Skip to main content
SpringerLink
Log in

Inhibition of Neoplastic Transformation and Bioavailability of Dietary Flavonoid Agents

  • Chapter
Flavonoids in the Living System

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 439))

Abstract

Evaluation of unknown biological effects of chemicals including food plant products requires the assessment of bioactivity and bioavailability. Epidemiologic studies show consistently a cancer protective effect of fruit and vegetable consumption, but there is little understanding of which phytochemicals account for this observation. Commonly studied antioxidant micronutrients are less consistently correlated with cancer protection relative to the food groups themselves, suggesting that other phytochemicals or a combination of food products play key roles in preventing cancer. We investigated the effects of the predominant dietary flavonoids and isoflavonoids at inhibiting neoplastic transformation induced by 3methylcholanthrene in C3H 10T1/2 murine fibroblasts. We found that most phenolic agents tested were equal to or superior to known chemopreventive agents such as carotenoids or vitamins in effectiveness. Hesperetin, hesperidin and catechin were the most potent agents among the flavonoids tested, inhibiting transformation completely when applied at 1.0 μM after exposure to the carcinogen. Structure-activity comparison revealed that among the compounds tested, flavonoids with a vicinal diphenol structure in ring ‘B’ and a saturated ‘C’ ring exhibited the strongest effects. Most agents tested showed dose-dependent patterns. Interestingly, the soy isoflavonoids were weakly active except when applied in combination, suggesting a synergistic effect. In addition, HPLC techniques were developed for determining the bioavailability of isoflavonoids in human biological fluids including urine, plasma and breast milk. We observed a relatively fast absorption, distribution and elimination of isoflavonoids including a biphasic pattern probably due to enterohepatic circulation. Total peak isoflavone levels in urine, plasma and in breast milk were found to be 60 μM, 2 μM and 0.2 μM, respectively and were reached 8—12 hours after consumption of soy foods. Lev els detected in human body fluids were found to be highly active at inhibiting neoplastic transformation, especially considering synergistic effects observed for combinations of daidzein and genistein, the predominant isoflavonoids occurring in soy foods.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adlercreutz, H.; Fotsis, T.; Bannwart, C.; Wahala, K.; Brunow, G.; Hase, T. Isotope dilution gas chromatographie-mass spectrometric method for the determination of lignans and isoflavonoids in human urine, including identification of genistein. Clin Chim Acta 1991, 199, 263–278.

    Article  PubMed  CAS  Google Scholar 

  • Adlercreutz, H.; Fotsis, T.; Lampe, J.; Wahala, T.; Makela, T.; Brunow, G.; Hase, T. Quantitative determination of lignans and isoflavonoids in plasma of omnivorous and vegetarian women by isotope dilution gas chromatography-mass spectrometry. Scand J Clin Lab Invest 1993, 53, 5–18.

    Article  CAS  Google Scholar 

  • Adlercreutz, H.; Fotsis, T.; Kurzer, M. S.; Wahala, K.; Makela, T.; Hase, T. Isotope dilution gas chromatographic-mass spectrometric method for the determination of unconjugated lignans and isoflavonoids in human feces, with preliminary results in omnivorous and vegetarian women. Anal. Biochem. 1995, 225, 101–108.

    Article  PubMed  CAS  Google Scholar 

  • Arnold, J. T.; Wilkinson, B. P.; Sharma, S.; Steele, V. E. Evaluation of chemopreventive agents in different mechanistic classes using a rat tracheal epithelial cell culture transformation assay. Cancer Research 1995, 55, 537–543.

    PubMed  CAS  Google Scholar 

  • Baird, D. D.; Umbach, D. M.; Lansdell, L.; Hughes, C. L.; Setchell, K. D. R.; Weinberg, C. R.; Haney, A. F.; Wilcox, A. J.; McLachlan, J. A. Dietary intervention study to.assess estrogenicity of dietary soy among postmenopausal women. J. Clin. Endocrinol. Metab. 1995, 80, 1685–1690.

    Article  PubMed  CAS  Google Scholar 

  • Barnes, S. Serum conjugated and unconjugated isoflavones by capillary reversed-phase HPLC-electrospray ionization-mass Spectrometry. NCI Meeting on “Dietary Phytoestrogens: Cancer Cause or Prevention?”; Sept.21–23, 1994; Herndon, VA; Abstract #1, 1994.

    Google Scholar 

  • Barnes, S.; Kirk, M.; Coward, L. Isoflavones and their conjugates in soy foods: extraction conditions and analysis by hplc-mass spectrometry. J. Agr. Food Chem. 1994, 42, 2466–2474.

    Article  CAS  Google Scholar 

  • Block, G.; Patterson, B.; Subar, A. Fruit, Vegetables, and Cancer Prevention: A Review of the Epidemiological Evidence. Nutr. Cancer 1992, 18, 1–29.

    Article  PubMed  CAS  Google Scholar 

  • Cassidy, A.; Bingham, S.; Setchell, K. D. R. Biological effect of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994, 60, 333–340.

    PubMed  CAS  Google Scholar 

  • Cooney, R. V.; Franke, A. A.; Harwood, P. J.; Hatch-Pigott, V.; Custer, L. J.; Mordan, L. J. Gamma-tocopherol detoxification of nitrogen dioxide: Superiority to alpha-tocopherol. Proc. Natl. Acad. Sci. USA 1993, 90, 1771–1775.

    Article  PubMed  CAS  Google Scholar 

  • Coward, L.; Kirk, M.; Albin, N.; Barnes, S. Analysis of plasma isoflavones by reversed-phase HPLC-multiple reaction ion monitoring-mass spectrometry. Clin. Chim. Acta 1996, 247, 121–142.

    Article  PubMed  CAS  Google Scholar 

  • Cruz, M. L. A.; Wong, W. W.; Mimouni, E; Hachey, D. L.; Setchell, K. D. R.; Klein, P. D.; Tsang, R. C. Effects of infant nutrition on cholesterol synthesis rates. Pediatric Research 1994, 35, 135–140.

    Article  PubMed  CAS  Google Scholar 

  • Das, N.P. Plant flavonoids in biology and medicine III, NY: A.R. Liss, 1990.

    Google Scholar 

  • Fotsis, T.; Pepper, M.; Adlercreutz, H.; Fieischmann, G.; Hase, T.; Montesano, T.; Schweigerer, L. Genistein, a dietary-derived inhibitor of in vitro aniogenesis. Proc. Natl. Acad. Sci. 1993, 90, 2690–2694.

    Article  PubMed  CAS  Google Scholar 

  • Franke, A. A.; Custer, L. J. High-performance liquid chromatography assay of isoflavonoids and coumestrol from human urine. J Chromatogr. B 1994, 662, 47–60.

    CAS  Google Scholar 

  • Franke, A. A.; Custer, L. J.; Cerna, C. M.; Narala, K. K. Quantitation of phytoestrogens in legumes by HPLC. J Agric Food Chem 1994, 42, 1905–1913.

    Article  CAS  Google Scholar 

  • Franke, A. A.; Custer, L. J. Daidzein and genistein concentrations in human milk after soy consumption. Clin. Chem. 1996, 42, 955–964.

    PubMed  CAS  Google Scholar 

  • Franke, A. A.; Custer, L. J.; Wang, W.; Shi, S. J. HPLC analysis of isoflavonoids and other phenolic agents from foods and from human fluids. Proc Soc Exp Biol Med 1998, 217, 263–273.

    PubMed  CAS  Google Scholar 

  • Fuhr, U.; Kummert, A. The fate of naringenin in humans: a key to grapefruit juice-drug interactions? Clin. Pharmacol. Ther. 1995, 58, 365–373.

    Article  PubMed  CAS  Google Scholar 

  • Griffith, L.A. Mammalian metabolism of flavonoids. In: The Flavonoids: Advances in Research, edited by Harborne, J.B. and Mabry, T.J. London/New York: Chapman and Hall, 1982, p. 681–718.

    Google Scholar 

  • Herrmann, K. On the occurrence of flavonol and flavone glycosides in vegetables. Z. Lebensm. Unters. Forsch. 1988, 186, 1–5.

    Article  CAS  Google Scholar 

  • Hirano, T.; Oka, K.; Akiba, M. Antiproliferative effects of synthetic and naturally occurring flavonoids on tumor cells of the human breast carcinoma cell line, ZR-75-1. Res Comm Chem Path Pharm 1989, 64, 69–78.

    CAS  Google Scholar 

  • Hirano, T.; Gotoh, M.; Oka, K. Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci. 1994, 55, 1061–1069.

    Article  PubMed  CAS  Google Scholar 

  • Hollman, P. C. H.; Gaag, M.; Mengelers, M. J. B.; Van Trijp, J. M. P.; de Vries, J. H. M.; Katan, M. B. Absorption and disposition kinetics of the dietary antioxidant quercetin in man. Free Rad. Biol. Med. 1996, 21, 703–707.

    Article  PubMed  CAS  Google Scholar 

  • Huang, M.-T. and Ferraro, T. Phenolic compounds and their effects on Health II. In: Phenolic Compounds and Cancer Prevention, edited by Huang, M.-T., Ho, C.-T. and Lee, C.Y. Washington, D.C.: American Cancer Society Press, 1992, p. 9–34.

    Google Scholar 

  • Hutchins, A. M.; Lampe, J. W.; Martini, M. C.; Campbell, D. R.; Slavin, J. L. Vegetables, fruits, and legumes: Effect on urinary isoflavonoid phytoestrogen and lignan excretion. J. Am. Diet Assoc. 1995a, 95, 769–774.

    Article  PubMed  CAS  Google Scholar 

  • Hutchins, A. M.; Slavin, J. L.; Lampe, J. W. Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products. J. Am. Diet Assoc. 1995b, 95, 545–551.

    Article  PubMed  CAS  Google Scholar 

  • Jung, G.; Hennings, G.; Pfeifer, M.; Bessler, W. G. Interaction of metal-complexing compounds with lymphocytes and lymphoid cell lines. Molecular Pharmacology 1983, 23, 698–702.

    PubMed  CAS  Google Scholar 

  • Kelly, G. E.; Nelson, C.; Waring, M. A.; Joannou, G. E.; Reeder, A. Y. Metabolites of dietary (soya) isoflavones in human urine. Clinica Chimica Acta 1993, 223, 9–22.

    Article  CAS  Google Scholar 

  • Kudou, S.; Fluery, Y; Welti, D.; Magnolato, D.; Uchida, T.; Kitamura, K.; Okubo, M. Malonyl isoflavone glycosides in soybean seeds (Glycine max MERRILL). Agric Biol Chem 1991, 55, 2227–2233.

    Article  CAS  Google Scholar 

  • Kurzer, M. S.; Lampe, J. W.; Martini, M. C; Adlercreutz, H. Fecal lignan and isoflavonoid excretion in premenopausal women consuming flaxseed power. Cancer Epidemiology, Biomarkers & Prevention 1995, 4, 353–358.

    CAS  Google Scholar 

  • Lamartiniere, C. A.; Moore, J.; Holland, M.; Barnes, S. Neonatal genistein chemoprevents mammary cancer. Proc. Soc. Exp. Bio. Med. 1995, 208, 120–123.

    CAS  Google Scholar 

  • Lawrence, R.A. Breastfeeding, St. Louis: Mosby, 1994. Ed. 4

    Google Scholar 

  • Le Marchan, L.; Yoshizawa, C. N.; Kolonel, L. N.; Hankin, J. H.; Goodman, M. T. Vegetable consumption and lung cancer risk: A population-based case-control study in Hawaii. J. Natl. Cancer Institute 1989, 81, 1158–1164.

    Article  Google Scholar 

  • Le Marchan, L.; Hankin, J. H.; Kolonel, L. N.; Beecher, G. R.; Wilkens, L. R.; Zhao, L. P. Intake of Specific Carotenoids and Lung Cancer Risk. Cancer Epidemiol., Biomarkers, & Prev. 1993, 2, 183–187.

    Google Scholar 

  • Lee, M.-J.; Wang, Z.-Y; Li, H.; Chen, L.; Sun, Y; Gobbo, S.; Balentine, D. A.; Yang, C. S. Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiology, Biomarkers & Prevention 1995, 4, 393–399.

    CAS  Google Scholar 

  • Leighton, T., Ginther, C., Fluss, L., Harter, W.K., Cansado, J. and Notario, V. Molecular characterization of quercetin and quercetin glycosides in Allium vegetables. In: Phenolic compounds in foods and their effects on Health II, edited by Huang, M.-T., Ho, C.-T. and Lee, C.Y. Washington, DC: American Chemical Society, 1992, p. 220–238.

    Chapter  Google Scholar 

  • Li, Y.; Wang, E.; Patten, C. J.; Chen, L.; Yang, C. S. Effects of flavonoids on cytochrome P450-dependent acetaminophen metabolism in rats and human liver microsomes. Drug Metab. Dispo. 1994, 22, 566–571.

    CAS  Google Scholar 

  • Mangels, A. R.; Holden, J. M.; Beecher, G. R.; Forman, M. R.; Lanza, E. Carotenoid Content of Fruits and Vegetables: An Evaluation of Analytic Data. Am. Diet. Assoc. 1993, 93, 284–296.

    Article  CAS  Google Scholar 

  • Marzo, A.; Arrigoni Martelli, E.; Bruno, G. Assay of hydroxyfarrerol in biological fluids. J. Chromatography 1990, 535, 255–261.

    Article  CAS  Google Scholar 

  • Messina, M.; Persky, V.; Setchell, K. D. R.; Barnes, S. Soy intake and cancer risk: A review of in vitro and in vivo data. Nutrition and Cancer 1994, 21, 113–131.

    Article  PubMed  CAS  Google Scholar 

  • Middleton, E., Jr. and Kandaswami, C. The impact of plant flavonoids on mammalian biology: Implications for immunity, inflammation and cancer. In: The Flavonoids: Advances in Research Since 1986, edited by Harborne, J.B. London: Chapman & Hall, 1994, p. 619–652.

    Google Scholar 

  • Mordan, L. J.; Bergin, L. M.; Budnick, J. E. L.; Meegan, R. R.; Bertram, J. S. Isolation of methylcholanthrene-in-itiated C3H/10T1/2 cells by inhibiting neoplastic progression with retinyl acetate. Carcinogenesis 1985, 3, 279–285.

    Article  Google Scholar 

  • Peterson, G.; Barnes, S. Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. The Prostate 1993, 22, 335–345.

    Article  PubMed  CAS  Google Scholar 

  • Peterson, T. G.; Barnes, S. Genistein inhibition of the growth of human breast cancer cells: indepdnence from estrogen receptors and the multi-drug resistance gene. Biochem. Biophys. Res. Comm. 1991, 179, 661–667.

    Article  PubMed  CAS  Google Scholar 

  • Price, K. R.; Fenwick, G. R. Naturally occurring oestrogens in foods-A review. Food Additives & Contaminants 1985, 2, 73–106.

    Article  CAS  Google Scholar 

  • Reznikoff, C. A.; Bertram, J. S.; Brankow, D. W.; Heidelberger, C. Quantitative and qualitative studies on chemical transformation of clones C3H mouse embryo cells sensitive to postconfluence inhibiton of cell division. Cancer Res. 1973, 33, 3239–3249.

    PubMed  CAS  Google Scholar 

  • Schweigerer, L.; Christeleit, K.; Fleischmann, G.; Adlercreutz, H.; Wahala, K.; Hasa, T.; Schwab, M.; Ludwig, R.; Fotsis, T. Identification in human urine of a natural growth inhibitor for cells derived from solid paediatric tumours. Eur J Clin Invest 1992, 22, 260–264.

    Article  PubMed  CAS  Google Scholar 

  • Setchell, K.D.R. in McLachlan, J.A. (editor) Estrogens in the environment, New York.Elsevier, 1985. pp. 69–83.

    Google Scholar 

  • Setchell, K. D. R.; Welch, M. B.; Lim, C. K. HPLC analysis of phytoestrogens in soy protein preparations with ultraviolet, electrochemical and thermospray mass spectrometric detection. J Chromatogr 1987, 386, 315–323.

    Article  PubMed  CAS  Google Scholar 

  • Sfakianos, J.; Coward, L.; Kirk, M.; Barnes, S. Intestinal uptake and biliary excretion of the isoflavone genistein in the rat: evidence for its enterohepatic circulation. J. Nutr. 1996 (in press).

    Google Scholar 

  • Stavric, B. The role of polyphenols as chemopreventers. Polyphenols Actualites 1995, 13, 19–21.

    Google Scholar 

  • Wakui, Y; Yanagisawa, E.; Ishibashi, E.; Matsuzaki, Y; Takeda, S.; Sasaki, H.; Aburada, M.; Oyama, T. Determination of baicalin and baicalein in rat plasma by high-performance liquid chromatography with electrochemical detection. J. Chromatogr. 1992, 575, 131–136.

    PubMed  CAS  Google Scholar 

  • Wang, H.; Murphy, P. A. Isoflavone content in commercial soybean foods. J Agric Food Chem 1994, 42, 1666–1673.

    Article  CAS  Google Scholar 

  • Xu, X.; Wang, H.-J.; Murphy, P. A.; Cook, L.; Hendrich, S. Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J. Nutr. 1994, 124, 825–832.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii, 96813, USA

    Adrian A. Franke, Robert V. Cooney, Laurie J. Custer, Lawrence J. Mordan & Yuichiro Tanaka

Authors
  1. Adrian A. Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert V. Cooney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurie J. Custer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lawrence J. Mordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuichiro Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. United States Department of Agriculture, Citrus and Subtropical Products Laboratory, P.O. Box 1909, 33883, Winter Haven, Florida, USA

    John A. Manthey

  2. State of Florida Department of Citrus, 700 Experiment Station Road, Lake Alfred, Florida, 33850, USA

    Béla S. Buslig

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Franke, A.A., Cooney, R.V., Custer, L.J., Mordan, L.J., Tanaka, Y. (1998). Inhibition of Neoplastic Transformation and Bioavailability of Dietary Flavonoid Agents. In: Manthey, J.A., Buslig, B.S. (eds) Flavonoids in the Living System. Advances in Experimental Medicine and Biology, vol 439. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5335-9_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-5335-9_17

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7434-3

  • Online ISBN: 978-1-4615-5335-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation