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. 2003 Dec;111(16):1877–1882. doi: 10.1289/ehp.6322

Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context.

Shu Zhang 1, Chunhua Qin 1, Stephen H Safe 1
PMCID: PMC1241760  PMID: 14644660

Abstract

Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon (Ah) receptor (AhR). In this study we investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin. We also investigated the AhR-dependent activities of cantharidin and emodin (in herbal extracts) in Ah-responsive MCF-7 human breast cells, HepG2 human liver cancer cells, and mouse Hepa-1 cells transiently or stably transfected with plasmids expressing a luciferase reporter gene linked to multiple copies of a consensus dioxin-responsive element. The AhR agonist activities of the compounds (1 and 10 micro M) were as high as 25% of the maximal response induced by 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and their potencies were dependent on cell context. Galangin, genistein, daidzein, and diosmin were active only in Hepa-1 cells, and cantharidin induced activity only in human HepG2 and MCF-7 cells. Western blot analysis confirmed that baicalein and emodin also induced CYP1A1 protein in the human cancer cell lines. The AhR antagonist activities of four compounds inactive as agonists in MCF-7 and HepG2 cells (kaempferol, quercetin, myricetin, and luteolin) were also investigated. Luteolin was an AhR antagonist in both cell lines, and the inhibitory effects of the other compound were dependent on cell context. These data suggest that dietary phytochemicals exhibit substantial cell context-dependent AhR agonist as well as antagonist activities. Moreover, because phytochemicals and other AhR-active compounds in food are present in the diet at relatively high concentrations, risk assessment of dietary toxic equivalents of TCDD and related compounds should also take into account AhR agonist/antagonist activities of phytochemicals.

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Selected References

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  1. Ahlborg U. G., Brouwer A., Fingerhut M. A., Jacobson J. L., Jacobson S. W., Kennedy S. W., Kettrup A. A., Koeman J. H., Poiger H., Rappe C. Impact of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls on human and environmental health, with special emphasis on application of the toxic equivalency factor concept. Eur J Pharmacol. 1992 Dec 1;228(4):179–199. doi: 10.1016/0926-6917(92)90029-c. [DOI] [PubMed] [Google Scholar]
  2. Ashida H., Fukuda I., Yamashita T., Kanazawa K. Flavones and flavonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin. FEBS Lett. 2000 Jul 7;476(3):213–217. doi: 10.1016/s0014-5793(00)01730-0. [DOI] [PubMed] [Google Scholar]
  3. Beischlag Timothy V., Wang Song, Rose David W., Torchia Joseph, Reisz-Porszasz Suzanne, Muhammad Khurshid, Nelson Walter E., Probst Markus R., Rosenfeld Michael G., Hankinson Oliver. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Mol Cell Biol. 2002 Jun;22(12):4319–4333. doi: 10.1128/MCB.22.12.4319-4333.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Biegel L., Harris M., Davis D., Rosengren R., Safe L., Safe S. 2,2',4,4',5,5'-hexachlorobiphenyl as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist in C57BL/6J mice. Toxicol Appl Pharmacol. 1989 Mar 1;97(3):561–571. doi: 10.1016/0041-008x(89)90261-5. [DOI] [PubMed] [Google Scholar]
  5. Birnbaum L. S., DeVito M. J. Use of toxic equivalency factors for risk assessment for dioxins and related compounds. Toxicology. 1995 Dec 28;105(2-3):391–401. doi: 10.1016/0300-483x(95)03237-a. [DOI] [PubMed] [Google Scholar]
  6. Bjeldanes L. F., Kim J. Y., Grose K. R., Bartholomew J. C., Bradfield C. A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9543–9547. doi: 10.1073/pnas.88.21.9543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Casper R. F., Quesne M., Rogers I. M., Shirota T., Jolivet A., Milgrom E., Savouret J. F. Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Mol Pharmacol. 1999 Oct;56(4):784–790. [PubMed] [Google Scholar]
  8. Chen I., Safe S., Bjeldanes L. Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem Pharmacol. 1996 Apr 26;51(8):1069–1076. doi: 10.1016/0006-2952(96)00060-3. [DOI] [PubMed] [Google Scholar]
  9. Chun Y. J., Ryu S. Y., Jeong T. C., Kim M. Y. Mechanism-based inhibition of human cytochrome P450 1A1 by rhapontigenin. Drug Metab Dispos. 2001 Apr;29(4 Pt 1):389–393. [PubMed] [Google Scholar]
  10. Ciolino H. P., Daschner P. J., Yeh G. C. Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res. 1998 Dec 15;58(24):5707–5712. [PubMed] [Google Scholar]
  11. Ciolino H. P., Wang T. T., Yeh G. C. Diosmin and diosmetin are agonists of the aryl hydrocarbon receptor that differentially affect cytochrome P450 1A1 activity. Cancer Res. 1998 Jul 1;58(13):2754–2760. [PubMed] [Google Scholar]
  12. Ciolino H. P., Yeh G. C. Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol. Mol Pharmacol. 1999 Oct;56(4):760–767. [PubMed] [Google Scholar]
  13. Davarinos N. A., Pollenz R. S. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. J Biol Chem. 1999 Oct 1;274(40):28708–28715. doi: 10.1074/jbc.274.40.28708. [DOI] [PubMed] [Google Scholar]
  14. Davis D., Safe S. Immunosuppressive activities of polychlorinated dibenzofuran congeners: quantitative structure-activity relationships and interactive effects. Toxicol Appl Pharmacol. 1988 Jun 15;94(1):141–149. doi: 10.1016/0041-008x(88)90344-4. [DOI] [PubMed] [Google Scholar]
  15. Dzeletovic S., Breuer O., Lund E., Diczfalusy U. Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem. 1995 Feb 10;225(1):73–80. doi: 10.1006/abio.1995.1110. [DOI] [PubMed] [Google Scholar]
  16. Ema M., Ohe N., Suzuki M., Mimura J., Sogawa K., Ikawa S., Fujii-Kuriyama Y. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J Biol Chem. 1994 Nov 4;269(44):27337–27343. [PubMed] [Google Scholar]
  17. Garrison P. M., Tullis K., Aarts J. M., Brouwer A., Giesy J. P., Denison M. S. Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals. Fundam Appl Toxicol. 1996 Apr;30(2):194–203. doi: 10.1006/faat.1996.0056. [DOI] [PubMed] [Google Scholar]
  18. Gasiewicz T. A., Kende A. S., Rucci G., Whitney B., Willey J. J. Analysis of structural requirements for Ah receptor antagonist activity: ellipticines, flavones, and related compounds. Biochem Pharmacol. 1996 Dec 13;52(11):1787–1803. doi: 10.1016/s0006-2952(96)00600-4. [DOI] [PubMed] [Google Scholar]
  19. Gradelet S., Astorg P., Pineau T., Canivenc M. C., Siess M. H., Leclerc J., Lesca P. Ah receptor-dependent CYP1A induction by two carotenoids, canthaxanthin and beta-apo-8'-carotenal, with no affinity for the TCDD binding site. Biochem Pharmacol. 1997 Jul 15;54(2):307–315. doi: 10.1016/s0006-2952(97)00176-7. [DOI] [PubMed] [Google Scholar]
  20. Jeong H. G., Lee S. S. Suppressive effects of estradiol on 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated transcriptional activation of murine Cyp1a-1 in mouse hepatoma Hepa 1c1c7 cells. Cancer Lett. 1998 Nov 27;133(2):177–184. doi: 10.1016/s0304-3835(98)00224-9. [DOI] [PubMed] [Google Scholar]
  21. Kumar M. B., Tarpey R. W., Perdew G. H. Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs. J Biol Chem. 1999 Aug 6;274(32):22155–22164. doi: 10.1074/jbc.274.32.22155. [DOI] [PubMed] [Google Scholar]
  22. Ma Q., Baldwin K. T. 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway. Role of the transcription activaton and DNA binding of AhR. J Biol Chem. 2000 Mar 24;275(12):8432–8438. doi: 10.1074/jbc.275.12.8432. [DOI] [PubMed] [Google Scholar]
  23. Morrissey R. E., Harris M. W., Diliberto J. J., Birnbaum L. S. Limited PCB antagonism of TCDD-induced malformations in mice. Toxicol Lett. 1992 Jan;60(1):19–25. doi: 10.1016/0378-4274(92)90043-j. [DOI] [PubMed] [Google Scholar]
  24. Nguyen T. A., Hoivik D., Lee J. E., Safe S. Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex. Arch Biochem Biophys. 1999 Jul 15;367(2):250–257. doi: 10.1006/abbi.1999.1282. [DOI] [PubMed] [Google Scholar]
  25. Phelan D., Winter G. M., Rogers W. J., Lam J. C., Denison M. S. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys. 1998 Sep 1;357(1):155–163. doi: 10.1006/abbi.1998.0814. [DOI] [PubMed] [Google Scholar]
  26. Quadri S. A., Qadri A. N., Hahn M. E., Mann K. K., Sherr D. H. The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis. Mol Pharmacol. 2000 Sep;58(3):515–525. doi: 10.1124/mol.58.3.515. [DOI] [PubMed] [Google Scholar]
  27. Ricci M. S., Toscano D. G., Mattingly C. J., Toscano W. A., Jr Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. J Biol Chem. 1999 Feb 5;274(6):3430–3438. doi: 10.1074/jbc.274.6.3430. [DOI] [PubMed] [Google Scholar]
  28. Roberts B. J., Whitelaw M. L. Degradation of the basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin receptor via the ubiquitin/proteasome pathway. J Biol Chem. 1999 Dec 17;274(51):36351–36356. doi: 10.1074/jbc.274.51.36351. [DOI] [PubMed] [Google Scholar]
  29. Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol. 1990;21(1):51–88. doi: 10.3109/10408449009089873. [DOI] [PubMed] [Google Scholar]
  30. Savouret J. F., Antenos M., Quesne M., Xu J., Milgrom E., Casper R. F. 7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. J Biol Chem. 2000 Oct 20;276(5):3054–3059. doi: 10.1074/jbc.M005988200. [DOI] [PubMed] [Google Scholar]
  31. Shertzer H. G., Puga A., Chang C., Smith P., Nebert D. W., Setchell K. D., Dalton T. P. Inhibition of CYP1A1 enzyme activity in mouse hepatoma cell culture by soybean isoflavones. Chem Biol Interact. 1999 Nov 15;123(1):31–49. doi: 10.1016/s0009-2797(99)00121-0. [DOI] [PubMed] [Google Scholar]
  32. Sinal C. J., Bend J. R. Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells. Mol Pharmacol. 1997 Oct;52(4):590–599. doi: 10.1124/mol.52.4.590. [DOI] [PubMed] [Google Scholar]
  33. Thenot S., Charpin M., Bonnet S., Cavailles V. Estrogen receptor cofactors expression in breast and endometrial human cancer cells. Mol Cell Endocrinol. 1999 Oct 25;156(1-2):85–93. doi: 10.1016/s0303-7207(99)00139-2. [DOI] [PubMed] [Google Scholar]
  34. Van den Berg M., Birnbaum L., Bosveld A. T., Brunström B., Cook P., Feeley M., Giesy J. P., Hanberg A., Hasegawa R., Kennedy S. W. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect. 1998 Dec;106(12):775–792. doi: 10.1289/ehp.98106775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wang H. W., Chen T. L., Yang P. C., Ueng T. H. Induction of cytochromes P450 1A1 and 1B1 by emodin in human lung adenocarcinoma cell line CL5. Drug Metab Dispos. 2001 Sep;29(9):1229–1235. [PubMed] [Google Scholar]
  36. Wormke M., Stoner M., Saville B., Safe S. Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. FEBS Lett. 2000 Jul 28;478(1-2):109–112. doi: 10.1016/s0014-5793(00)01830-5. [DOI] [PubMed] [Google Scholar]
  37. Zhao F., Mayura K., Harper N., Safe S. H., Phillips T. D. Inhibition of 3,3',4,4',5-pentachlorobiphenyl-induced fetal cleft palate and immunotoxicity in C57BL/6 mice by 2,2',4,4',5,5'-hexachlorobiphenyl. Chemosphere. 1997 Mar-Apr;34(5-7):1605–1613. doi: 10.1016/s0045-6535(97)00456-6. [DOI] [PubMed] [Google Scholar]
  38. Zhao F., Mayura K., Kocurek N., Edwards J. F., Kubena L. F., Safe S. H., Phillips T. D. Inhibition of 3,3',4,4',5-pentachlorobiphenyl-induced chicken embryotoxicity by 2,2',4,4',5,5'-hexachlorobiphenyl. Fundam Appl Toxicol. 1997 Jan;35(1):1–8. doi: 10.1006/faat.1996.2251. [DOI] [PubMed] [Google Scholar]
  39. van Leeuwen F. X., Feeley M., Schrenk D., Larsen J. C., Farland W., Younes M. Dioxins: WHO's tolerable daily intake (TDI) revisited. Chemosphere. 2000 May-Jun;40(9-11):1095–1101. doi: 10.1016/s0045-6535(99)00358-6. [DOI] [PubMed] [Google Scholar]

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