Emerging Trends in Flavonoid Research and Associated Toxicity

  • Abhinay Thakur
  • Ashun Chaudhary
  • Hardeep Singh Tuli
  • Anil K. Sharma


Flavonoids are highly diverse plant compounds that generally occur in a wide range of fruits, vegetables, nuts, and beverages. They are regularly consumed in the human diet and have various biological activities, including anti-inflammatory, anti-cancer, and anti-viral actions. Flavonoids may be one of the safest non-immunogenic drugs because they are small organic compounds that are normally absorbed by the human body over long periods of time. During the past few decades, there has been an increased flux of research activity on flavonoids, and many patents have been filed on flavonoids with therapeutic potential, with the number consistently showing an increasing trend.

Flavonoids are usually considered safe for consumption, but they also have side effects, e.g., upset stomach and headaches. Additionally, some preliminary evidence suggests that some flavonoids selected for study may generate byproducts that ultimately lead to loss of protein function in the body. Moreover, taking very high doses of some flavonoids may interfere with the functioning of the kidneys, or may cause changes in bacterial chromosomes, or may interfere with the body’s absorption of drugs, factors that ultimately decrease the activity of the immune system. This chapter summarizes the current research on the health effects of some flavonoids, and suggests possible expectations of their effects, as well as their different roles in cancer prevention versus treatment.


Flavonoids Therapeutic potential Cancer Treatment Patents 


  1. Adhami VM, Mukhtar H (2006) Polyphenols from green tea and pomegranate for prevention of prostate cancer. Free Radic Res 40(10):1095–1104. CrossRefPubMedGoogle Scholar
  2. Austin CA, Patel S, Ono K, Nakane H, Fisher LM (1992) Site-specific DNA cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivatives. Biochem J 282(5):883–889CrossRefGoogle Scholar
  3. Azuma Y, Onishi Y, Sato Y, Kizaki H (1995) Effects of protein tyrosine kinase inhibitors with different modes of action on topoisomerase activity and death of IL 2-dependent CTLL-2 cells. J Biochem 118(2):312–318CrossRefGoogle Scholar
  4. Bjeldanes LF, Chang GW (1977) Mutagenic activity of quercetin and related compounds. Science 197(4303):577–578CrossRefGoogle Scholar
  5. Borghi-Scoazec G, Vial T, Bobin J, Trepo C (2002) Phyto Soya®-induced cytolytic hepatitis [in French]. Gastroenterol Clin Biol 26:181–183PubMedGoogle Scholar
  6. Breimer LH (1990) Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis: the role of DNA base damage. Mol Carcinog 3(4):188–197CrossRefGoogle Scholar
  7. Brown JP, Dietrich PS (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(3):223–240CrossRefGoogle Scholar
  8. Caria H, Chaveca T, Laires A, Rueff J (1995) Genotoxicity of quercetin in the micronucleus assay in mouse bone marrow erythrocytes, human lymphocytes, V79 cell line, and identification of kinetochore-containing (CREST staining) micronuclei in human lymphocytes. Mutat Res 343(2,3):85–94CrossRefGoogle Scholar
  9. Carver JH, Carrano AV, MacGregor JT (1983) Genetic effects of the flavonols quercetin, kaempferol, and galangin on Chinese hamster ovary cells in vitro. Mutat Res 113(1):45–60CrossRefGoogle Scholar
  10. Cermak R (2008) Effect of dietary flavonoids on pathways involved in drug metabolism. Expert Opin in Drug Metab Toxicol 4(1):17–35. CrossRefGoogle Scholar
  11. Chang YC, Nair MG, Nitiss JL (1995) Metabolites of daidzein and genistein and their biological activities. J Nat Prod 58(12):1901–1905CrossRefGoogle Scholar
  12. Chaudhary A, Choudhary S, Sharma U, Vig AP, Singh B, Arora S (2018) Purple head broccoli (Brassica oleracea L. var. italica Plenck), a functional food crop for antioxidant and anticancer potential. J Food Sci Technol 55(5):1806–1815CrossRefGoogle Scholar
  13. Chen G, Zhu L, Liu Y, Zhou Q, Chen H, Yang J (2009) Isoliquiritigenin, a flavonoid from licorice, plays a dual role in regulating gastrointestinal motility in vitro and in vivo. Phytother Res 23:498–506CrossRefGoogle Scholar
  14. Dassonneville L, Bailly C (1998) Chromosome translocations and leukemias induced by inhibitors of topoisomerase II anticarcinogenic drugs. Bull Cancer 85(3):254–261PubMedGoogle Scholar
  15. Dickancaité E, Nemeikaité A, Kalvelyté A, Cénas N (1998) Prooxidant character of flavonoid cytotoxicity: structure-activity relationships. Biochem Mol Biol Int 45(5):923–930PubMedGoogle Scholar
  16. Doroshow JH, Locker GY, Myers CE (1980) Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest 65(1):128–135CrossRefGoogle Scholar
  17. Espin JC, Garcia-Conesa MT, Tomas-Barberan FA (2007) Nutraceuticals: facts and fiction. Phytochemistry 68(22–24):2986–3008. CrossRefPubMedGoogle Scholar
  18. Galati G, O’Brien P (2004) Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties. Free Radic Biol Med 37:287–303CrossRefGoogle Scholar
  19. Galati G, Lin A, Sultan A, O’Brien P (2006) Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med 40:570–580CrossRefGoogle Scholar
  20. Gandolfo G, Girelli G, Conti L, Perrone M, Arista M, Damico C (1992) Hemolytic anemia and thrombocytopenia induced by cyanidanol. Acta Haematol 88:96–99CrossRefGoogle Scholar
  21. Garcia-Closas R, Gonzalez CA, Agudo A, Riboli E (1999) Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes Control 10(1):71–75CrossRefGoogle Scholar
  22. García-Cortés M, Borraz Y, Lucena M, Peláez G, Salmerón J, Diago M, Martínez-Sierra M, Navarro J, Planas R, Soria M, Bruguera M, Andrade R (2008) Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry [in Spanish]. Rev Esp Enferm Dig 100:688–695CrossRefGoogle Scholar
  23. Halliwell B (2007) Dietary polyphenols: good, bad, or indifferent for your health? Cardiovasc Res 73(2):341 347. CrossRefGoogle Scholar
  24. Heim M, Eckstein R, Huhn D, Mempel W (1982) Cyanidanol-induced immune haemolytic anaemia and acute renal failure. Blut 45:64Google Scholar
  25. Hodnick WF, Kung FS, Roettger WJ, Bohmont CW, Pardini RS (1986) Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids. A structure-activity study. Biochem Pharmacol 35(14):2345–2357CrossRefGoogle Scholar
  26. Jaeger A, Rodier L, Tempe J, Lutum P, Mayer S, Mantz J (1979a) Hemolyses aigue immunoallergiques thrombopenie et insuffsance renale aigue dues a un traitement par les catechine. Nouv Press Med 8:3741–3743Google Scholar
  27. Jaeger A, Tempe J, Rodier L, Luthun P, Mantz J (1979b) Acute immunoallergic hemolysis with acute renal failure induced by catechin. Vet Hum Toxicol 21:100S–101SGoogle Scholar
  28. Jaeger A, George C, Lanbert H, Rodier L, Lejonc J, Larcan A, Mantz J (1980) Les accidents immune-allergiques au cours des traitements par un veinotrope contenant des catechines. Therapie 355:733–741Google Scholar
  29. Jørgensen LV, Cornett C, Justesen U, Skibsted LH, Dragsted LO (1998) Two electron electrochemical oxidation of quercetin and kaempferol changes only the flavonoid C-ring. Free Radic Res 29(4):339–350CrossRefGoogle Scholar
  30. Jurado J, Alejandre-Durán E, Alonso-Moraga A, Pueyo C (1991) Study on the mutagenic activity of 13 bioflavonoids with the Salmonella Ara test. Mutagenesis 6(4):289–295CrossRefGoogle Scholar
  31. Kahn M, Senderowicz A, Sausville E, Barrett K (2001) Possible mechanisms of diarrheal side effects associated with the use of a novel chemotherapeutic agent, flavopiridol. Clin Cancer Res 7:343–349PubMedGoogle Scholar
  32. Karrasch T, Kim J, Jang B, Jobin C (2007) The flavonoid luteolin worsens chemical induced colitis in NF-kappaB(EgFP) transgenic mice through blockade of NF-kappaB-dependent protective molecules. PLoS One 2:e596CrossRefGoogle Scholar
  33. Kennedy J, Wang CC, Wu CH (2008) Patient disclosure about herb and supplement use among adults in the US. Evid Based Complement Alternat Med 5(4):451–456CrossRefGoogle Scholar
  34. Koo LC (1988) Dietary habits and lung cancer risk among Chinese females in Hong Kong who never smoked. Nutr Cancer 11(3):155–172CrossRefGoogle Scholar
  35. Kurahashi N, Inoue M, Iwasaki M, Tanaka Y, Mizokami M, Tsugane S (2009) Isoflavone consumption and subsequent risk of hepatocellular carcinoma in a population-based prospective cohort of Japanese men and women. Int J Cancer 124:1644–1649CrossRefGoogle Scholar
  36. Lee HP, Gourley L, Duffy SW, Estéve J, Lee J, Day NE (1991) Dietary effects on breast-cancer risk in Singapore. Lancet 337(8751):1197–1200CrossRefGoogle Scholar
  37. Lin J, Ho Y (1994) Flavonoid-induced acute nephropathy. Am J Kidney Dis 23:433–440CrossRefGoogle Scholar
  38. MacGregor JT, Jurd L (1978) Mutagenicity of plant flavonoids: structural requirements for mutagenic activity in Salmonella typhimurium. Mutat Res 54(3):297–309CrossRefGoogle Scholar
  39. Mazzanti G, Mennitit-Ippolito F, Moro P, Cassetti F, Raschetti R, Santuccio C, Mastrangelo S (2009) Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur J Clin Pharmacol 65:331–341CrossRefGoogle Scholar
  40. Mennecier D, Saloum T, Roycourt A, Nexon M, Thiolet C, Farret O (1999) Chronic diarrhea and lymphocytic colitis associated with Daflon therapy. Gastroentérol Clin Biol 23:1101–1102PubMedGoogle Scholar
  41. Menniti-Ippolito F, Mazzanti G, Santuccio C, Angela Moro P, Calapai G, Firenzuoli F, Valeri A, Raschetti R (2008) Surveillance of suspected adverse reactions to natural health products in Italy. Pharmacoepidemiol Drug Saf 17:626–635CrossRefGoogle Scholar
  42. Middleton E, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 52(4):673–751PubMedPubMedCentralGoogle Scholar
  43. Olson RD, Boerth RC, Gerber JG, Nies AS (1981) Mechanism of adriamycin cardiotoxicity: evidence for oxidative stress. Life Sci 29(14):1393–1401CrossRefGoogle Scholar
  44. Pascual-Teresa S, Moreno DA, Garcia-Viguera C (2010) Flavanols and anthocyanins in cardiovascular health: a review of current evidence. Int J Mol Sci 11(4):1679 1703. CrossRefPubMedCentralGoogle Scholar
  45. Popp R, Schimmer O (1991) Induction of sister-chromatid exchanges (SCE), polyploidy, and micronuclei by plant flavonoids in human lymphocyte cultures. A comparative study of 19 flavonoids. Mutat Res 246(1):205–213CrossRefGoogle Scholar
  46. Pritsos CA, Pardini RS (1984) A redox cycling mechanism of action for 2,3-dichloro-1,4-naphthoquinone with mitochondrial membranes and the role of sulfhydryl groups. Biochem Pharmacol 33(23):3771–3777CrossRefGoogle Scholar
  47. Pritsos CA, Jensen DE, Pisani D, Pardini RS (1982) Involvement of superoxide in the interaction of 2,3-dichloro-1,4-naphthoquinone with mitochondrial membranes. Arch Biochem Biophys 217(1):98–109CrossRefGoogle Scholar
  48. Rahman A, Shahabuddin S, Hadi SM, Parish JH, Ainley K (1989) Strand scission in DNA induced by quercetin and Cu(II): role of Cu(I) and oxygen free radicals. Carcinogenesis 10(10):1833–1839CrossRefGoogle Scholar
  49. Rassiat E, Michiels C, Piard F, Faivre J (2001) Lymphocytic colitis in a woman with Biermer’s disease treated with Cirkan. Presse Med 30:970PubMedGoogle Scholar
  50. Ross J, Kasum C (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22:19–34CrossRefGoogle Scholar
  51. Rotoli B, Giglio F, Bile M, Formisano S (1985) Immune mediated acute intravascular hemolysis caused by cianidanol (Catergen). Haematologica 70:495–499PubMedGoogle Scholar
  52. Rueff J, Laires A, Borba H, Chaveca T, Gomes MI, Halpern M (1986) Genetic toxicology of flavonoids: the role of metabolic conditions in the induction of reverse mutation, SOS functions, and sister-chromatid exchanges. Mutagenesis 1(3):179–183CrossRefGoogle Scholar
  53. Sahu SC, Gray GC (1993) Interactions of flavonoids, trace metals, and oxygen: nuclear DNA damage and lipid peroxidation induced by myricetin. Cancer Lett 70(1,2):73–79CrossRefGoogle Scholar
  54. Sahu SC, Gray GC (1996) Pro-oxidant activity of flavonoids: effects on glutathione and glutathione-S transferase in isolated rat liver nuclei. Cancer Lett 104(2):193–196CrossRefGoogle Scholar
  55. Sahu SC, Gray GC (1997) Lipid peroxidation and DNA damage induced by morin and naringenin in isolated rat liver nuclei. Food Chem Toxicol 35(5):443–447CrossRefGoogle Scholar
  56. Salama A, Mueller-Eckhardt C (1987) Cianidanol and its metabolites bind tightly to red cells and are responsible for the production of auto- and/or drug-dependent antibodies against these cells. Br J Haematol 66:263–266CrossRefGoogle Scholar
  57. Sarma D, Barrett M, Chavez M, Gardiner P, Ko R, Mahady G, Marles R, Pellicore L, Giancaspro G, Low Dog T (2008) Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf 31:469–484CrossRefGoogle Scholar
  58. Seifried HE, Anderson DE, Fisher EI, Milner JA (2007) A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem 18(9):567–579. CrossRefPubMedGoogle Scholar
  59. Severson RK, Nomura AM, Grove JS, Stemmermann GNA (1989) Prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 49(7):1857–1860PubMedGoogle Scholar
  60. Skibola C, Smith M (2000) Potential health impacts of excessive flavonoid intake. Free Radic Biol Med 29:375–383CrossRefGoogle Scholar
  61. Suzuki S, Takada T, Sugawara Y, Muto T, Kominami R (1991) Quercetin induces recombinational mutations in cultured cells as detected by DNA fingerprinting. Jpn J Cancer Res 82(10):1061–1064CrossRefGoogle Scholar
  62. Tajima K, Tominaga S (1985) Dietary habits and gastrointestinal cancers: a comparative case-control study of stomach and large intestinal cancers in Nagoya, Japan. Jpn J Cancer Res 76(8):705–716PubMedGoogle Scholar
  63. Takami S, Imai T, Hasumura M, Cho Y, Onose J, Hirose M (2008) Evaluation of toxicity of green tea catechins with 90-day dietary administration to F344 rats. Food Chem Toxicol 46:2224–2229CrossRefGoogle Scholar
  64. Thiolet C, Bredin C, Rimlinger H, Nizou C, Mennecier D, Farret O (2003) Lymphocytic colitis following administration of Cyclo 3 fort. Presse Med 32:1323–1324PubMedGoogle Scholar
  65. Thomasset SC, Berry DP, Garcea G, Marczylo T, Steward WP, Gescher AJ (2007) Dietary polyphenolic phytochemicals-promising cancer chemopreventive agents in humans? A review of their clinical properties. Int J Cancer 120(3):451–458. CrossRefPubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Abhinay Thakur
    • 1
  • Ashun Chaudhary
    • 2
  • Hardeep Singh Tuli
    • 3
  • Anil K. Sharma
    • 3
  1. 1.PG Department of ZoologyDAV CollegeJalandharIndia
  2. 2.Department of BiotechnologyM. M. Engineering College, Maharishi Markandeshwar (Deemed to be University)Mullana-AmbalaIndia
  3. 3.Department of BiotechnologyMaharishi Markandeshwar (Deemed to be University)Mullana-AmbalaIndia

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