalekar, A. S., Reiling, S., and Vaz, R. J. (2010). Identification of optimum computational protocols for modeling the aryl hydrocarbon receptor (AHR) and its interaction with ligands. Bioorganic and Medicinal Chemistry Letters, 20, 6616-6619.
77. Yoshikawa, E., Miyagi, S., Dedachi, K., Ishihara-Sugano, M., Itoh, S., and Kurita, N. (2010). Specific interactions between aryl hydrocarbon receptor and dioxin congeners: ab initio fragment molecular orbital calculations. Journal of Molecular Graphics and Modelling, 29, 197-205.
78. Bohonowych, J. E. and Denison, M. S. (2007). Persistent binding of ligands to the aryl hydrocarbon receptor. Toxicological Sciences, 98, 99-110.
79. Pertrulis, J. R. and Bunce, N. J. (2000). Competitive behavior in the interactive toxicology of halogenated aromatic compounds. Journal of Biochemical Toxicology, 14, 73-81.
80. Henry, E. C. and Gasiewicz, T. A. (1993). Transformation of the aryl hydrocarbon receptor to a DNA-binding form is accompanied by release of the 90 kDa heat-shock protein and increased affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemical Journal, 294, 95-101.
81. Denison, M. S. and Wilkinson, C. F. (1985). Identification of the Ah receptor in selected mammalian species and its role in the induction of aryl hydrocarbon hydroxylase. European Journal of Biochemistry, 147, 429-435.
82. Denison, M. S.,Vella, L. M., and Okey,A. B. (1986). Structure and function of the Ah receptor for 2,3,7,8-tetrachlorodibenzop-dioxin: species differences in molecular properties of the receptor from mouse and rat hepatic cytosol. Journal of Biological Chemistry, 261, 3987-3995.
83. Aarts, J. M. M. J. G., Denison, M. S., Cox, M. A., Schalk, M. A. C., Garrison, P. M., Tullis, K., de Haan, L. H. J., and Brouwer, A. (1996). Species-specific antagonism of Ah receptor action by 2,20,5,50-tetrachloro-and 2,20,3,30,4,40-hexachlorobiphenyl. European Journal of Pharamcology, 293, 463-474.
84. Kikuchi, H., Kato, H., Mizuno, M., Hossain, A., Ikawa, S., Miyazaki, J., and Watanabe, M. (1996). Differences in inducibility of CYP1A1-mRNA by benzimidazole compounds between human and mouse cells: evidences of a humanspecific signal transduction pathway for CYP1A1 induction. Archives of Biochemistry and Biophysics, 334, 235-240.
85. Shih, H., Pickwell, G. V., Guenette, D. K., Bilir, B., and Quattrochi, L. C. (1999). Species differences in hepatocyte induction of CYP1A1 and CYP1A2 by omeprazole. Human and Experimental Toxicology, 18, 95-105.
86. Sadar, M. D., Ash, R. Sundqvist, J., Olsson, P. E., and Andersson, T. B. (1996). Phenobarbital induction of CYP1A1 gene expression in a primary culture of rainbow trout hepatocytes. Journal of Biological Chemistry, 271, 17635-17643.
87. Sadar,M. D.,Westlind, A., Blomstrand, F., and Andersson, T. B. (1996). Induction of CYP1A1 by GABA receptor ligands. Biochemical and Biophysical Research Communications, 229, 231-237.
88. Abnet, C. C., Tanguay, R. L., Heideman,W., and Peterson, R. E. (1999). Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells: greater insight into species differences in toxic potency of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners. Toxicology and Applied Pharmacology, 159, 41-51.
89. Zhou, J.-G., Henry, E. C., Palermo, C. M., Dertinger, S. D., and Gasiewicz, T. A. (2003). Species-specific transcriptional activity of synthetic flavonoids in guinea pig and mouse cells as a result of differential activation of the aryl hydrocarbon receptor to interact with dioxin-responsive elements. Molecular Pharmacology, 63, 915-924.
90. Zhao, B., Degroot, D., Hayashi, A., He, G., and Denison, M. S. (2010). CH223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. Toxicological Sciences, 117, 393-340.
91. Henry, E. C. and Gasiewicz, T. A. (2008). Molecular determinants of species-specific agonist and antagonist activity of a substituted flavone towards the aryl hydrocarbon receptor. Archives of Biochemistry and Biophysics, 472, 77-88.
92. Karchner, S. I., Franks, D. G.,Kennedy, S.W., and Hahn, M. E. (2006). The molecular basis for differential dioxin sensitivity in birds: role of the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences of the United States of America, 103, 6252-6257.
93. Okey,A. B., Boutros, P. C., Harper, and P. A. (2005). Polymorphisms of human nuclear receptors that control expression of drug-metabolizing enzymes. Pharmacogenetics and Genomics, 15, 371-379.
94. Ema, M., Ohe, N., Suzuki, M., Mimura, J., Sogawa, K., Ikawa, S., and Fujii-Kuriyama, Y. (1994). Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. Journal of Biological Chemistry, 269, 27337-27343.
95. Ramadoss, P. and Perdew, G. H. (2004). Use of 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin as a probe to determine the relative ligand affinity of human versus mouse aryl hydrocarbon receptor in cultured cells. Molecular Pharmcacology, 66, 129-136.
96. Flaveny, C. A., Murray, I. A., Chiaro, C. R., and Perdew, G. H. (2009). Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice. Molecular Pharmacology, 75, 1412-1420.
97. Jeyakumar, M., Carlson, K.E., Gunther, J.R., Katzenellenbogen, J.A. (2011). Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. Journal of Biological Chemistry, 286, 12971-12982.
98. Ellmann, S., Sticht, H., Thiel, F., Beckmann, M. W., Strick, R., and Strissel, P. L. (2009). Estrogen and progesterone receptors: from molecular structures to clinical targets. Cell and Molecular Life Sciences, 66, 2405-2426.
99. De Bosscher, K. (2010). Selective glucocorticoid receptor modulators. Journal of Steroid Biochemistry and Molecular Biology, 120, 96-104.
100. Norris, J. D., Joseph, J. D., Sherk, A. B., Juzumiene, D., Turnbull, P. S., Rafferty, S.W., Cui, H., Anderson, E., Fan, D., Dye, D. A., Deng, X., Kazmin, D., Chang, C. Y., Willson, T. M., and McDonnell, D. P. (2009). Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands. Chemical Biology, 16, 452-460.
101. Murray, I. A., Krishnegowda, G., DiNatale, B. C., Flaveny, C., Chiaro, C., Lin, J. M., Sharma, A. K., Amin, S., and Perdew, G. H. (2010). Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits antiinflammatory properties. Chemical Research in Toxicology, 23, 955-966.
102. Murray, I. A., Morales, J. L., Flaveny, C. A., Dinatale, B. C., Chiaro, C., Gowdahalli, K., Amin, S., and Perdew, G. H. (2010). Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Molecular Pharmacology, 77, 247-254.
103. Zhang, S., Rowlands, C., and Safe, S. (2008). Ligand-dependent interactions of the Ah receptor with coactivators in a mammalian two-hybrid assay. Toxicology and Applied Pharmacology, 227, 196-206.
104. Zhang, S., Lei, P., Liu, X., Li, X., Walker, K., Kotha, L., Rowlands, C., and Safe, S. (2009). The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocrine-Related Cancer, 16, 835-844.
105. Henry, E. C. and Gasiewicz, T. A. (2003). Agonist but not antagonist ligands induce conformational change in the mouse aryl hydrocarbon receptor as detected by partial proteolysis. Molecular Pharmacology, 63, 392-400.
106. Kronenberg, S., Esser, C., and Carlberg, C. (2000). An aryl hydrocarbon receptor conformation acts as the functional core of nuclear dioxin signaling. Nucleic Acids Research, 28, 2286-2291.
107. Gerbal-Chaloin, S., Pichard-Garcia, L., Fabre, J.M., Sa-Cunha, A., Poellinger, L.,Maurel, P., andDaujat-Chavanieu, M. (2006). Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide. Cell Signalling, 18, 740-750.
108. Lees, M. J. and Whitelaw, M. L. (1999). Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt. Molecular and Cellular Biology, 19, 5811-5822.
109. Fretland, A. J., Safe, S., and Hankinson, O. (2004). Lack of antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin's (TCDDs) induction of cytochrome P4501A1 (CYP1A1) by the putative selective aryl hydrocarbon receptor modulator 6-alkyl-1,3,8-trichlorodibenzofuran (6-MCDF) in the mouse hepatoma cell line Hepa-1c1c7. Chemico-Biological Interactions, 150, 161-170.
110. Hestermann, E. V. and Brown, M. (2003). Agonist and chemopreventative ligands induce differential transcriptional cofactor recruitment by aryl hydrocarbon receptor. Molecular and Cellular Biology, 23, 7920-7925.
111. Boronat, S., Casado, S., Navas, J. M., and Pina, B. (2007). Modulation of aryl hydrocarbon receptor transactivation by carbaryl, a nonconventional ligand. FEBS Journal, 274, 3327-3339.
112. Wihlen, B., Ahmed, S., Inzunza, J., and Matthews, J. (2009). Estrogen receptor subtype-and promoter-specific modulation of aryl hydrocarbon receptor-dependent transcription. Molecular Cancer Research, 7, 977-986.
113. Matthews, J., Wihlen, B., Thomsen, J., and Gustafsson, J. A. (2005). Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters. Molecular and Cellular Biology, 25, 5317-5328.
114. Wang,S.,Ge,K.,Roeder,R.G., andHankinson,O. (2004).Role ofmediator in transcriptional activation by the aryl hydrocarbon receptor. Journal of Biological Chemistry, 279, 13593-13600.
115. Pansoy, A., Ahmed, S., Valen, E., Sandelin, A., and Matthews, J. (2010). 3-Methylcholanthrene induces differential recruitment of aryl hydrocarbon receptor to human promoters. Toxicological Sciences, 117, 90-100.
116. Yao, E. F. and Denison, M. S. (1992). DNA sequence determinants for binding of transformed Ah receptor to a dioxinresponsive enhancer. Biochemistry, 31, 5060-5067.
117. Lusska, A., Shen, E., and Whitlock, J. P., Jr. (1993). Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor. Journal of Biological Chemistry, 268, 6575-6580.
118. Bank, P. A., Yao, E. F., Phelps, C. L., Harper, P. A., and Denison, M. S. (1992). Species-specific binding of transformed Ah receptor to a dioxin responsive transcriptional enhancer. European Journal of Pharmacology, 228, 85-94.
119. Matikainen, T., Perez, G. I., Jurisicova, A., Pru, J. K., Schlezinger, J. J., Ryu, H. Y., Laine, J., Sakai, T., Korsmeyer, S. J., Casper, R. F., Sherr, D. H., and Tilly, J. L. (2001). Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nature Genetics, 28, 355-360.
120. Gouédard, C., Barouki, R., and Morel, Y. (2004). Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism. Molecular and Cellular Biology, 24, 5209-5222.
121. Gruber, C. J., Gruber, D M., Gruber, I. M., Wieser, F., and Huber, J. C. (2004). Anatomy of the estrogen response element. Trends in Endocrinology and Metabolism, 15, 73-78.
122. Mason, C. E., Shu, F. J.,Wang, C., Session, R. M., Kallen, R. G., Sidell, N.,Yu, T., Liu, M. H., Cheung, E., and Kallen, C. B. (2010). Location analysis for the estrogen receptor-alpha reveals binding to diverse ERE sequences and widespread binding within repetitive DNA elements. Nucleic Acids Research, 38, 2355-2368.
123. DuSell, C. D., Nelson, E. R., Wittmann, B. M., Fretz, J. A., Kazmin, D., Thomas, R. S., Pike, J.W., and McDonnell, D. P. (2010). Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Molecular Endocrinology, 24, 33-46.
124. Safe, S. (2010). 3-Methylcholanthrene induces differential recruitment of aryl hydrocarbon receptor to human promoters. Toxicological Sciences, 117, 1-3.
125. Chen, I., McDougal, A., Wang, F., and Safe, S. (1998). Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis, 19, 1631-1639.
126. McDougal, A., Wilson, C., and Safe, S. (1997). Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists. Cancer Letters, 120, 53-63.
127. Okino, S. T., Pookot, D., Basak, S., and Dahiya, R. (2009). Toxic and chemopreventive ligands preferentially activate distinct aryl hydrocarbon receptor pathways: implications for cancer prevention. Cancer Prevention Research, 2, 251-256.
128. Piskorska-Pliszczynska, J., Astroff, B., Zacharewski, T., Harris, M., Rosengren, R., Morrison, V., Safe, L., and Safe, S. (1991). Mechanism of action of 2,3,7,8-tetrachlorodibenzo-pdioxin antagonists: characterization of 6-[125I]methyl-8-iodo-1,3-dichlorodibenzofuran-Ah receptor complexes. Archives of Biochemistry and Biophysics, 284, 193-200.
129. Lawrence, B. P., Denison, M. S., Novak, H., Vorderstrasse, B. A., Harrer, N., Neruda, W., Reichel, C., and Woisetschläger, M. (2008). Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. Blood, 112, 1158-1165.
130. Peng, T. L., Chen, J., Mao, W., Liu. X., Tao, Y., Chen, L. Z., and Chen, M. H. (2009). Potential therapeutic significance of increased expression of aryl hydrocarbon receptor in human gastric cancer. World Journal of Gastroenterology, 15, 1719-1729.
131. Casado, F. L., Singh, K. P., and Gasiewicz, T. A. (2010). The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. Blood Cells and Molecular Disease, 44, 199-206.
132. Esser, C. and Krutmann, J. (2010). UV irradiation and skin pigmentation. Aryl hydrocarbon receptor-"new kid on the block". Hautarzt, 61, 561-566.
133. Hall, J., Barhoover, M. A., Kazmin, D., McDonnell, D. P., Greenlee, W. F., and Thomas, R. S. (2010). Activation of the aryl hydrocarbon receptor inhibits invasive and metastatic feature of human breast cancer cells and promotes breast cancer cell differentiation. Molecular Endocrinology, 24, 359-369.
134. Marshall, N. B. and Kerkvliet, N. I. (2010). Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells. Annals of the New York Academy of Sciences, 1183, 25-37.
135. Behnisch, P. A., Hosoe, K., and Sakai, S.-I. (2003). Brominated dioxin-like compounds: in vitro assessment in comparison to classical dioxin-like compounds and other polyaromatic compounds. Environment International, 29, 861-877.
136. Gillner, M., Bergman, J., Cambillau, C., Alexandersson, M., Fernstrom, B., and Gustafsson, J.-A. (1993). Interactions of indolo[3,2-b]carbazoles and related polycyclic aromatic hydrocarbons with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver. Molecular Pharmacology, 44, 336-345.
137. Bunce, N. J., Landers, J. P., Schneider, U. A., Safe, S. H., and Zacharewski, T. R. (1989). Chlorinated trans stilbenes: competitive binding to theAh receptor, induction of cytochrome P-450 monooxygenase activity and partial 2,3,7,8-TCDD antagonism. Toxicology and Environmental Chemistry, 28, 217-229.
138. Adachi, J., Mori, Y., Matsui, S., Takigami, H., Fujino, J., Kitagawa, H., Miller, C. A., 3rd, Kato, T., Saeki, K., and Matsuda, T. (2001). Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. Journal of Biological Chemistry, 276, 31475-31478.
139. Gillner, M., Bergman, J., Cambillau, C., and Gustafsson, J.-A. (1989). Interactions of rutaecarpine alkaloids with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver. Carcinogenesis, 10, 651-654.
140. Gasiewicz, T. A., Kende, A. S., Rucci, G., Whitney, B., and Willey, J. J. (1996). Analysis of structural requirements for Ah receptor antagonist activity: ellipticines, flavones, and related compounds. Biochemical Pharmacology, 52, 1787-1803.
141. Heath-Pagliuso, S., Rogers, W. J., Tullis, K., Seidel, S. D., Cenijn, P. H., Brouwer, A., and Denison, M. S. (1998). Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry, 37, 11508-11515.
142. Schroeder, J. C., Dinatale, B. C., Murray, I. A., Flaveny, C. A., Liu, Q., Laurenzana, E. M., Lin, J. M., Strom, S. C., Omiecinski, C. J., Amin, S., and Perdew, G. H. (2010). The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry, 49, 393-400.
143. Lu, Y.-F., Santostefano, M., Cunningham, B. D. M., Threadgill, M. D., and Safe, S. (1996). Substituted flavones as aryl hydrocarbon (Ah) receptor agonists and antagonists. Biochemical Pharmacology, 51, 1077-1087.
144. Kobayashi,Y., Matsuura,Y.,Kotani, E., Fukuda,T.,Aoyagi,T., Tobinaga, S., Yoshida, T., and Kuroiwa, Y. (1993). Structural requirements of the induction of hepatic microsomal cytochrome P450 by imidazole-and pyridine-containing compounds in rats. Journal of Biochemistry, 114, 697-701.
145. Phelan, D., Winter, G. M., Rogers, W. J., Lam, J. C., and Denison, M. S. (1998). Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Archives of Biochemistry and Biophysics, 357, 155-163.
146. Cheung, Y.-L., Snelling, J., Mohammed, N. N. D., Gray, T. J. B., and Ioannides, C. (1996). Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: implications for their carcinogenicity. Toxicology and Applied Pharmacology, 139, 203-211.
147. Lee, I. J., Jeong, K. S., Roberts, B. J., Kallarakal, A. T., Fernandez-Salguero, P., Gonzalez, F. J., and Song, B. J. (1996). Transcriptional induction of the cytochrome P4501A1 gene by a thiazolium compound, YH439. Molecular Pharmacology, 49, 980-988.
148. Denison, M. S., Phelan, D.,Winter,M. G., and Ziccardi, M. H. (1998). Carbaryl, a carbamate insecticide, is a ligand for the hepatic Ah (dioxin) receptor. Toxicology and Applied Pharmacology, 152, 406-414.
149. Merchant, M., Morrison, V., Santostefano, M., and Safe, S. (1992). Mechanism of action of aryl hydrocarbon receptor antagonists: inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin induced CYP1A1 gene expression. Archives of Biochemistry and Biophysics, 298, 389-394.
150. Gasiewicz, T. A. and Rucci, G. (1991). Alpha-naphthoflavone acts as an antagonist of 2,3,7,8-tetrachlorodibenzo-p-dioxin by forming an inactive complex with the Ah receptor. Molecular Pharmacology, 40, 607-612.
151. Lee, J. E. and Safe, S. (2000). 30,40-Dimethoxyflavone as an aryl hydrocarbon receptor antagonist in human breast cancer cells. Toxicological Sciences, 58, 235-242.
152. Zhang, S., Qin, C., and Safe, S. H. (2003). Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environmental Health Perspectives, 111, 1877-1882.
153. Ashida, H. (2000). Suppressive effects of flavonoids on dioxin toxicity. Biofactors, 12, 201-206.
154. Hamada, M., Satsu, H., Natsume, Y., Nishiumi, S., Fukuda, I., Ashida, H., and Shimizu, M. (2006). TCDD-induced CYP1A1 expression, an index of dioxin toxicity, is suppressed by flavonoids permeating the human intestinalCaco-2 cell monolayers. Journal of Agriculture and Food Chemistry, 54, 8891-8898.
155. Shibazaki, M., Takeuchi, T., Ahmed, S., and Kikuchia, H. (2004). Blockage by SB203580 of Cyp1a1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the possible mechanism: possible involvement of the p38 mitogen-activated protein kinase pathway in shuttling of Ah receptor overexpressed in COS-7 cells. Annals of the New York Academy of Sciences, 1030, 275-281.
156. Chen, I., McDougal, A., Wang, F., and Safe, S. (1998). Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis, 19, 1631-1639.
157. Fernandez, N., Roy, M., and Lesca, P. (1988). Binding characteristics of Ah receptors from rats and mice before and after separation from hepatic cytosols. 7-Hydroxyellipticine as a competitive antagonist of cytochrome P450 induction. European Journal of Biochemistry, 172, 585-589.
158. Joiakim, A., Mathieu, P. A., Palermo, C., Gasiewicz, T. A., and Reiners, J. J., Jr. (2003). The jun N-terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metabolism and Disposition, 31, 1279-1282.
159. Williams, S. N., Shih, S., Guenette, D. K., Brackney, W., Denison, M. S., Pickwell, G. V., and Quattrochi, L. C. (2000). Green tea flavonoids inhibit TCDD-induced CYP1A1 and CYP1A2 gene expression in human livers cells. Chemico-Biological Interactions, 28, 211-219.
160. Kim, S. H., Henry, E. C., Kim, D. K., Kim, Y. H., Shin, K. J., Han, M. S., Lee, T. G., Kang, J. K., Gasiewicz, T. A., Ryu, S. H., and Suh, P. G. (2006). Novel compound 2-methyl-2Hpyrazole-3-carboxylic acid (2-methyl-4-4-o-tolylazo-phenyl) amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Molecular Pharmacology, 69, 1871-1878.
161. Savouret, J. F., Antenos, M., Quesne, M., Xu, J., Milgrom, E., and Casper, R. F. (2001). 7-Ketocholesterol is an endogenous modulator for the aryl hydrocarbon receptor. Journal of Biological Chemistry, 276, 3054-3059.
162. Ledirac, N., Delescluse, C., Lesca, P., Piechocki, M. P., Hines, R. N., de Sousa, G., Pralavorio, M., and Rahmani, R. (2000). Diflubenzuron, a benoyl-urea insecticide, is a potent inhibitor of TCDF-induced CYP1A1 expression in HepG2 cells. Toxicology and Applied Pharmacology, 164, 273-279.
163. Casper, R. F., Quesne, M., Rogers, I. M., Shirota, T., Jolivet, A., Milgrom, E., and Savouret, J. F. (1999). Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Molecular Pharmacology, 56, 784-790.
164. Boitano, A. E.,Wang, J., Romeo, R., Bouchez, L. C., Parker, A. E., Sutton, S. E.,Walker, J. R., Flaveny, C. A., Perdew, G. H., Denison,M. S., Schultz, P. G., and Cooke,M. P. (2010). Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science, 329, 1345-1348.