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A potential protective mechanism of soya isoflavones against 7,12-dimethylbenz[a]anthracene tumour initiation

Published online by Cambridge University Press:  09 March 2007

Ho Yee Chan
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
Lai K. Leung*
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Food and Nutritional Sciences Programme, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
*Corresponding author: Dr Lai K. Leung, fax +852 26037732, email
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Epidemiological studies indicate that Asian women have a lower breast cancer incidence compared with their counterparts in the West, and the difference has been related to soya consumption. Animal studies have suggested that soya may prevent dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis in the breast. In the present study a cell culture model was developed to address the effect of soya isoflavones on the DMBA-induced DNA damage. DMBA is metabolized into a DNA-attacking moiety by two phase I cytochrome P450 (CYP) enzymes CYP1A1 and CYP1B1. DNA mutation caused by this genotoxic agent is a crucial step in cancer initiation. Substances that interfere with the CYP1 enzyme activities can affect the initiation. In the present study, genistein was found to be an effective inhibitor of recombinant human CYP1A1 and CYP1B1 with Ki of 15·35 and 0·68 μmol/l. The other soya isoflavone daidzein, on the other hand, did not demonstrate any significant inhibition of the enzyme activities. At the transcriptional level, DMBA induced the CYP1 enzyme expressions by stimulating the xenobiotic response element (XRE)-dependent transactivation pathway. When genistein (25 μmol/l) was co-administered with DMBA, the XRE-Luc activity the CYP1 mRNA abundances were significantly suppressed. The present study illustrated that the soya isoflavone genistein, but not daidzein, protected against DMBA genotoxicity.

Research Article
Copyright © The Nutrition Society 2003


Appelt, LC & Reicks, MM (1999) Soy induces phase II enzymes but does not inhibit dimethylbenz[a]anthracene-induced carcinogenesis in female rats. J Nutr 129, 18201826.CrossRefGoogle Scholar
Backlund, M, Johansson, I, Mkrtchian, S & Ingelman-Sundberg, M (1997) Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. J Biol Chem 272, 3175531763.CrossRefGoogle ScholarPubMed
Breinholt, V & Larsen, JC (1998) Detection of weak estrogenic flavonoids using a recombinant yeast strain and a modified MCF-7 cell proliferation assay. Chem Res Toxicol 11, 622629.CrossRefGoogle Scholar
Buters, JT, Sakai, S & Richter, T (1999) Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci USA 96, 19771982.CrossRefGoogle ScholarPubMed
Chae, YH, Ho, DK, Cassady, JM, Cook, VM, Marcus, CB & Baird, WM (1992) Effects of synthetic and naturally occurring flavonoids on metabolic activation of benzo[a]pyrene in hamster embryo cell cultures. Chem Biol Interact 82, 181193.CrossRefGoogle ScholarPubMed
Chang, HC, Churchwell, MI, Delclos, KB, Newbold, RR & Doerge, DR (2000) Mass spectrometric determination of genistein tissue distribution in diet-exposed Sprague-Dawley rats. J Nutr 130, 19631970.CrossRefGoogle ScholarPubMed
Ciolino, HP & Yeh, GC (1999) Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol. Mol Pharmacol 56, 760767.Google ScholarPubMed
Cohen, LA, Zhao, Z, Pittman, B & Scimeca, JA (2000) Effect of intact and isoflavone-depleted soy protein on NMU-induced rat mammary tumorigenesis. Carcinogenesis 21, 929935.CrossRefGoogle ScholarPubMed
Constantinou, AI, Lantvit, D, Hawthorne, M, Xu, X, van Breemen, RB & Pezzuto, JM (2001) Chemopreventive effects of soy protein and purified soy isoflavones on DMBA-induced mammary tumors in female Sprague-Dawley rats. Nutr Cancer 41, 7581.CrossRefGoogle ScholarPubMed
Day, JK, Besch-Williford, C, McMann, TR, Hufford, MG, Lubahn, DB & MacDonald, RS (2001) Dietary genistein increased DMBA-induced mammary adenocarcinoma in wild-type, but not ER alpha KO, mice. Nutr Cancer 39, 226232.CrossRefGoogle Scholar
Dertinger, SD, Lantum, HB, Silverstone, AE & Gasiewicz, TA (2000) Effect of 3′-methoxy-4′-nitroflavone on benzo[a]pyrene toxicity. Aryl hydrocarbon receptor-dependent and -independent mechanisms. Biochem Pharmacol 60, 189196.CrossRefGoogle ScholarPubMed
Dohr, O, Vogel, C & Abel, J (1995) Different response of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) – sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. Arch Biochem Biophys 321, 405412.CrossRefGoogle ScholarPubMed
Environmental Protection Agency (1990) Aerometric Information Retrieval System (AIRS), Data for 1985–1990. Washington, DC: Environmental Protection Agency.Google Scholar
Fritz, WA, Coward, L, Wang, J & Lamartiniere, CA (1998) Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19, 21512158.CrossRefGoogle ScholarPubMed
Gallo, D, Giacomelli, S, Cantelmo, F et al. (2001) Chemoprevention of DMBA-induced mammary cancer in rats by dietary soy. Breast Cancer Res Treat 69, 153164.CrossRefGoogle ScholarPubMed
Giri, AK & Lu, LJ (1995) Genetic damage and the inhibition of 7,12-dimethyl-benz[a]anthracene-induced genetic damage by the phytoestrogens, genistein and daidzein, in female ICR mice. Cancer Lett 95, 125133.CrossRefGoogle Scholar
Gonzalez, FJ & Gelboin, HV (1994) Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metab Rev 26, 165183.CrossRefGoogle ScholarPubMed
Hakkak, R, Korourian, S, Shelnutt, SR, Lensing, S, Ronis, MJ & Badger, TM (2000) Diets containing whey proteins or soy protein isolate protect against 7,12-dimethylbenz[a]anthracene-induced mammary tumors in female rats. Cancer Epidemiol Biomarkers Prev 9, 113117.Google ScholarPubMed
Helsby, NA, Chipman, JK, Gescher, A & Kerr, D (1998) Inhibition of mouse and human CYP1A- and 2E1dependent substrate metabolism by the isoflavonoids genistein and equol. Food Chem Toxicol 36, 375382.CrossRefGoogle ScholarPubMed
Hilakivi-Clarke, L, Onojafe, I, Raygada, M et al. (1999) Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. Br J Cancer 80, 16821688.CrossRefGoogle ScholarPubMed
Horn, TL, Reichert, MA, Bliss, RL & Malejka-Giganti, D (2002) Modulations of P450 mRNA in liver and mammary gland and P450 activities and metabolism of estrogen in liver by treatment of rats with indole-3-carbinol. Biochem Pharmacol 64, 393404.CrossRefGoogle ScholarPubMed
International Agency for Research on Cancer (1983) Polynuclear aromatic compounds, part I, chemical, environmental and experimental data. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Human, 32, 1453.Google Scholar
Iscan, M, Klaavuniemi, T, Coban, T, Kapucuoglu, N, Pelkonen, O & Raunio, H (2001) The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. Breast Cancer Res Treat 70, 4754.CrossRefGoogle ScholarPubMed
Izumi, T, Piskula, MK, Osawa, S et al. (2000) Soy isoflavone aglycones are absorbed faster and in higher amounts than their glucosides in humans. J Nutr 130, 16951699.CrossRefGoogle ScholarPubMed
Jin, Z & MacDonald, RS (2002) Soy isoflavones increase latency of spontaneous mammary tumour in mice. J Nutr 132, 31863190.CrossRefGoogle ScholarPubMed
Ju, YH, Allred, CD, Allred, KF, Karko, KL, Doerge, DR & Helferich, WG (2001) Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. J Nutr 131, 29572962.CrossRefGoogle ScholarPubMed
Kleiner, HE, Vulimiri, SV, Reed, MJ, Uberecken, A & DiGiovanni, J (2002) Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz-[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation. Chem Res Toxicol 15, 226235.CrossRefGoogle ScholarPubMed
Kronenberg, S, Esser, C & Carlberg, C (2000) An aryl hydrocarbon receptor conformation acts as the functional core of nuclear dioxin signaling. Nucleic Acids Res 28, 22862291.CrossRefGoogle ScholarPubMed
Lamartiniere, CA, Cotroneo, MS, Fritz, WA, Wang, J, Mentor-Marcel, R & Elgavish, A (2002) Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr 132, 552S558S.CrossRefGoogle ScholarPubMed
Lamartiniere, CA, Moore, J, Holland, MB & Barnes, S (1995) Neonatal genistein chemoprevents mammary carcinogenesis. Proc Soc Exp Biol Med 208, 120123.CrossRefGoogle Scholar
Lamartiniere, CA, Moore, JB, Brown, NM et al. (1995 b) Genistein suppresses mammary cancer in rats. Carcinogenesis 16, 28332840.CrossRefGoogle ScholarPubMed
Le Bail, JC, Varnet, F, Nicolas, JC & Habrioux, G (1998) Estrogenic and anti-proliferative activities on MCF-7 human breast cancer cells by flavonoids. Cancer Lett 130, 209216.CrossRefGoogle Scholar
Lee, H, Wang, HW, Su, HY & Hao, NJ (1994) The structure-activity relationships of flavonoids as inhibitors of cytochrome p-450 enzymes in rat liver microsomes and the mutagenicity of 2-amino-3-methyl-imidazo[4,5-f]quinoline. Mutagenesis 9, 101106.CrossRefGoogle ScholarPubMed
Leung, LK & Wang, TT (2000) Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. J Nutr 130, 29222926.CrossRefGoogle Scholar
Li, D, Wang, M, Dhingra, K & Hittelman, WN (1996) Aromatic DNA adducts in adjacent tissues of breast cancer patients: clues to breast cancer etiology. Cancer Res 56, 287293.Google ScholarPubMed
MacDonald, CJ, Ciolino, HP & Yeh, GC (2001) Dibenzoylmethane modulates aryl hydrocarbon receptor function and expression of cytochromes P50 1A1, 1A2, and 1B1. Cancer Res 61, 39193924.Google ScholarPubMed
Morton, MS, Arisaka, O, Miyake, N, Morgan, LD & Evans, BAJ (2002) Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. J Nutr 132, 31683171.CrossRefGoogle ScholarPubMed
Mosmann, T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65, 5563.CrossRefGoogle ScholarPubMed
Peterson, G & Barnes, S (1991) Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochem Biophys Res Commun 179, 661667.CrossRefGoogle ScholarPubMed
Po, LS, Wang, TT, Chen, ZY & Leung, LK (2002) Genistein-induced apoptosis in MCF-7 cells involves changes in Bak and Bcl-x without evidence of anti-oestrogenic effects. Br J Nutr 88, 463469.CrossRefGoogle Scholar
Rowlands, JC, He, L, Hakkak, R, Ronis, MJJ & Badger, TM (2001) Soy and whey proteins downregulate DMBA-induced liver and mammary gland CYP1 expression in female rats. J Nutr 131, 32813287.CrossRefGoogle ScholarPubMed
Safe, S (2001) Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol Lett 120, 17.CrossRefGoogle Scholar
Shao, ZM, Alpaugh, ML, Fontana, JA & Barsky, SH (1998) Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by p21WAF1/CIP1 induction G2/M arrest and apoptosis. J Cell Biochem 69, 4454.3.0.CO;2-V>CrossRefGoogle ScholarPubMed
Shertzer, HG, Puga, A, Chang, C et al. (1999) Inhibition of CYP1A1 enzyme activity in mouse hepatoma cell culture by soybean isoflavones. Chem Biol Interact 123, 3149.CrossRefGoogle ScholarPubMed
Shimizu, Y, Nakatsuru, Y, Ichinose, M et al. (2000) Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 97, 779782.CrossRefGoogle ScholarPubMed
Smith, WA, Freeman, JW & Gupta, RC (2001) Effect of chemopreventive agents on DNA adduction induced by the potent mammary carcinogen dibenzo[a,l]pyrene in the human breast cells MCF-7. Mutat Res 480481, 97108.CrossRefGoogle ScholarPubMed
So, FV, Guthrie, N, Chambers, AF & Carroll, KK (1997) Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Lett 112, 127133.CrossRefGoogle ScholarPubMed
Spink, BC, Fasco, MJ, Gierthy, JF & Spink, DC (1998 a) 12-O-tetradecanoylphorbol-13-acetate upregulates the Ah receptor and differentially alters CYP1B1 and CYP1A1 expression in MCF-7 breast cancer cells. J Cell Biochem 70, 289296.3.0.CO;2-J>CrossRefGoogle Scholar
Spink, DC, Spink, BC, Cao, JQ et al. (1998) Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells. Carcinogenesis 19, 291298.CrossRefGoogle ScholarPubMed
Taioli, E (1999) International collaborative study on genetic susceptibility to environmental carcinogens. Cancer Epidemiol Biomarkers Prev 8, 727728.Google ScholarPubMed
Upadhyaya, P & El-Bayoumy, K (1998) Effect of dietary soy protein isolate, genistein, and 1,4-phenylenebis(methylene)selenocyanate on DNA binding of 7,12-dimethyl-benz[a]anthracene in mammary glands of CD rats. Oncol Rep 5, 15411545.Google Scholar
Wang, C & Kurzer, MS (1997) Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutr Cancer 28, 236247.CrossRefGoogle ScholarPubMed
Wang, TT & Phang, JM (1995) Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. Cancer Res 55, 24872489.Google ScholarPubMed
Zhang, Y, Hendrich, S & Murphy, PA (2003) Glucuronides are the main isoflavone metabolites in women. J Nutr 133, 399404.CrossRefGoogle ScholarPubMed
Zheng, W, Xie, DW & Jin, F (2000) Genetic polymorphism of P450 1B1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 9, 147150.Google ScholarPubMed
Ziegler, RG, Hoover, RN & Pike, MC (1993) Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85, 18191827.CrossRefGoogle ScholarPubMed
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