Advertisement

Genetic and Carcinogenic Effects of Plant Flavonoids: An Overview

  • James T. MacGregor
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 177)

Abstract

Flavonoids, a diverse group of naturally occurring plant constituents which share the common structural feature of two phenyl rings linked by a three-carbon chain (Geissman and Hinreiner, 1952), are practically ubiquitous among vascular plants (Geissman, 1962), including food plants (Bate-Smith, 1954; Kühnau, 1976). The three-carbon chain may be formed into a third six-membered ring through an oxygen on one of these phenyl rings, and the naturally occurring derivatives are frequently polyphenolic. The structure and numbering of some common naturally-occurring flavonoids are illustrated in Figure 1.

Keywords

Mutagenic Activity Sister Chromatid Exchange Strain TA100 Plant Flavonoid Hamster Embryo Cell 
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. 1.
    Aeschbacher, H-U., Meier, H. and Ruch, E. (1982). Nonmutagenicity in vivo of the food flavonol quercetin. Nutrition and Cancer 4, 90–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Amacher, D.E., Paillet, S. and Ray, V.A. (1979). Point mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells, I. Application to genetic toxicology testing. Mutat. Res. 64, 391–406.PubMedCrossRefGoogle Scholar
  3. 3.
    Ambrose, A.M., Robbins, D.J., and Deeds, F. (1952). Comparative toxicities of quercetin and quercitrin. J. Am. Pharm. Assoc. 41, 119–122.Google Scholar
  4. 4.
    Axelrod, J. and Tomchick, R. (1959). Activation and inhibition of adrenaline metabolism. Nature (Lond.) 184, 2027.CrossRefGoogle Scholar
  5. 5.
    Bate-Smith, E.C. (1954). Flavonoid compounds in foods. Adv. Food. Res. 5, 261–300.PubMedCrossRefGoogle Scholar
  6. 6.
    Belt, J.A., Thomas, J.A., Buchsbaum, R.N. and Racker, E. (1979). Inhibition of lactate transport and glycolysis in Erlich ascites tumor cells by bioflavonoids. Biochemistry 18, 3506–3511.PubMedCrossRefGoogle Scholar
  7. 7.
    Bjeldanes, L.F. and Chang, 6.W. (1977). Mutagenic activity of quercetin and related compounds. Science 197, 577–578.PubMedCrossRefGoogle Scholar
  8. 8.
    Brown, J.P. (1980). A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat. Res. 75, 243–277.PubMedCrossRefGoogle Scholar
  9. 9.
    Brown, J.P. and Dietrich, P.S. (1979). Mutagenicity of plant flavonols in the Salmonella/mammalian microsome test-Activation of flavonol glycosides by mixed glycosidases from rat cecal bacteria and other sources. Mutat Res. 66, 223–240.PubMedCrossRefGoogle Scholar
  10. 10.
    Buening, M.K., Chang, R.L., Huang, M-T., Fortner, J.G., Wood, A.W. and Conney, A.H. (1981). Activation and inhibition of benzo(a)pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occurring flavonoids. Cancer Res. 41, 67–72.PubMedGoogle Scholar
  11. 11.
    Carrano, A.V. and Thompson, L.H. (1982). Sister chromatid exchange and single gene mutation. Cytogenet. Cell Genet. 33, 57–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Carver, J.H., Carrano, A.V. and Macgregor, J.T. (1983). Genetic effects of the flavonols galangin, kaempferol, and quercetin on Chinese hamster ovary cells in vitro. Mutat. Res. 113. 45–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Conney, A.H. (1982). Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res. 42, 4875–4917.PubMedGoogle Scholar
  14. 14.
    Cea, G.F.A., Etcheberry, K.F.C. and Dulout, F.N. (1983). Induction of micronuclei in mouse bone marrow by the flavonoid 5,31,41-trihydroxy-3,6,7,8-tetramethoxyflavone (THTMF). Mutat. Res. 119, 339–342.PubMedCrossRefGoogle Scholar
  15. 15.
    Clark, W.G. and Geissman, T.A. (1949). Potentiation of effects of epinephrine by flavonoid (“vitamin P-like”) compounds. Relation of structure to activity. J. Pharmacol. Exp.Ther. 95, 363–381.PubMedGoogle Scholar
  16. 16.
    Clemetson, C.A.B, and Anderson, L. (1966). Plant polyphenolics as antioxidants for ascorbic acid. Ann. N.Y. Acad. Sci. 136339–378.CrossRefGoogle Scholar
  17. 17.
    Deeds, F. (1968). Flavonoid metabolism, inComprehensive Biochemistry, Vol. 20, ed. M. Florkin and E.H. Stotz, Elsevier, Amsterdam, pp. 127–171.Google Scholar
  18. 18.
    Detty, W.E., Heston, B.O. and Wender, S.H. (1955). Amperometric titrations of some flavonoid compounds with cupric sulfate. 3. Am. Chem. Soc. 77162–165.CrossRefGoogle Scholar
  19. 19.
    Elliger, C.A., Henika, P.R. and Macgregor, J.T. (In press). Mutagenicity of flavones, chromones and acetophenones in Salmonella typhimurium: New structure-activity relationships. Mutat. Res. 00, 000–000.Google Scholar
  20. 20.
    Erturk, E., Nunoya, T., Hatcher, J.F., Pamukcu, A.M. and Bryan, G.T. (1983). Comparison of bracken fern and quercetin carcinogenicity in rats. Proc. Seventy-Fourth Ann. Mtg. Am. Assoc. Cancer Res. 24, 53 (March, 1983 ).Google Scholar
  21. 21.
    Fiebrich, F. and Koch, H. (1979). Silymarin, an inhibitor of lipoxygenase. Experientia 35, 1548–1550.PubMedCrossRefGoogle Scholar
  22. 22.
    Fiebrich, F. and Koch, H. (1979). Silymarin, an inhibitor of prostaglandin synthetase. Experientia 35. 1550–1552.PubMedCrossRefGoogle Scholar
  23. 23.
    Geissman, T.A. and Hinreiner, E. (1952). Theories of the biogenesis of flavonoid compounds. Bot. Rev. 18, 77 - 244.CrossRefGoogle Scholar
  24. 24.
    Geissman, T.A. (1962). The Chemistry of Flavonoid Compounds, MacMillan, New York.Google Scholar
  25. 25.
    Graziani, Y. (1977). Bioflavonoid regulation of ATPase and hexokinase activity in Erlich ascites cell mitochondria. Biochim. Biophys. Acta. 460, 364–373.PubMedCrossRefGoogle Scholar
  26. 26.
    Graziani, Y. and Chayoth, R. (1979). Regulation of cyclic AMP level and synthesis of DNA, RNA and protein by quercetin in Erlich ascites tumor cells. Biochem. Pharmacol. 28, 397–403.PubMedCrossRefGoogle Scholar
  27. 27.
    Graziani, Y., Chayoth, R., Karny, N., Feldman, B. and Levy, J. (1982). Regulation of protein kinases activity by quercetin in Erlich ascites tumor cells. Biochim. Biophys. Acta. 714415–421.PubMedCrossRefGoogle Scholar
  28. 28.
    Graziani, Y., Winikoff, J. and Chayoth, R. (1977). Regulation of cyclic AMP level and lactic acid production in Erlich ascites tumor cells. Biochim. Biophys. Acta 497, 499–506.PubMedCrossRefGoogle Scholar
  29. 29.
    Griffiths, L.A. (1975). The role of the intestinal microflora in flavonoid metabolism, in Flavonoid Chem. Biochem.. Proc. 4th Hung. Bioflavonoid Symp., Elsevier, Amsterdam, pp. 201–213.Google Scholar
  30. 30.
    Griffiths, L.A. (1982). Mammalian metabolism of flavonoids, in The Flavonoids: Advances in Research, ed. J.B. Harborne and T.J. Mabry, Chapman and Hall, Lond., pp. 681–718.Google Scholar
  31. 31.
    Gugler, R., Leschik, M. and Dengler, H.J. (1975). Disposition of quercetin in man after single oral and intravenous doses. Eur. J. Clin. Pharmacol. 9, 229–234.PubMedCrossRefGoogle Scholar
  32. 32.
    Hardigree, A.A. and Epler, J.L. (1977). Mutagenicity of plant flavonols in microbial systems. Abstr. 8th Ann. Htg. Environmental Mutagen Society, Colorado Springs, Colorado, p. 48.Google Scholar
  33. 33.
    Hardigree, A.A. and Epler, J.L. (1978). Comparative mutagenesis of plant flavonoids in microbial systems. Mutat. Res. 58, 231–239.PubMedCrossRefGoogle Scholar
  34. 34.
    Hirono, I., Ueno, I., Hosaka, S., Takanashi, H., Matsushima, T., Sugimura, T. and Natori, S. (1981). Carcinogenicity examination of quercetin and rutin in ACI rats. Cancer Lett. 11. 15–21.CrossRefGoogle Scholar
  35. 34a.
    Hirose, M., Fukushima, S., Sakata, T., Inui, M. and Ito, N. (1983). Effect of quercetin on two-stage carcinogenesis of the rat urinary bladder. Cancer Lett. 21, 23–27.PubMedCrossRefGoogle Scholar
  36. 35.
    Horowitz, R.M. (1981). Flavonoids, mutagens, and citrus, in Quality of Selected Fruits and Vegetables of North America, ed. R. Teranishi and H. Barrera-Benitez, American Chemical Society, Washington, D.C., pp. 43–59.CrossRefGoogle Scholar
  37. 36.
    Hosaka, S. and Hirono, I. (1981). Carcinogenicity test of quercetin by pulmonary adenoma bioassay in strain A mice. Gann 72, 327–328.PubMedGoogle Scholar
  38. 37.
    Hozier, J., Sawyer, J., Moore, M., Howard, B. and Clive, D. (1981). Cytogenetic analysis of the L5178Y/TK TlC mouse lymphoma mutagenesis assay system. Mutat. Res. 84, 169–181.PubMedCrossRefGoogle Scholar
  39. 38.
    Ishitsuka, H., Ohsawa, C., Ohiwa, T., Umeda, I. and Suhara, Y. (1982). Antipicornavirus flavone Ro 09-0179. Antimicrob. Ag. Chemother. 22, 611–616.CrossRefGoogle Scholar
  40. 39.
    Kato, R., Nakadate, T., Yamamoto, S. and Sugimura, T. (1983). Inhibition of T2-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxygenase inhibition. Carcinogenesis 4, 1301–1305.PubMedCrossRefGoogle Scholar
  41. 40.
    K’uhnau, J. (1976). The flavonoids. A class of semi-essential food components: Their role in human nutrition. Wld. Rev. Nutr. Diet. 24, 117–191.Google Scholar
  42. 41.
    Lang, D.R. and Racker, E. (1974). Effects of quercetin and Fx inhibitor on mitochondrial ATPase and energy-linked reactions in submitochondrial particles. Biochim. Biophys. Acta 333, 180–186.PubMedCrossRefGoogle Scholar
  43. 42.
    Lee, T-P., Matteliano, M.L. and Middleton, E., Jr. (1982). Effect of quercetin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism. Life Sci. 31. 2765–2774.PubMedCrossRefGoogle Scholar
  44. 43.
    Macgregor, J.T. and Jurd, L. (1978). Mutagenicity of plant flavonoids: Structural requirements for mutagenic activity in Salmonella typhimuri um. Mutat. Res. 54, 297–309.PubMedCrossRefGoogle Scholar
  45. 44.
    Macgregor, J.T., Wehr, C.M., Manners, G.D., Jurd, L., Minkler, J.L. and Carrano, A.V. (1983). In vivo exposure to plant flavonols: Influence on frequencies of micronuclei in mouse erythrocytes and sister-chromatid exchange in rabbit lymphocytes. Mutat. Res. 124, 255–270.PubMedCrossRefGoogle Scholar
  46. 45.
    Martin, G.J., Graff, M., Brendel, R. and Beiler, J.M. (1949). Effect of vitamin P compounds on the action of histidine decarboxylase. Arch. Biochem. 21, 177–180.PubMedGoogle Scholar
  47. 46.
    Martin, G.J., Szent-Györgyi, A., et aK (1955). Bioflavonoids and the capillary. Ann. N.Y. Acad. Sci. 61, 637–736.CrossRefGoogle Scholar
  48. 47.
    Maruta, A., Enaka, K. and Umeda, H. (1979). Mutagenicity of quercetin and kaempferol on cultured mammalian cells. Gann 70, 273–276.PubMedGoogle Scholar
  49. 48.
    Mazaki, M., Ishii, T. and Uyeta, M. (1982). Mutagenicity of hydrolysates of citrus fruit juices. Mutat. Res. 101283–291.PubMedCrossRefGoogle Scholar
  50. 49.
    Mccann, J. and Ames, B.N. (1975). Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals: Discussion. Proc. Nat. Acad. Sci. USA 73, 950–954.CrossRefGoogle Scholar
  51. 50.
    Mccann, J., Choi, E., Yamasaki, E. and Ames, B.N. (1975). Detection of carcinogens as mutagens in the Salmonella/ microsome test: Assay of 300 chemicals. Proc. Nat. Acad. Sci. USA 72, 5135–5139.PubMedCrossRefGoogle Scholar
  52. 51.
    Meltz, M.L. and Macgregor, J.T. (1981). Activity of the plant flavonol quercetin in the mouse lymphoma L5178Y TK mutation, DNA single-strand break and BALB/c 3T3 chemical transformation assays. Mutat. Res. 88, 317–324.PubMedCrossRefGoogle Scholar
  53. 52.
    Middleton, E., Jr. and Drzewiecki, G. (1982). Effects of flavonoids and transitional metal cations on antigen-induced histamine release from human basophils. Biochem. Pharmacol. 31, 1449–1453.PubMedCrossRefGoogle Scholar
  54. 53.
    Middleton, E., Jr., Drzewiecki, G. and Krishnarao, D. (1981). Quercetin: An inhibitor of antigen-induced human basophil histamine release. J. Immunol. 127, 546–550.PubMedGoogle Scholar
  55. 54.
    Morino, K., Matsukura, N., Kawachi, T., Ohgaki, H., Sugimura, T. and Hirono, I. (1982). Carcinogenicity test of quercetin and rutin in golden hamsters by oral administration. Carcinogenesis 3, 93–97.PubMedCrossRefGoogle Scholar
  56. 55.
    Nagao, M., Morita, N., Yahagi, T., Shimizu, M., Kuroyanagi, M., Fukuoka, M., Yoshihira, K., Natori, S., Fujino, T. and Sugimura, T. (1981). Mutagenicities of 61 flavonoids and 11 related compounds. Environ. Mutagenesis 3, 401–419.CrossRefGoogle Scholar
  57. 56.
    Pamukcu, A.M., Yalciner, S., Hatcher, J.F. and Bryan, G.T. (1980). Quercetin, a rat intestinal and bladder carcinogen present in bracken fern (Pteridium aquilinum). Cancer Res. 40, 3468–3472.PubMedGoogle Scholar
  58. 57.
    Perry, K.L. and Walker, G.C. (1982). Identification of plasmid (pKM101)-coded proteins involved in mutagenesis and UV resistance. Nature (Lond.) 300, 278–281.CrossRefGoogle Scholar
  59. 58.
    Perry, P. and Evans, H.J. (1975). Cytological detection of mutagen-carcinogen exposure by sister chromatid exchange. Nature (Lond.) 258, 121–125.CrossRefGoogle Scholar
  60. 59.
    Podhajcer, O.L., Friedlander, M. and Graziani,Y. (1980). Effect of liposome-encapsulated quercetin on DNA synthesis, lactate production, and cyclic adenosine 31:5’-monophosphate level in Erlich ascites tumor cells. Cancer Res. 40, 1344–1350.PubMedGoogle Scholar
  61. 60.
    Popova, T.P., Litvinenko, V. L. and Kovalev, I.P. (1973). Flavones of Scutellaria baicalensis roots. Khim. Prir. Soedin 6, 729–733.Google Scholar
  62. 61.
    Popova, T.P., Litvinenko, V. L. and Pakaln, D.A. (1979). Study of phenol compounds of populations of Scutellaria sevanensis, Farm Zh. (Kiev) 6, 49–53.Google Scholar
  63. 62.
    Richardson, G.A., El-Rafey, M.S. and Long, M.L. (1947). Flavones and flavone derivatives as antioxidants. J. Dairy Sci. 30, 397–413.CrossRefGoogle Scholar
  64. 63.
    Sacks, L.E. and Macgregor, J.T. (1982). The B. subtil is multigene sporulation test for mutagens: Detection of mutagens inactive in the Salmonella his reversion test. Hutat. Res. 95, 191–202.CrossRefGoogle Scholar
  65. 64.
    Sacks, L.E. and Macgregor, J.T. (In press). The Bacillus subtilis multigene sporulation test for detection of environmental mutagens, in Chemical Mutagens, Vol. 9, ed. F.J. deSerres, Plenum Press, p. 000-000.Google Scholar
  66. 65.
    Sahu, R.K., Basu, R. and Sharma, A. (1981). Genetic toxicological testing of some plant flavonoids by the micronucleus test. Mutat. Res. 89, 69–74.PubMedCrossRefGoogle Scholar
  67. 66.
    Saito, D., Shirai, A., Matsushima, T., Sugimura, T., and Hirono, I. (1980). Test of carcinogenicity of quercetin, a widely distributed mutagen in food. Teratogen. Carcinogen. Mutagen. 1, 213–221.CrossRefGoogle Scholar
  68. 67.
    Savage, P.C. (1977). Microbial ecology of the gastrointestinal tract. Ann. Rev. Microbiol. 31, 107–133.CrossRefGoogle Scholar
  69. 68.
    Scarborough, H. and Bacharach, A.L. (1949). Vitamin P. Vitamins and Hormones 7, 1–55.CrossRefGoogle Scholar
  70. 69.
    Scheline, R.R. (1978). Mammalian Metabolism of Plant XenobioticsAcademic Press, N.Y., pp. 295–329.Google Scholar
  71. 70.
    Schwartz, A. Sutton, S.L. and Middleton, E., Jr. (1982). Quercetin inhibition of the induction and function of cytotoxic T lymphocytes. Immunopharmacol. 4, 125–138.CrossRefGoogle Scholar
  72. 71.
    Simpson, T.H. and Uri, N. (1956). Hydroxyflavones as inhibitors of the aerobic oxidation of unsaturated fatty acids. Chemistry and Industry. 956–957.Google Scholar
  73. 72.
    Spector, M., O’Neal, S. and Racker, E. (1980). Reconstitution of the Na+K+ pump of Erlich ascites tumor and enhancement of efficiency by quercetin. J. Biol. Chem. 255, 5504–5507.PubMedGoogle Scholar
  74. 73.
    Suolinna, E-M., Buchsbaum, R.N. and Racker, E. (1975). The effect of flavonoids on aerobic glycolysis and growth of tumor cells. Cancer Res. 35, 1865–1872.PubMedGoogle Scholar
  75. 74.
    Suolinna, E-M., Lang, D. and Racker, E. (1974). Quercetin, an artificial regulator of the high aerobic glycolysis of tumor cells. J. Natl. Cancer Inst. 53, 1515–1519.PubMedGoogle Scholar
  76. 75.
    Sugimura, T., Nagao, M., Matsushima, T., Yahagi, T., Scino, Y., Shirai, A., Sawamura, M., Natori, S., Yoshihira, K., Fukuoka, M. and Kuroyanagi, M. (1977). Mutagenicity of flavone derivatives. Proc. Jpn. Acad.. Ser. B. 53, 194–197.CrossRefGoogle Scholar
  77. 76.
    Takanashi, H., Aiso, S. and Hirono, I. (1983). Carcinogenicity test of quercetin and kaempferol in rats by oral administration. J. Food Safety 5, 55–60.CrossRefGoogle Scholar
  78. 77.
    Ueno. I., Nakano, N. and Hirono, I. (1983). Metabolic fate of [ C] quercetin in the ACI rat. Japan. J. Exp. Med. 53, 41–50.Google Scholar
  79. 78.
    Umezawa, K., Matsushima, T., Sugimura, T., Hirakawa, T., Tanaka, M., Katoh, Y., and Takayama, S. (1977). In vitrotransformation of hamster embryo cells by quercetin. Toxicol. Lett. 1, 175–178.Google Scholar
  80. 79.
    United States Department of Health and Human Services (1983). Fiscal Year 1983 Annual Plan. National Toxicology Program. Research Triangle Park, N.C.Google Scholar
  81. 80.
    van der Hoeven, J.C.M., Bruggeman, I.M. and Debets, F.M.H. (In press). Genotoxicity of quercetin in cultured mammalian cells. Mutat. Res. 000. 000–000.Google Scholar
  82. 81.
    Varma, S.D. and Kinoshita, J.H. (1976). Inhibition of lens aldose reductase by flavonoids - Their possible role in the prevention of diabetic cataracts. Biochem. Pharmacol. 25., 2505–2513.Google Scholar
  83. 82.
    Vogel, E. (1975). Some aspects of the detection of potential mutagenic agents in Drosophila. Mutat. Res. 29, 241–250.PubMedCrossRefGoogle Scholar
  84. 83.
    Wargovich, M.J. and Newmark, H.L. (1983). Inability of several mutagen-blocking agents to inhibit 1, 2-dimethylhydrazine-induced DNA-damaging activity in colonic epithelium. Mutat. Res. 121, 77–80.PubMedCrossRefGoogle Scholar
  85. 84.
    Watson, W.A.F. (1982). The mutagenic activity of quercetin and kaempferol in Drosophila melanogaster. Mutat. Res. 103, 145–147.PubMedCrossRefGoogle Scholar
  86. 85.
    Wattenberg, L.W. and Leong, J.L. (1968). Inhibition of the carcinogenic action of 7,12-dimethylbenz(a)anthracene by beta-naphthoflavone. Proc. Soc. Exp. Biol. Med. 128, 940–943.Google Scholar
  87. 86.
    Wattenberg, L.W. and Leong, J.L. (1970). Inhibition of the carcinogenic action of benzo(a)pyrene by flavones. Cancer Res. 30, 1922–1925.PubMedGoogle Scholar
  88. 87.
    Wattenberg, L.W., Page, M.A. and Leong, S.L. (1968). Induction of increased benzpyrene hydroxylase activity by flavone and related compounds. Cancer Res. 28, 934–937.PubMedGoogle Scholar
  89. 88.
    Wollenweber, E. and Dietz, V.H. (1981). Occurrence and distribution of free flavonoid aglycones in plants. Phytochem. 20, 869–932.CrossRefGoogle Scholar
  90. 89.
    Yoshida, M.A., Sasaki, M., Sugimura, K., and Kawachi, T. (1980). Cytogenetic effects of quercetin on cultured mammalian cells. Proc. Japan Acad. 56(B), 443–447.Google Scholar
  91. 90.
    Zaprometov, M.N. (1959). Vitamin P and its uses, in Vitamin P, Its Properties and Uses, Akademiya Nauk SSSR, Vitamin Sources and their Utilization, Collection 4, Trans, for Nat. Sci. Found., Washington, D.C. by Israel Program for Scientific Translations, Jerusalem, 1963, pp. 3–21.Google Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • James T. MacGregor
    • 1
  1. 1.Western Regional Research CenterUnited States Department of AgricultureBerkeleyUSA

Personalised recommendations