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Regulation of dioxin receptor function by different beta-carboline alkaloids

  • Molecular Toxicology
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Abstract

The dioxin receptor, also known as arylhydrocarbon receptor (AhR), is a ligand-activated transcription factor that mediates the toxicity of dioxins and related environmental contaminants. In addition, there is a growing list of natural compounds, mainly plant polyphenols that can modulate AhR function and downstream signaling with quite unknown consequences for cellular function. We investigate the potential of four different β-carboline alkaloids to stimulate AhR signaling in human hepatoma cells and keratinocytes. Three test substances, namely rutaecarpine, annomontine and xestomanzamine A, increase AhR-driven reporter gene activity as well as expression of two AhR target genes in a dose-dependent and time-dependent manner. Additionally, the three test alkaloids stimulate cytochrome P450 (CYP) 1 enzyme activity without showing any antagonistic effects regarding benzo(a)pyrene-stimulated CYP1 activation. The AhR-activating property of the β-carbolines is completely abrogated in AhR-deficient cells providing evidence that rutaecarpine, annomontine and xestomanzamine A are natural stimulators of the human AhR. The toxicological relevance of beta-carboline-mediated AhR activation is discussed.

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Abbreviations

AhR:

Arylhydrocarbon receptor

AhRR:

Arylhydrocarbon receptor repressor

ARNT:

Arylhydrocarbon receptor nuclear translocator

BaP:

Benzo(a)pyrene

bHLH-PAS:

Basic Helix-Loop-Helix Per/ARNT/Sim

CYP:

Cytochrome P450

EGCG:

Epigallocatechine-3-gallate

EROD:

Ethoxyresorufin-O-deethylase

FICZ:

6-Formylindolo[3,2-b]carbazole

HSP90:

Heat-shock protein 90

MNF:

3′-Methoxy-4′-nitroflavone

3MC:

3-Methylcholanthrene

PKC:

Protein kinase C

TCDD:

2,3,7,8-Tetrachlorodibenzo-p-dioxin

UV:

Ultraviolet

XRE:

Xenobiotic responsive element

References

  • Agostinis P, Garmyn M, Van Laethem A (2007) The Aryl hydrocarbon receptor: an illuminating effector of the UVB response. Sci STKE 2007:e49

    Article  Google Scholar 

  • Amakura Y, Tsutsumi T, Sasaki K, Nakamura M, Yoshida T, Maitani T (2008) Influence of food polyphenols on aryl hydrocarbon receptor-signaling pathway estimated by in vitro bioassay. Phytochemistry 69:3117–3130

    Article  CAS  PubMed  Google Scholar 

  • Asres K, Seyoum A, Veeresham C, Bucar F, Gibbons S (2005) Naturally derived anti-HIV agents. Phytother Res 19:557–581

    Article  CAS  PubMed  Google Scholar 

  • Bock KW, Köhle C (2006) Ah receptor: dioxin-mediated toxic responses as hints to deregulated physiologic functions. Biochem Pharmacol 72:393–404

    Article  CAS  PubMed  Google Scholar 

  • Breyer-Pfaff U, Wiatr G, Stevens I, Gaertner HJ, Mundle G, Mann K (1996) Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking. Life Sci 58:1425–1432

    Article  CAS  PubMed  Google Scholar 

  • Cao R, Peng W, Wang Z, Xu A (2007) Beta-carboline alkaloids: biochemical and pharmacological functions. Curr Med Chem 14:479–500

    Article  CAS  PubMed  Google Scholar 

  • Chao HR, Wang YF, Chen HT, Ko YC, Chang EE, Huang YJ, Tsai FY, Tsai CH, Wu CH, Tsou TC (2007) Differential effect of arecoline on the endogenous dioxin-responsive cytochrome P450 1A1 and on a stably transfected dioxin-responsive element-driven reporter in human hepatoma cells. J Hazard Mater 149:234–237

    Article  CAS  PubMed  Google Scholar 

  • Costa EV, Pinheiro ML, Xavier CM, Silva JR, Amaral AC, Souza AD, Barison A, Campos FR, Ferreira AG, Machado GM, Leon LL (2006) A pyrimidine-beta-carboline and other alkaloids from Annona foetida with antileishmanial activity. J Nat Prod 69:292–294

    Article  CAS  PubMed  Google Scholar 

  • de Meester C (1995) Genotoxic potential of beta-carbolines: a review. Mutat Res 339:139–153

    CAS  PubMed  Google Scholar 

  • Delescluse C, Ledirac N, de Sousa G, Pralavorio M, Botta-Fridlund D, Letreut Y, Rahmani R (1997) Comparative study of CYPlAl induction by 3-methylcholanthrene in various human hepatic and epidermal cell types. Toxicol In Vitro 11:443–450

    Article  CAS  PubMed  Google Scholar 

  • Dorow R, Horowski R, Paschelke G, Amin M (1983) Severe anxiety induced by FG 7142, a beta-carboline ligand for benzodiazepine receptors. Lancet 2:98–99

    Article  CAS  PubMed  Google Scholar 

  • Fekkes D, Tuiten A, Bom I, Pepplinkhuizen L (2001) Pharmacokinetics of the beta-carboline norharman in man. Life Sci 69:2113–2121

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140:173–179

    Article  CAS  PubMed  Google Scholar 

  • Fritsche E, Cline JE, Nguyen NH, Scanlan TS, Abel J (2005) Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors. Environ Health Perspect 113:871–876

    Article  CAS  PubMed  Google Scholar 

  • Fritsche E, Schafer C, Calles C, Bernsmann T, Bernshausen T, Wurm M, Hubenthal U, Cline JE, Hajimiragha H, Schroeder P, Klotz LO, Rannug A, Furst P, Hanenberg H, Abel J, Krutmann J (2007) Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci USA 104:8851–8856

    Article  CAS  PubMed  Google Scholar 

  • Gradin K, Wilhelmsson A, Poellinger L, Berghard A (1993) Nonresponsiveness of normal human fibroblasts to dioxin correlates with the presence of a constitutive xenobiotic response element-binding factor. J Biol Chem 268:4061–4068

    CAS  PubMed  Google Scholar 

  • Haarmann-Stemmann T, Abel J (2006) The arylhydrocarbon receptor repressor (AhRR): structure, expression, and function. Biol Chem 387:1195–1199

    Article  CAS  PubMed  Google Scholar 

  • Haarmann-Stemmann T, Bothe H, Kohli A, Sydlik U, Abel J, Fritsche E (2007) Analysis of the transcriptional regulation and molecular function of the aryl hydrocarbon receptor repressor in human cell lines. Drug Metab Dispos 35:2262–2269

    Article  CAS  PubMed  Google Scholar 

  • Haarmann-Stemmann T, Bothe H, Abel J (2009) Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways. Biochem Pharmacol 77:508–520

    Article  CAS  PubMed  Google Scholar 

  • Hahn ME (2002) Aryl hydrocarbon receptors: diversity and evolution. Chem Biol Interact 141:131–160

    Article  CAS  PubMed  Google Scholar 

  • Herraiz T (2000) Analysis of the bioactive alkaloids tetrahydro-beta-carboline and beta-carboline in food. J Chromatogr A 881:483–499

    Article  CAS  PubMed  Google Scholar 

  • Herraiz T, Guillen H, Aran VJ (2008) Oxidative metabolism of the bioactive and naturally occurring beta-carboline alkaloids, norharman and harman, by human cytochrome P450 enzymes. Chem Res Toxicol 21:2172–2180

    Article  CAS  PubMed  Google Scholar 

  • Ioannides C, Lewis DF (2004) Cytochromes P450 in the bioactivation of chemicals. Curr Top Med Chem 4:1767–1788

    Article  CAS  PubMed  Google Scholar 

  • Iwanari M, Nakajima M, Kizu R, Hayakawa K, Yokoi T (2002) Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences. Arch Toxicol 76:287–298

    Article  CAS  PubMed  Google Scholar 

  • Lee SK, Kim NH, Lee J, Kim DH, Lee ES, Choi HG, Chang HW, Jahng Y, Jeong TC (2004) Induction of cytochrome P450 s by rutaecarpine and metabolism of rutaecarpine by cytochrome P450 s. Planta Med 70:753–757

    Article  CAS  PubMed  Google Scholar 

  • Lee SK, Bista SR, Jeong H, Kim DH, Kang MJ, Jahng Y, Jeong TC (2007) The effects of rutaecarpine on the pharmacokinetics of acetaminophen in rats. Arch Pharm Res 30:1629–1634

    Article  CAS  PubMed  Google Scholar 

  • Lu YF, Santostefano M, Cunningham BD, Threadgill MD, Safe S (1995) Identification of 3′-methoxy-4′-nitroflavone as a pure aryl hydrocarbon (Ah) receptor antagonist and evidence for more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cells. Arch Biochem Biophys 316:470–477

    Article  CAS  PubMed  Google Scholar 

  • Machemer DE, Tukey RH (2005) The role of protein kinase C in regulation of TCDD-mediated CYP1A1 gene expression. Toxicol Sci 87:27–37

    Article  CAS  PubMed  Google Scholar 

  • Medjakovic S, Jungbauer A (2008) Red clover isoflavones biochanin A and formononetin are potent ligands of the human aryl hydrocarbon receptor. J Steroid Biochem Mol Biol 108:171–177

    Article  CAS  PubMed  Google Scholar 

  • Meggio F, Donella Deana A, Ruzzene M, Brunati A, Cesaro L, Guerra B, Meyer T, Mett H, Fabbro D, Furet P, Dobrowolska G, Pinna L (1995) Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. Eur J Biochem 234:317–322

    Article  CAS  PubMed  Google Scholar 

  • Mimura J, Ema M, Sogawa K, Fujii-Kuriyama Y (1999) Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes Dev 13:20–25

    Article  CAS  PubMed  Google Scholar 

  • Moon YJ, Wang X, Morris ME (2006) Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro 20:187–210

    Article  CAS  PubMed  Google Scholar 

  • Murk AJ, Legler J, Denison MS, Giesy JP, van de Guchte C, Brouwer A (1996) Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water. Fundam Appl Toxicol 33:149–160

    Article  CAS  PubMed  Google Scholar 

  • Nebert DW, Dalton TP, Okey AB, Gonzalez FJ (2004) Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 279:23847–23850

    Article  CAS  PubMed  Google Scholar 

  • Nishihashi H, Kanno Y, Tomuro K, Nakahama T, Inouye Y (2006) Primary structure and organ-specific expression of the rat aryl hydrocarbon receptor repressor gene. Biol Pharm Bull 29:640–647

    Article  CAS  PubMed  Google Scholar 

  • Palermo CM, Westlake CA, Gasiewicz TA (2005) Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. Biochemistry 44:5041–5052

    Article  CAS  PubMed  Google Scholar 

  • Park S, Henry EC, Gasiewicz TA (2000) Regulation of DNA binding activity of the ligand-activated aryl hydrocarbon receptor by tyrosine phosphorylation. Arch Biochem Biophys 381:302–312

    Article  CAS  PubMed  Google Scholar 

  • Pfau W, Skog K (2004) Exposure to beta-carbolines norharman and harman. J Chromatogr B Analyt Technol Biomed Life Sci 802:115–126

    Article  CAS  PubMed  Google Scholar 

  • Ramadoss P, Marcus C, Perdew GH (2005) Role of the aryl hydrocarbon receptor in drug metabolism. Expert Opin Drug Metab Toxicol 1:9–21

    Article  CAS  PubMed  Google Scholar 

  • Rovescalli AC, Brunello N, Franzetti C, Racagni G (1986) Interaction of putative endogenous tryptolines with the hypothalamic serotonergic system and prolactin secretion in adult male rats. Neuroendocrinology 43:603–610

    Article  CAS  PubMed  Google Scholar 

  • Schmidt JV, Su GH, Reddy JK, Simon MC, Bradfield CA (1996) Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci U S A 93:6731–6736

    Article  CAS  PubMed  Google Scholar 

  • Seidel SD, Li V, Winter GM, Rogers WJ, Martinez EI, Denison MS (2000) Ah receptor-based chemical screening bioassays: application and limitations for the detection of Ah receptor agonists. Toxicol Sci 55:107–115

    Article  CAS  PubMed  Google Scholar 

  • Sheu J (1999) Pharmacological effects of rutaecarpine, an alkaloid isolated from Evodia rutaecarpa. Cardiovasc Drug Rev 17:237–245

    Article  CAS  Google Scholar 

  • Totsuka Y, Takamura-Enya T, Nishigaki R, Sugimura T, Wakabayashi K (2004) Mutagens formed from beta-carbolines with aromatic amines. J Chromatogr B Analyt Technol Biomed Life Sci 802:135–141

    Article  CAS  PubMed  Google Scholar 

  • Tsuchiya Y, Nakajima M, Itoh S, Iwanari M, Yokoi T (2003) Expression of aryl hydrocarbon receptor repressor in normal human tissues and inducibility by polycyclic aromatic hydrocarbons in human tumor-derived cell lines. Toxicol Sci 72:253–259

    Article  CAS  PubMed  Google Scholar 

  • Ueng YF, Wang JJ, Lin LC, Park SS, Chen CF (2001) Induction of cytochrome P450-dependent monooxygenase in mouse liver and kidney by rutaecarpine, an alkaloid of the herbal drug Evodia rutaecarpa. Life Sci 70:207–217

    Article  CAS  PubMed  Google Scholar 

  • Ueng YF, Jan WC, Lin LC, Chen TL, Guengerich FP, Chen CF (2002) The alkaloid rutaecarpine is a selective inhibitor of cytochrome P450 1A in mouse and human liver microsomes. Drug Metab Dispos 30:349–353

    Article  CAS  PubMed  Google Scholar 

  • Ueng YF, Tsai TH, Don MJ, Chen RM, Chen TL (2005) Alteration of the pharmacokinetics of theophylline by rutaecarpine, an alkaloid of the medicinal herb Evodia rutaecarpa, in rats. J Pharm Pharmacol 57:227–232

    Article  CAS  PubMed  Google Scholar 

  • Vanden Heuvel JP, Clark GC, Thompson CL, McCoy Z, Miller CR, Lucier GW, Bell DA (1993) CYP1A1 mRNA levels as a human exposure biomarker: use of quantitative polymerase chain reaction to measure CYP1A1 expression in human peripheral blood lymphocytes. Carcinogenesis 14:2003–2006

    Article  Google Scholar 

  • Venault P, Chapouthier G (2007) From the behavioral pharmacology of beta-carbolines to seizures, anxiety, and memory. ScientificWorldJournal 7:204–223

    Article  CAS  PubMed  Google Scholar 

  • Vogel CF, Matsumura F (2009) A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family. Biochem Pharmacol 77:734–745

    Article  CAS  PubMed  Google Scholar 

  • Yu AM, Idle JR, Krausz KW, Kupfer A, Gonzalez FJ (2003) Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmine. J Pharmacol Exp Ther 305:315–322

    Article  CAS  PubMed  Google Scholar 

  • Zeng X, Zeng X (1999) Relationship between the clinical effects of berberine on severe congestive heart failure and its concentration in plasma studied by HPLC. Biomed Chromatogr 13:442–444

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Qin C, Safe SH (2003) Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect 111:1877–1882

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Katarina Gradin and Lorenz Poellinger (Karolinska Institutet, Sweden) for generously providing the XRE-HepG2 reporter cells and to Yoshio Inouye (Toho University, Japan) for the kind donation of the pcDNA5-rAhRR plasmid. We thank Birgit Neumann and Ulrike Hübenthal for technical support. This work was supported by the graduate school 1427 of the Deutsche Forschungsgemeinschaft (DFG, Bonn, Germany).

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Authors and Affiliations

  1. Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-Universität Düsseldorf gGmbH, Auf’m Hennekamp 50, 40225, Düsseldorf, Germany

    Thomas Haarmann-Stemmann, Christine Götz, Nathalie Krug, Hanno Bothe, Ellen Fritsche & Josef Abel

  2. Institut für Pharmazeutische Biologie und Biotechnologie, Heinrich-Heine-Universität, Universitätsstr. 1, 40225, Düsseldorf, Germany

    Jandirk Sendker & Peter Proksch

  3. Department of Dermatology, University Hospital, RWTH Aachen, Aachen, Germany

    Ellen Fritsche

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  1. Thomas Haarmann-Stemmann
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Correspondence to Thomas Haarmann-Stemmann.

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Haarmann-Stemmann, T., Sendker, J., Götz, C. et al. Regulation of dioxin receptor function by different beta-carboline alkaloids. Arch Toxicol 84, 619–629 (2010). https://doi.org/10.1007/s00204-010-0548-2

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