Advertisement

Inhibition of Neoplastic Transformation and Bioavailability of Dietary Flavonoid Agents

  • Adrian A. Franke
  • Robert V. Cooney
  • Laurie J. Custer
  • Lawrence J. Mordan
  • Yuichiro Tanaka
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Breast Milk Neoplastic Transformation Human Body Fluid Dietary Flavonoid Transformation Assay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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
  7. 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.CrossRefGoogle Scholar
  8. Block, G.; Patterson, B.; Subar, A. Fruit, Vegetables, and Cancer Prevention: A Review of the Epidemiological Evidence. Nutr. Cancer 1992, 18, 1–29.PubMedCrossRefGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. Das, N.P. Plant flavonoids in biology and medicine III, NY: A.R. Liss, 1990.Google Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.Google Scholar
  16. 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.CrossRefGoogle Scholar
  17. Franke, A. A.; Custer, L. J. Daidzein and genistein concentrations in human milk after soy consumption. Clin. Chem. 1996, 42, 955–964.PubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. Fuhr, U.; Kummert, A. The fate of naringenin in humans: a key to grapefruit juice-drug interactions? Clin. Pharmacol. Ther. 1995, 58, 365–373.PubMedCrossRefGoogle Scholar
  20. 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
  21. Herrmann, K. On the occurrence of flavonol and flavone glycosides in vegetables. Z. Lebensm. Unters. Forsch. 1988, 186, 1–5.CrossRefGoogle Scholar
  22. 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.Google Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.Google Scholar
  32. Lamartiniere, C. A.; Moore, J.; Holland, M.; Barnes, S. Neonatal genistein chemoprevents mammary cancer. Proc. Soc. Exp. Bio. Med. 1995, 208, 120–123.Google Scholar
  33. Lawrence, R.A. Breastfeeding, St. Louis: Mosby, 1994. Ed. 4Google Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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
  36. 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.Google Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.Google Scholar
  39. 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.CrossRefGoogle Scholar
  40. Marzo, A.; Arrigoni Martelli, E.; Bruno, G. Assay of hydroxyfarrerol in biological fluids. J. Chromatography 1990, 535, 255–261.CrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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
  43. 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.CrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. Price, K. R.; Fenwick, G. R. Naturally occurring oestrogens in foods-A review. Food Additives & Contaminants 1985, 2, 73–106.CrossRefGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. Setchell, K.D.R. in McLachlan, J.A. (editor) Estrogens in the environment, New York.Elsevier, 1985. pp. 69–83.Google Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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
  52. Stavric, B. The role of polyphenols as chemopreventers. Polyphenols Actualites 1995, 13, 19–21.Google Scholar
  53. 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.PubMedGoogle Scholar
  54. Wang, H.; Murphy, P. A. Isoflavone content in commercial soybean foods. J Agric Food Chem 1994, 42, 1666–1673.CrossRefGoogle Scholar
  55. 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.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Adrian A. Franke
    • 1
  • Robert V. Cooney
    • 1
  • Laurie J. Custer
    • 1
  • Lawrence J. Mordan
    • 1
  • Yuichiro Tanaka
    • 1
  1. 1.Cancer Research Center of HawaiiHonoluluUSA

Personalised recommendations