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Genetic and Carcinogenic Effects of Plant Flavonoids: An Overview

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Part of the book series: Advances in Experimental Medicine and Biology ((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.

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References

  1. Aeschbacher, H-U., Meier, H. and Ruch, E. (1982). Nonmutagenicity in vivo of the food flavonol quercetin. Nutrition and Cancer 4, 90–98.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  3. Ambrose, A.M., Robbins, D.J., and Deeds, F. (1952). Comparative toxicities of quercetin and quercitrin. J. Am. Pharm. Assoc. 41, 119–122.

    CAS  Google Scholar 

  4. Axelrod, J. and Tomchick, R. (1959). Activation and inhibition of adrenaline metabolism. Nature (Lond.) 184, 2027.

    Article  CAS  Google Scholar 

  5. Bate-Smith, E.C. (1954). Flavonoid compounds in foods. Adv. Food. Res. 5, 261–300.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  7. Bjeldanes, L.F. and Chang, 6.W. (1977). Mutagenic activity of quercetin and related compounds. Science 197, 577–578.

    Article  PubMed  CAS  Google Scholar 

  8. Brown, J.P. (1980). A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat. Res. 75, 243–277.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  11. Carrano, A.V. and Thompson, L.H. (1982). Sister chromatid exchange and single gene mutation. Cytogenet. Cell Genet. 33, 57–61.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  13. Conney, A.H. (1982). Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res. 42, 4875–4917.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  16. Clemetson, C.A.B, and Anderson, L. (1966). Plant polyphenolics as antioxidants for ascorbic acid. Ann. N.Y. Acad. Sci. 136339–378.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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. 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. Fiebrich, F. and Koch, H. (1979). Silymarin, an inhibitor of lipoxygenase. Experientia 35, 1548–1550.

    Article  PubMed  CAS  Google Scholar 

  22. Fiebrich, F. and Koch, H. (1979). Silymarin, an inhibitor of prostaglandin synthetase. Experientia 35. 1550–1552.

    Article  PubMed  CAS  Google Scholar 

  23. Geissman, T.A. and Hinreiner, E. (1952). Theories of the biogenesis of flavonoid compounds. Bot. Rev. 18, 77 - 244.

    Article  CAS  Google Scholar 

  24. Geissman, T.A. (1962). The Chemistry of Flavonoid Compounds, MacMillan, New York.

    Google Scholar 

  25. Graziani, Y. (1977). Bioflavonoid regulation of ATPase and hexokinase activity in Erlich ascites cell mitochondria. Biochim. Biophys. Acta. 460, 364–373.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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. 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.

    Article  PubMed  CAS  Google Scholar 

  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. Hardigree, A.A. and Epler, J.L. (1978). Comparative mutagenesis of plant flavonoids in microbial systems. Mutat. Res. 58, 231–239.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. 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.

    Chapter  Google Scholar 

  37. Hosaka, S. and Hirono, I. (1981). Carcinogenicity test of quercetin by pulmonary adenoma bioassay in strain A mice. Gann 72, 327–328.

    PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

  39. Ishitsuka, H., Ohsawa, C., Ohiwa, T., Umeda, I. and Suhara, Y. (1982). Antipicornavirus flavone Ro 09-0179. Antimicrob. Ag. Chemother. 22, 611–616.

    Article  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. 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. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. 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.

    PubMed  CAS  Google Scholar 

  47. Martin, G.J., Szent-Györgyi, A., et aK (1955). Bioflavonoids and the capillary. Ann. N.Y. Acad. Sci. 61, 637–736.

    Article  Google Scholar 

  48. Maruta, A., Enaka, K. and Umeda, H. (1979). Mutagenicity of quercetin and kaempferol on cultured mammalian cells. Gann 70, 273–276.

    PubMed  CAS  Google Scholar 

  49. Mazaki, M., Ishii, T. and Uyeta, M. (1982). Mutagenicity of hydrolysates of citrus fruit juices. Mutat. Res. 101283–291.

    Article  PubMed  CAS  Google Scholar 

  50. 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.

    Article  Google Scholar 

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    Article  PubMed  CAS  Google Scholar 

  54. Middleton, E., Jr., Drzewiecki, G. and Krishnarao, D. (1981). Quercetin: An inhibitor of antigen-induced human basophil histamine release. J. Immunol. 127, 546–550.

    PubMed  CAS  Google Scholar 

  55. 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.

    Article  PubMed  CAS  Google Scholar 

  56. 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.

    Article  CAS  Google Scholar 

  57. 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.

    PubMed  CAS  Google Scholar 

  58. 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.

    Article  CAS  Google Scholar 

  59. Perry, P. and Evans, H.J. (1975). Cytological detection of mutagen-carcinogen exposure by sister chromatid exchange. Nature (Lond.) 258, 121–125.

    Article  CAS  Google Scholar 

  60. 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.

    PubMed  CAS  Google Scholar 

  61. 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. 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. Richardson, G.A., El-Rafey, M.S. and Long, M.L. (1947). Flavones and flavone derivatives as antioxidants. J. Dairy Sci. 30, 397–413.

    Article  CAS  Google Scholar 

  64. 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.

    Article  CAS  Google Scholar 

  65. 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. 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.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    Article  CAS  Google Scholar 

  68. Savage, P.C. (1977). Microbial ecology of the gastrointestinal tract. Ann. Rev. Microbiol. 31, 107–133.

    Article  CAS  Google Scholar 

  69. Scarborough, H. and Bacharach, A.L. (1949). Vitamin P. Vitamins and Hormones 7, 1–55.

    Article  CAS  Google Scholar 

  70. Scheline, R.R. (1978). Mammalian Metabolism of Plant XenobioticsAcademic Press, N.Y., pp. 295–329.

    Google Scholar 

  71. 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.

    Article  CAS  Google Scholar 

  72. 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. 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.

    PubMed  CAS  Google Scholar 

  74. 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.

    PubMed  CAS  Google Scholar 

  75. 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.

    PubMed  CAS  Google Scholar 

  76. 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.

    Article  CAS  Google Scholar 

  77. 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.

    Article  CAS  Google Scholar 

  78. 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. 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.

    CAS  Google Scholar 

  80. 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. 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. 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. Vogel, E. (1975). Some aspects of the detection of potential mutagenic agents in Drosophila. Mutat. Res. 29, 241–250.

    Article  PubMed  CAS  Google Scholar 

  84. 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.

    Article  PubMed  CAS  Google Scholar 

  85. Watson, W.A.F. (1982). The mutagenic activity of quercetin and kaempferol in Drosophila melanogaster. Mutat. Res. 103, 145–147.

    Article  PubMed  CAS  Google Scholar 

  86. 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.

    CAS  Google Scholar 

  87. Wattenberg, L.W. and Leong, J.L. (1970). Inhibition of the carcinogenic action of benzo(a)pyrene by flavones. Cancer Res. 30, 1922–1925.

    PubMed  CAS  Google Scholar 

  88. 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.

    PubMed  CAS  Google Scholar 

  89. Wollenweber, E. and Dietz, V.H. (1981). Occurrence and distribution of free flavonoid aglycones in plants. Phytochem. 20, 869–932.

    Article  CAS  Google Scholar 

  90. 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. 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 

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MacGregor, J.T. (1984). Genetic and Carcinogenic Effects of Plant Flavonoids: An Overview. In: Friedman, M. (eds) Nutritional and Toxicological Aspects of Food Safety. Advances in Experimental Medicine and Biology, vol 177. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-4790-3_23

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