Skip to main content
SpringerLink
Log in

The Brassica-derived phytochemical indolo[3,2-b]carbazole protects against oxidative DNA damage by aryl hydrocarbon receptor activation

  • Genotoxicity and Carcinogenicity
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Epidemiological studies suggest that a high intake of Brassica vegetables protects against colon carcinogenesis. Brassica vegetables are rich in glucosinolates which are hydrolysed during digestion to various products including indole-3-carbinol. In animal studies, a protective effect of indole-3-carbinol has been demonstrated in colon carcinogenesis. Indole-3-carbinol is highly unstable and, therefore, the observed protection likely results from condensation products of indole-3-carbinol, e.g. diindolylmethane or indolo[3,2-b]carbazole (ICZ). Interestingly, ICZ is a potent activator of the aryl hydrocarbon receptor (AhR), a transcription factor known to mediate toxic effects of environmental pollutants, such as dioxin and polycyclic aromatic hydrocarbons. Here, we show that ICZ protects against oxidative DNA damage in various cell lines including the colon carcinoma cell line Caco-2. When preincubated for 24 h, ICZ decreases DNA single-strand break (SSB) and 8-oxo-dG formation induced by tertiary-butylhydroperoxide (t-BOOH), hydrogen peroxide or benzo[a]pyrene. Simultaneous addition of ICZ does not protect against t-BOOH-induced SSB formation, which disproves a direct radical scavenging effect. The repair of SSBs was not enhanced, but the data indicate that ICZ attenuates the ROS level following t-BOOH. The antioxidant response factor Nrf2 was not activated following ICZ. Functional inhibition of the AhR and AhR-/ARNT-defective cell lines demonstrate that the AhR/ARNT pathway is mandatory for the observed ROS defence caused by ICZ, supporting the hypothesis that AhR-mediated regulation of defence genes is involved. The data point to a hitherto unknown protective function of ICZ and a novel role of the AhR in the defence against oxidative DNA damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Almenier HA, Al Menshawy HH, Maher MM, Al Gamal S (2012) Oxidative stress and inflammatory bowel disease. Front Biosci (Elite Ed) 4:1335–1344

    Article  Google Scholar 

  • Arif JM, Gairola CG, Kelloff GJ, Lubet RA, Gupta RC (2000) Inhibition of cigarette smoke-related DNA adducts in rat tissues by indole-3-carbinol. Mutat Res 432:11–18

    Article  Google Scholar 

  • Arlt A, Sebens S, Krebs S et al (2013) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32:4825–4835

    Article  CAS  PubMed  Google Scholar 

  • Baasanjav-Gerber C, Hollnagel HM, Brauchmann J, Iori R, Glatt H (2011) Detection of genotoxicants in Brassicales using endogenous DNA as a surrogate target and adducts determined by (32)postlabelling as an experimental end point. Mutagenesis 26:407–413

    Article  CAS  PubMed  Google Scholar 

  • Bailey GS, Hendricks JD, Shelton DW, Nixon JE, Pawlowski NE (1987) Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol. J Natl Cancer Inst 78:931–934

    CAS  PubMed  Google Scholar 

  • Barouki R, Coumoul X, Fernandez-Salguero PM (2007) The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 581:3608–3615

    Article  CAS  PubMed  Google Scholar 

  • Barouki R, Aggerbeck M, Aggerbeck L, Coumoul X (2012) The aryl hydrocarbon receptor system. Drug Metab Drug Interact 27:3–8

    Article  CAS  Google Scholar 

  • Bergander L, Wincent E, Rannug A, Foroozesh M, Alworth W, Rannug U (2004) Metabolic fate of the Ah receptor ligand 6-formylindolo[3,2-b]carbazole. Chem Biol Interact 149:151–164

    Article  CAS  PubMed  Google Scholar 

  • Birt DF, Walker B, Tibbels MG, Bresnick E (1986) Anti-mutagenesis and anti-promotion by apigenin, robinetin and indole-3-carbinol. Carcinogenesis 7:959–963

    Article  CAS  PubMed  Google Scholar 

  • Bjeldanes LF, Kim J-Y, Grose KR, Bartholomew JC, Bradfield CA (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. Proc Natl Acad Sci USA 88:9543–9547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonnesen C, Eggleston IM, Hayes JD (2001) Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 61:6120–6130

    CAS  PubMed  Google Scholar 

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106:761–771

    Article  CAS  PubMed  Google Scholar 

  • Boutros PC, Moffat ID, Franc MA et al (2004) Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting. Biochem Biophys Res Commun 321:707–715

    Article  CAS  PubMed  Google Scholar 

  • Bradfield CA, Bjeldanes LF (1987) Structure-activity relationships of dietary indoles: a proposed mechanism of action as modifiers of xenobiotic metabolism. J Toxicol Environ Health 21:311–323

    Article  CAS  PubMed  Google Scholar 

  • Chen YH, Riby J, Srivastava P, Bartholomew J, Denison M, Bjeldanes LF (1995) Regulation of CYP1A1 by indolo[3,2-b]carbazole in murine hepatoma cells. J Biol Chem 270:22548–22555

    Article  CAS  PubMed  Google Scholar 

  • Cho JS, Chang MS, Rho HM (2001) Transcriptional activation of the human Cu/Zn superoxide dismutase gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin through the xenobiotic-responsive element. Mol Genet Genomics 266:133–141

    Article  CAS  PubMed  Google Scholar 

  • Conolly M, Fernandez-Cruz ML, Navas JM (2015) Recovery of redox homeostasis altered by CuNPs in H4IIE liver cells does not reduce the cytotoxic effects of these NPs: an investigation using aryl hydrocarbon receptor (AhR) dependent antioxidant activity. Chem Biol Interact 228:57–68

    Article  CAS  Google Scholar 

  • Dalton TP, Puga A, Shertzer HG (2002) Induction of cellular oxidative stress by aryl hydrocarbon receptor activation. Chem Biol Interact 141:77–95

    Article  CAS  PubMed  Google Scholar 

  • De Kruif CA, Marsman JW, Venekamp JC et al (1991) Structure elucidation of acid reaction products of indole-3-carbinol: detection in vivo and enzyme induction in vitro. Chem Biol Interact 80:303–315

    Article  PubMed  Google Scholar 

  • De Souza AR, Zago M, Pollock SJ et al (2011) Genetic ablation of the aryl hydrocarbon receptor causes cigarette smoke-induced mitochondrial dysfunction and apoptosis. J Biol Chem 286:43214–43228

    Article  CAS  Google Scholar 

  • De Waard PW, de Kok TM, Maas LM et al (2008) Influence of TCDD and natural Ah receptor agonists on benzo[a]pyrene-DNA adduct formation in the Caco-2 human colon cell line. Mutagenesis 23:67–73

    Article  PubMed  CAS  Google Scholar 

  • Denison MS, Soshilov AA, He G, deGroot DE, Zhao B (2011) Exactly the same but different: promiscuity and diversity in the molecular mechanism of action of the aryl hydrocarbon receptor. Toxicol Sci 124:1–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dietrich C, Kaina B (2010) The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth. Carcinogenesis 31:1319–1328

    Article  CAS  PubMed  Google Scholar 

  • Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H (2002) Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med 32:1102–1115

    Article  CAS  PubMed  Google Scholar 

  • Ebert B, Seidel A, Lampen A (2005) Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis 26:1754–1763

    Article  CAS  PubMed  Google Scholar 

  • Ebert B, Seidel A, Lampen A (2007) Phytochemicals induce breast cancer resistance protein in Caco-2 cells and enhance the transport of benzo[a]pyrene-3-sulfate. Toxicol Sci 96:227–236

    Article  CAS  PubMed  Google Scholar 

  • Epe B, Hegler J, Wild D (1990) Identification of ultimate DNA damaging oxygen species. Environ Health Perspect 88:111–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glatt H, Davis W, Meinl W, Hermersdörfer H, Venitt S, Phillips DH (1998) Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis 19:1709–1713

    Article  CAS  PubMed  Google Scholar 

  • Glatt H, Baasanjav-Gerber C, Schumacher F et al (2011) 1-Methoxy-3-indolylmethyl glucosinolate, a potent genotoxicant in bacterial and mammalian cells: mechanism of bioactivation. Chem Biol Interact 192:81–86

    Article  CAS  PubMed  Google Scholar 

  • Gouédard C, Barouki R, Morel Y (2004) Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism. Mol Cell Biol 24:5209–5222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He Y-H, Friesen MD, Ruch RJ, Schut AJ (2000) Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-adduct formation, acceleration of PhIP metabolism and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol 48:15–23

    Article  Google Scholar 

  • Higdon JV, Delage B, Williams DE, Dashwood RH (2007) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 55:224–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hockley SL, Arlt VM, Brewer D et al (2007) AHR- and DNA-damage-mediated gene expression responses induced by benzo(a)pyrene in human cell lines. Chem Res Toxicol 20:1797–1810

    Article  CAS  PubMed  Google Scholar 

  • Hoffer A, Chang C, Puga A (1992) Dioxin induces transcription of fos and jun genes by Ah receptor-dependent and -independent pathways. Toxicol Appl Pharmacol 141:238–247

    Article  Google Scholar 

  • Holst B, Williamson G (2004) A critical review of the bioavailability of glucosinolates and related compounds. Nat Prod Rep 21:425–447

    Article  CAS  PubMed  Google Scholar 

  • Huang G, Elferink CJ (2012) A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression. Mol Pharmacol 81:338–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji T, Xu C, Sun L et al (2015) Aryl hydrocarbon receptor activation down-regulates IL-7 and reduces inflammation in a mouse model of DSS-induced colitis. Dig Dis Sci 60:1958–1966

    Article  CAS  PubMed  Google Scholar 

  • Kassie F, Parzefall W, Musk S et al (1996) Genotoxic effects of crude juices from Brassica vegetables and juices and extracts from phytopharmaceutical preparations and spices of cruciferous plants origin in bacterial and mammalian cells. Chem Biol Interact 102:1–16

    Article  CAS  PubMed  Google Scholar 

  • Kassie F, Anderson LB, Scherber R et al (2007) Indole-3-carbinol inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo(a)pyrene-induced lung tumorigenesis in A/J mice and modulates carcinogen-induced alterations in protein levels. Cancer Res 67:6502–6511

    Article  CAS  PubMed  Google Scholar 

  • Kawajiri K, Kobayashi Y, Ohtake F et al (2009) Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in APC Min/+ mice with natural ligands. Proc Natl Acad Sci USA 106:13481–13486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SH, Henry EC, Kim DK et al (2006) Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolyazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol 69:1871–1878

    Article  CAS  PubMed  Google Scholar 

  • Klaunig JE, Kamendulis LM (2004) The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 44:239–267

    Article  CAS  PubMed  Google Scholar 

  • Klaunig JE, Kamendulis LM, Hocevar BA (2010) Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 38:96–109

    Article  CAS  PubMed  Google Scholar 

  • Kleman ML, Poellinger L, Gustafsson J-A (1994) Regulation of human dioxin receptor function by indolocarbazoles, receptor ligands of dietary origin. J Biol Chem 269:5137–5144

    CAS  PubMed  Google Scholar 

  • Knerr S, Schaefer J, Both S et al (2006) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced cytochrome P450s alter the formation of reactive oxygen species in liver cells. Mol Nutr Food Res 50:378–384

    Article  CAS  PubMed  Google Scholar 

  • Köhle C, Bock KW (2006) Activation of coupled Ah receptor and Nrf2 gene batteries by dietary phytochemicals in relation to chemoprevention. Biochem Pharmacol 72:795–805

    Article  PubMed  CAS  Google Scholar 

  • Krzyzanowski D, Bartosz G, Grzelak A (2014) Collateral sensitivity: ABCG2-overexpressing cells are more vulnerable to oxidative stress. Free Radic Biol Med 76:47–52

    Article  CAS  PubMed  Google Scholar 

  • Kushad MM, Brown AF, Kurilich AC et al (1999) Variation of glucosinolates in vegetable crops of Brassica oleracea. J Agric Food Chem 47:1541–1548

    Article  CAS  PubMed  Google Scholar 

  • Kwak M-K, Kensler TW (2010) Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol 244:66–67

    Article  CAS  PubMed  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  • Lin P-H, Lin C-H, Huang C-C, Chuang M-C, Lin P (2007) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces oxidative stress, DNA strand breaks, and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines. Toxicol Lett 172:146–158

    Article  CAS  PubMed  Google Scholar 

  • Lippmann D, Lehmann C, Florian S et al (2014) Glucosinolates from pak choi and broccoli induce enzymes and inhibit inflammation and colon cancer differently. Food Funct 5:1073–1081

    Article  CAS  PubMed  Google Scholar 

  • Lo R, Matthews J (2012) High-resolution genome-wide mapping of AhR and ARNT binding sites by ChIP-Seq. Toxicol Sci 130:349–361

    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 

  • Marlowe J, Puga A (2005) Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 96:1174–1184

    Article  CAS  PubMed  Google Scholar 

  • Maruthanila VL, Poornima J, Mirunalini S (2014) Attenuation of carcinogenesis and the mechanism underlying the influence of indole-3-carbinol and its metabolite 3,3′-diindolylmethane: a therapeutic marvel. Adv Pharmacol Sci 2014:832161

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumura F (2012) Nongenomic routes of action of TCDD: identity, characteristics, and toxicological significance. In: Pohjanvirta R (ed) The AH receptor in biology and toxicology, 1st edn. Wiley, Hoboken

    Google Scholar 

  • Moiseeva EP, Almeida GM, Jones GD, Manson MM (2007) Extended treatment with physiological concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther 6:3071–3079

    Article  CAS  PubMed  Google Scholar 

  • Nebert D, Dalton TP, Okey AB, Gonzales FJ (2004) Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 23:23847–23850

    Article  Google Scholar 

  • Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21:102–116

    Article  CAS  PubMed  Google Scholar 

  • Nikolova T, Ensminger M, Löbrich M, Kaina B (2010) Homologous recombination protects mammalian cells from replication-associated DNA double-strand breaks arising in response to methyl methanesulfonate. DNA Repair 9:1050–1063

    Article  CAS  PubMed  Google Scholar 

  • Nikolova T, Dvorak M, Jung F et al (2014) The γH2AX assay for genotoxic and nongenotoxic agents: comparison of H2AX phosphorylation with cell death response. Toxicol Sci 140:103–117

    Article  CAS  PubMed  Google Scholar 

  • Niture SK, Khatri R, Jaiswal AK (2014) Regulation of Nrf2—an update. Free Radic Biol Med 66:36–44

    Article  CAS  PubMed  Google Scholar 

  • Olive PL, Banath JP (2006) The comet assay: a method to measure DNA damage in individual cells. Nat Protoc 1:23–29

    Article  CAS  PubMed  Google Scholar 

  • Park EY, Rho HM (2002) The transcriptional activation of the human copper/zinc superoxide dismutase gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin through two different regulator sites, the antioxidant responsive element and xenobiotic responsive element. Mol Cell Biochem 240:47–55

    Article  CAS  PubMed  Google Scholar 

  • Park J-YK, Shigenaga MK, Ames BN (1996) Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage. Proc Natl Acad Sci USA 93:2322–2327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park J-H, Mangal D, Frey AJ, Harvey RG, Blair IA, Penning TM (2009) Aryl hydrocarbon receptor facilitates DNA strand breaks and 8-oxo-2′-deoxyguanosine formation by the aldo-keto reductase product benzo[a]pyrene-7,8-dione. J Biol Chem 284:29725–29734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pohjanvirta R, Korkalainen M, McGuire J et al (2002) Comparison of acute toxicities of indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive rats. Food Chem Toxicol 40:1023–1032

    Article  CAS  PubMed  Google Scholar 

  • Puga A, Ma C, Marlowe JL (2009) The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol 77:713–722

    Article  CAS  PubMed  Google Scholar 

  • Reddy MV, Storer RD, Laws GM et al (2002) Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests. Environ Mol Mutagen 40:1–17

    Article  CAS  PubMed  Google Scholar 

  • Roos WP, Nikolova T, Quiros S et al (2009) Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O(6)-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs. DNA Repair 8:72–86

    Article  CAS  PubMed  Google Scholar 

  • Salbe AD, Bjeldanes LF (1989) Effect of diet and route of administration on the DNA binding of aflatoxin B1 in the rat. Carcinogenesis 10:629–634

    Article  CAS  PubMed  Google Scholar 

  • Sarill M, Zago M, Sheridan JA et al (2015) The aryl hydrocarbon receptor suppresses cigarette-smoke-induced oxidative stress in association with dioxin response element (DRE)-independent regulation of sulfiredoxin 1. Free Radic Biol Med 89:342–357

    Article  CAS  PubMed  Google Scholar 

  • Saw CL, Kong AN (2011) Nuclear factor-erythroid 2-related factor 2 as a chemopreventive target in colorectal cancer. Expert Opin Ther Targets 15:281–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schumacher F, Florian S, Schnapper A et al (2014) A secondary metabolite of Brassicales, 1-methoxy-3-indolylmethyl glucosinolate, as well as its degradation product, 1-methoxy-3-indolylmethyl alcohol, forms DNA adducts in the mouse, but in varying tissues and cells. Arch Toxicol 88:823–836

    CAS  PubMed  Google Scholar 

  • Shen D, Dalton TP, Nebert D, Shertzer HG (2005) Glutathione redox state regulates mitochondrial reactive oxygen production. J Biol Chem 280:25305–25312

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Robertson LW, Ludewig G (2015) Regulatory effects of dioxin-like and non-dioxin-like PCBs and other AhR ligands on the antioxidant enzymes paraoxonase 1/2/3. Environ Sci Pollut Res. doi:10.1007/s11356-015-4722-1

    Google Scholar 

  • Shertzer HG (1984) Indole-3-carbinol protects against covalent binding of benzo[a]pyrene and N-nitrosodimethylamine metabolites to mouse liver macromolecules. Chem Biol Interact 48:81–90

    Article  CAS  PubMed  Google Scholar 

  • Shertzer HG, Clay CD, Genter MB et al (2004) CYP1A2 protects against reactive oxygen production in mouse liver microsomes. Free Radic Biol Med 36:605–617

    Article  CAS  PubMed  Google Scholar 

  • Smith PK, Krohn RI, Hermanson GT et al (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85

    Article  CAS  PubMed  Google Scholar 

  • Sogawa K, Numayama-Tsuruta K, Takahashi T et al (2004) A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-ARNT heterodimer. Biochem Biophys Res Commun 318:746–755

    Article  CAS  PubMed  Google Scholar 

  • Stohs SJ, Hassoun EA (2012) Dioxin-activated AhR: toxic responses and the induction of oxidative stress. In: Pohjanvirta R (ed) The AH receptor in biology and toxicology, 1st edn. Wiley, Hoboken

    Google Scholar 

  • Stoner G, Casto B, Ralston S et al (2002) Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis 23:265–272

    Article  CAS  PubMed  Google Scholar 

  • Stresser DM, Williams DE, Griffin DA, Bailey GS (1995) Mechanism of tumour modulation by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats. Drug Metab Dispos 23:965–975

    CAS  PubMed  Google Scholar 

  • Swanson HI, Bradfield CA (1993) The AH-receptor: genetics, structure and function. Pharmacogenetics 3:213–230

    Article  CAS  PubMed  Google Scholar 

  • Teino I, Kuuse S, Ingerpuu S, Maimets T, Tiido T (2012) The aryl hydrocarbon receptor regulates mouse Fshr promoter activity through an E-box binding site. Biol Reprod 86:1–12

    Article  CAS  Google Scholar 

  • Thornton AS, Oda Y, Stuart GR, Glickman BW, de Boer JG (2001) Mutagenicity of TCDD in Big Blue® transgenic rats. Mutat Res 478:45–50

    Article  CAS  PubMed  Google Scholar 

  • Traka M, Mithen R (2009) Glucosinolates, isothiocyanates and human health. Phytochem Rev 8:269–282

    Article  CAS  Google Scholar 

  • Tritscher AM, Seacat AM, Yager JD et al (1996) Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats. Cancer Lett 98:219–225

    Article  CAS  PubMed  Google Scholar 

  • Tuomisto J (2005) Does mechanistic understanding help in risk assessment—the example of dioxin. Toxicol Appl Pharmacol 207:S2–S10

    Article  CAS  Google Scholar 

  • Van Breemen RB, Li Y (2005) Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol 1:175–185

    Article  PubMed  Google Scholar 

  • Verhoeven DTH, Verhagen H, Goldbohm RA, van den Brandt PA, van den Poppel G (1997) A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem Biol Interact 103:79–129

    Article  CAS  PubMed  Google Scholar 

  • Wätjen W, Weber N, Lou YJ et al (2007) Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells. Food Chem Toxicol 45:119–124

    Article  PubMed  CAS  Google Scholar 

  • Wattenberg LW, Loub WD (1978) Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res 38:1410–1413

    CAS  PubMed  Google Scholar 

  • Weiss C, Faust D, Dürk H et al (2005) TCDD induces c-jun expression via a novel Ah (Dioxin) receptor-mediated p38-MAPK-dependent pathway. Oncogene 24:4975–4983

    Article  CAS  PubMed  Google Scholar 

  • Weiss C, Faust D, Schreck I et al (2008) TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A. Oncogene 27:2198–2207

    Article  CAS  PubMed  Google Scholar 

  • Wiesner M, Schreiner M, Glatt HR (2014) High mutagenic activity of juice from pak choi (Brassica rapa ssp. chinensis) sprouts due to its content of 1-methoxy-3-indolylmethyl glucosinolate, and its enhancement by elicitation with methyl jasmonate. Food Chem Toxicol 67:10–16

    Article  CAS  PubMed  Google Scholar 

  • Wilson SR, Joshi AD, Elferink CJ (2014) The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner. J Pharmacol Exp Ther 345:419–429

    Article  CAS  Google Scholar 

  • Wyde ME, Wong VA, Kim AH, Lucier GW, Walker NJ (2001) Induction of hepatic 8-oxo-deoxyguanosine adducts by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sprague-Dawley rats is female-specific and estrogen-dependent. Chem Res Toxicol 14:849–855

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Cai X, Yang J et al (2014) Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation. Mol Cancer 13:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida M, Katashima S, Ando J et al (2004) Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N′-nitro-N-nitrosoguanidine, with induction of cytochrome P450 in the liver and consequent modulation of estrogen metabolism. Carcinogenesis 25:2257–2264

    Article  CAS  PubMed  Google Scholar 

  • Zhao B, Degroot DE, Hayashi A, He G, Denison MS (2010) CH223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. Toxicol Sci 117:393–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou J, Gasiewicz TA (2003) 3′-Methoxy-4′-nitroflavone, a reported aryl hydrocarbon receptor antagonist, enhances Cyp1a1 transcription by a dioxin responsive element-dependent mechanism. Arch Biochem Biophys 416:68–80

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are indebted to Anna Frumkina for expert technical assistance. The technical support by Julia Altmaier, FACS and Array Core Facility, is gratefully acknowledged. The work was supported by the Deutsche Forschungsgemeinschaft (Di 793/3-1).

Author information

Authors and Affiliations

  1. Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131, Mainz, Germany

    Dagmar Faust, Teodora Nikolova, Bernd Kaina & Cornelia Dietrich

  2. Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, Weinbergweg 22, 06120, Halle (Saale), Germany

    Wim Wätjen

Authors
  1. Dagmar Faust
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teodora Nikolova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wim Wätjen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernd Kaina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cornelia Dietrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cornelia Dietrich.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Faust, D., Nikolova, T., Wätjen, W. et al. The Brassica-derived phytochemical indolo[3,2-b]carbazole protects against oxidative DNA damage by aryl hydrocarbon receptor activation. Arch Toxicol 91, 967–982 (2017). https://doi.org/10.1007/s00204-016-1672-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-016-1672-4

Keywords

Search

Navigation