Flavonoids

Abstract

The flavonoids form a group of approximately nine thousand plant metabolites. Chemically, they can be classified as polyphenols or phenolics. Subgroups of flavonoids include flavones, flavonols, flavanols, flavanones, chalcones, aurones, isoflavones, anthocyanins, and proanthocyanidins. Subgroup representatives vary structurally by their oxygenation, methylation, prenylation, and glycosylation pattern. Their name is derived from ‘flavus’ (Greek, meaning ‘yellow’), indicating that many representatives are yellow plant pigments. Physiologically, flavonoids play roles in allelopathy, attraction of pollinators, protection against damage from sunlight, protection against herbivores and microbes, and in plant growth and development. Many health effects of fruits, vegetables, and dietary supplements (nutraceuticals) have been attributed to the presence of flavonoids. Flavonoids exhibit antioxidant, anti‐inflammatory, anticancer, antiobesity, cardioprotective, and neuroprotective activities. Modulation of cell signalling pathways rather than antioxidant activity may explain the health‐promoting effects of flavonoids in vivo. Most flavonoids are poorly absorbed, extensively metabolised and primarily excreted as glucuronides and sulfates.

Key Concepts:

  • Flavonoids are synthesised by virtually all green plants except algae. They are biosynthesised from phenylalanine and three molecules of malonic acid to form chalconaringenin, from which virtually all other flavonoid skeleta are derived, that is, flavanones, flavones, flavonols, aurones, isoflavones, anthocyanins, and proanthocyanidins.

  • In plants, flavonoids are important for growth and development, attraction of pollinator animals, nitrogen‐fixation in leguminous plants, and for protection against damage by herbivores, microbes, UV and reactive oxygen species.

  • Flavonoids ingested by animals and humans are mainly in the form of glycosides which are hydrolysed in the intestines. The resulting free forms (aglycones) can be degraded to phenolic acids or conjugated with glucuronic acid, sulfate, and methyl groups by the intestinal microflora and the liver.

  • Plasma and intracellular concentrations of flavonoids are low because of poor absorption, extensive metabolism and quick excretion from the body. Isoflavones are the most bioavailable flavonoids in humans.

  • Flavonoids, as aglycones or conjugate metabolites, may confer health benefits related to cancer, inflammatory disease, cardiovascular disease, neurological disorders, metabolic syndrome, obesity and osteoporosis. Epidemiological studies show that consumption of flavonoid‐rich foods is associated with reduced risk of developing cancer and cardiovascular disease.

  • Modulation of cell signalling pathways via NF‐κB, Nrf2 and protein kinases, rather than antioxidant activity, may mediate most of the biological activities of flavonoids in vivo. The direct antioxidant activity of flavonoids has not been established in humans.

  • Flavonoids may interfere in the absorption and metabolism of drugs and nutrients but they themselves are of low or negligible toxicity at the concentrations found in foods.

  • Clinical studies are needed to better understand the pharmacokinetics and health‐promoting effects and side effects, if any, of flavonoids when used as dietary supplements or as pure compounds in pharmacological doses.

Keywords: flavonoids; biosynthesis; bioavailability; antioxidant; inflammation; cardiovascular disease; neurological disorders; metabolic syndrome; osteoporosis; cell signalling

Figure 1.

Enzymes involved in the biosynthesis of flavonoids: 1, phenylalanine ammonia lyase (PAL); 2, cinnamate‐4‐hydroxylase (C4H); 3, 4‐coumarate:CoA ligase (4CL); 4, chalcone synthase (CHS); 5, chalcone reductase (CHR); 6, aureusidin synthase (AS); 7 chalcone isomerase (CHI); 8, flavone synthases I and II (FNS); 9, flavanone 3‐hydroxylase (F3H); 10, flavonol synthase (FLS); 11, dihydroflavonol 4‐reductase (DFR); 12, leucoanthocyanidin reductase (LAR); 13, anthocyanidin synthase (ANS); 14, anthocyanidin reductase (ANR); 15, unknown condensing enzyme(s) (CON); 16, 2‐hydroxyflavanone synthase (IFS); 17, 2‐hydroxyisoflavanone dehydratase (IFD); 18, isoflavone 2′‐hydroxylase; 19, isoflavone reductase (IFR); 20, pterocarpan synthase (PTS). Adapted from Dao et al., ; Dewick, ; He et al., ; Pang et al., ; Xie et al., .

Figure 2.

Metabolism of flavonoids by mammalian and bacterial enzymes. Biotransformations in panels (a) and (e) are typically mediated by hepatic phase I and II enzymes. Panels (b), (c), (d) and (e) show biotransformations carried out by intestinal bacteria. Adapted from Del Rio et al., ; Legette et al., ; Setchell and Clerici, ; Yuan et al., .

Figure 3.

Redox cycling of flavonoids. Oxidation of catecholic flavonoids leads to ortho‐quinone formation. The quinones are redox active and promote generation of reactive oxygen species (ROS) via redox cycling thereby leading to deoxyribonucleic acid (DNA) damage and oxidative modification of proteins. Quinones are also potent electrophiles that can covalently modify DNA and other endogenous nucleophiles, such as glutathione and proteins. The reactivity of both, the ROS and the quinone, towards thiols may modulate redox homoeostasis and signalling, thereby changing the balance between health promoting and adverse effects of redox‐active flavonoids.

Figure 4.

Modulation of the Keap1‐Nrf2 signalling pathway by flavonoids. Flavonoids activate the Keap1‐Nrf2 signalling pathway (green arrows) through phosphorylation of Nrf2 by upstream kinases, oxidation of cysteine thiols or direct binding of electrophiles to cysteine thiols of Keap1 (Fraga and Oteiza, ; Mann et al., ; Surh et al., ).

Figure 5.

Modulation of NF‐κB‐mediated signalling pathways by flavonoids. Flavonoids exert their anti‐inflammatory activity by interfering with multiple steps of the NF‐κB activation process (Banerjee et al., ; Fraga and Oteiza, ; Surh et al., ). EGCG inhibits the activity of IKK or suppresses the activation of IKK and the degradation of IκBα. Epicatechin and catechin inhibit the phosphorylation of IKKβ, the subsequent degradation of IκBα and the binding of NF‐κB to its DNA consensus sequence. Quercetin inhibits the degradation of IκBα and the nuclear translocation of p50 and p65 subunits of NF‐κB. Genistein could interfere in the binding of NF‐κB to DNA. Epicatechin and B dimers can interact with the DNA‐binding site in the NF‐κB proteins, preventing the interaction of NF‐κB with κB DNA binding sites, thus inhibiting gene transcription. Catechins inhibit the proteolytic activity of the 26S proteosome that inhibits IκB degradation.

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References

Banerjee S, Li Y, Wang Z and Sarkar FH (2008) Multi‐targeted therapy of cancer by genistein. Cancer Letters 269: 226–242.

Brasier AR (2010) The nuclear factor‐kappaB‐interleukin‐6 signalling pathway mediating vascular inflammation. Cardiovascular Research 86: 211–218.

Brown AL, Lane J, Coverly J et al. (2009) Effects of dietary supplementation with the green tea polyphenols epigallocatechin‐3‐gallate on insulin resistance and associated metabolic risk factors: randomized controlled trial. British Journal of Nutrition 101: 886–894.

Cherniack EP (2011) Polyphenols: planting the seeds of treatment for the metabolic syndrome. Nutrition 27: 617–623.

Corradini E, Foglia P, Giansanti P et al. (2011) Flavonoids: chemical properties and analytical methodologies of identification and quantitation in foods and plants. Natural Product Research 25: 469–495.

Dao TTH, Linthorst HJM and Verpoorte R (2011) Chalcone synthase and its function in plant resistance. Phytochemistry Reviews 10: 397–412.

Del Rio D, Borges G and Crozier A (2010) Berry flavonoids and phenolics: bioavailability and evidence of protective effects. British Journal of Nutrition 104: S67–S90.

Dewick PM (2009) Medicinal Natural Products: A Biosynthetic Approach, 3rd ed. Chichester, UK: Wiley & Sons.

Dixon RA and Paiva NL (1995) Stress‐induced phenylpropanoid metabolism. Plant Cell 7: 1085–1097.

Dong JY and Qin LQ (2011) Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta‐analysis of prospective studies. Breast Cancer Research and Treatment 125: 315–323.

Egert S, Bosy‐Westphal A, Seiberl J et al. (2009) Quercetin reduces systolic blood pressure and plasma oxidised low‐density lipoprotein concentrations in overweight subjects with a high‐cardiovascular disease risk phenotype: a double‐blinded, placebo‐controlled cross‐over study. British Journal of Nutrition 102: 1065–1074.

Forkmann H and Heller W (1999) Biosynthesis of flavonoids. In: Sankawa U (ed.) Comprehensive Natural Products Chemistry, vol. 1, pp. 713–748. Amsterdam: Elsevier.

Fraga CG and Oteiza PI (2011) Dietary flavonoids: Role of (‐)‐epicatechin and related procyanidins in cell signaling. Free Radical Biology and Medicine 51: 813–823.

Frezza M, Schmitt S and Dou QP (2011) Targeting the ubiquitin‐proteasome pathway: an emerging concept in cancer therapy. Current Topics in Medicinal Chemistry 11: 2888–2905.

Galland L (2010) Diet and inflammation. Nutrition in Clinical Practice 25: 634–640.

Gonzalez‐Castejon M and Rodriguez‐Casado A (2011) Dietary phytochemicals and their potential effects on obesity: a review. Pharmacological Research 64: 438–455.

Gonzalez R, Ballester I, Lopez‐Posadas R et al. (2011) Effects of flavonoids and other polyphenols on inflammation. Critical Reviews in Food Science and Nutrition 51: 331–362.

Grünz G, Haas K, Soukup S et al. (2012) Structural features and bioavailability of four flavonoids and their implications for lifespan‐extending and antioxidant actions in C. elegans. Mechanisms of Ageing and Development 133: 1–10.

Gutierrez‐Merino C, Lopez‐Sanchez C, Lagoa R et al. (2011) Neuroprotective actions of flavonoids. Current Medicinal Chemistry 18: 1195–1212.

Harborne JB and Grayer RJ (1994) Flavonoids and insects. In: Harborne JB (ed.) The Flavonoids – Advances in Research since 1986, pp. 589–618. London: Chapman and Hall.

He XZ, Blount JW, Ge S, Tang Y and Dixon RA (2011) A genomic approach to isoflavone biosynthesis in kudzu (Pueraria lobata). Planta 233: 843–855.

Heller H and Forkmann A (1994) Biosynthesis of Flavonoids. In: Harborne JB (ed.) The Flavonoids – Advances in Research Since 1986, pp. 499–535. London: Chapman and Hall.

Higdon J (2007) An Evidence‐Based Approach to Dietary Phytochemicals. New York: Thieme.

Hollman PC, Cassidy A, Comte B et al. (2011) The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established. Journal of Nutrition 141: 989S–1009S.

Hollman PCH (2004) Absorption, bioavailability, and metabolism of flavonoids. Pharmaceutical Biology 42: 74–83.

Ibrahim RK and Varin L (1993) Flavonoid enzymology In: Lea PJ (ed.) Methods in Plant Biochemistry, vol. 9, pp. 99–131. London: Academic Press.

Jager AK and Saaby L (2011) Flavonoids and the CNS. Molecules 16: 1471–1485.

King RA and Bursill DB (1998) Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. American Journal of Clinical Nutrition 67: 867–872.

Legette L, Ma L, Reed RL et al. (2012) Pharmacokinetics of xanthohumol and metabolites in rats after oral and intravenous administration. Molecular Nutrition & Food Research 56: 466–474.

Lotito SB and Frei B (2006) Consumption of flavonoid‐rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radical Biology and Medicine 41: 1727–1746.

Lotito SB, Zhang WJ, Yang CS, Crozier A and Frei B (2011) Metabolic conversion of dietary flavonoids alters their anti‐inflammatory and antioxidant properties. Free Radical Biology and Medicine 51: 454–463.

Manach C, Scalbert A, Morand C, Rémésy C and Jiménez L (2004) Polyphenols: food sources and bioavailability. American Journal of Clinical Nutrition 79: 727–747.

Mann GE, Bonacasa B, Ishii T and Siow RC (2009) Targeting the redox sensitive Nrf2‐Keap1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones. Current Opinion in Pharmacology 9: 139–145.

Middleton E Jr, Kandaswami C and Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacological Reviews 52: 673–751.

Nicolle E, Souard F, Faure P and Boumendjel A (2011) Flavonoids as promising lead compounds in type 2 diabetes mellitus: molecules of interest and structure‐activity relationship. Current Medicinal Chemistry 18: 2661–2672.

Nishiumi S, Miyamoto S, Kawabata K et al. (2011) Dietary flavonoids as cancer‐preventive and therapeutic biofactors. Frontiers in Bioscience (Scholar Edition) 3: 1332–1362.

Nones JE, Spohr TC and Gomes FC (2011) Hesperidin, a flavone glycoside, as mediator of neuronal survival. Neurochemical Research 36: 1776–1784.

Pang Y, Peel GJ, Wright E, Wang Z and Dixon RA (2007) Early steps in proanthocyanidin biosynthesis in the model legume Medicago truncatula. Plant Physiology 145: 601–615.

Prasain JK, Carlson SH and Wyss JM (2010) Flavonoids and age‐related disease: risk, benefits and critical windows. Maturitas 66: 163–171.

Prochazkova D, Bousova I and Wilhelmova N (2011) Antioxidant and prooxidant properties of flavonoids. Fitoterapia 82: 513–523.

Rains TM, Agarwal S and Maki KC (2011) Antiobesity effects of green tea catechins: a mechanistic review. Journal of Nutritional Biochemistry 22: 1–7.

Sasaki K, Mito K, Ohara K, Yamamoto H and Yazaki K (2008) Cloning and characterization of naringenin 8‐prenyltransferase, a flavonoid‐specific prenyltransferase of Sophora flavescens. Plant Physiology 146: 1075–1084.

Setchell KDR and Clerici C (2010a) Equol: History, chemistry, and formation. Journal of Nutrition (Supplement: Equol, Soy, and Menopause) 140: 1355S–1362S.

Setchell KDR and Clerici C (2010b) Equol: Pharmacokinetics and biological actions. Journal of Nutrition (Supplement: Equol, Soy, and Menopause) 140: 1363S–1368S.

Shelnutt SR, Cimino CO, Wiggins PA, Ronis MJ and Badger TM (2002) Pharmacokinetics of the glucuronide and sulfate conjugates of genistein and daidzein in men and women after consumption of a soy beverage. American Journal of Clinical Nutrition 76: 588–594.

Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nature Reviews Cancer 3: 768–780.

Surh YJ, Kundu JK, Na HK and Lee JS (2005) Redox‐sensitive transcription factors as prime targets for chemoprevention with anti‐inflammatory and antioxidative phytochemicals. Journal of Nutrition 135: 2993S–3001S.

Tunon MJ, Garcia‐Mediavilla MV, Sanchez‐Campos S and Gonzalez‐Gallego J (2009) Potential of flavonoids as anti‐inflammatory agents: modulation of pro‐inflammatory gene expression and signal transduction pathways. Current Drug Metabolism 10: 256–271.

Varin L (1992) Flavonoid sulphation: phytochemistry, enzymology and molecular biology. Recent Advances in Phytochemistry 26: 233–254.

Winkel BSJ (2006) Chapter 3: The biosynthesis of flavonoids. In: Grotewold E (ed.) The Science of Flavonoids, pp. 71–95. New York: Springer.

Xiao J and Kai G (2012) A review of dietary polyphenol‐plasma protein interactions: characterization, influence on the bioactivity, and structure‐affinity relationship. Critical Reviews in Food Science and Nutrition 52: 85–101.

Xie DY, Sharma SB, Paiva NL, Ferreira D and Dixon RA (2003) Role of anthocyanidin reductase, encoded by BANYULS in plant flavonoid biosynthesis. Science 299: 396–399.

Yuan JP, Wang JH and Liu X (2007) Metabolism of dietary soy isoflavones to equol by human intestinal microflora – implications for health. Molecular Nutrition & Food Research 51: 765–781.

Zhang Q, Tu T, d'Avignon DA and Gross ML (2009) Balance of beneficial and deleterious health effects of quinones: a case study of the chemical properties of genistein and estrone quinones. Journal of the American Chemical Society 131: 1067–1076.

Further Reading

Andersen ØM and Markham KR (2006) Flavonoids: Chemistry, Biochemistry and Applications. Boca Raton, FL: CRC Press.

Beecher GR (2003) Overview of dietary flavonoids: nomenclature, occurrence and intake. Journal of Nutrition 133: 3248S–3254S.

Gupta SC, Kim JH, Kannappan R et al. (2011) Role of nuclear factor κB‐mediated inflammatory pathways in cancer‐related symptoms and their regulation by nutritional agents. Experimental Biology and Medicine (Maywood) 236: 658–671.

Ross JA and Kasum CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annual Review of Nutrition 22: 19–34.

Salminen A, Kauppinen A and Kaarniranta K (2012) Phytochemicals suppress nuclear factor‐κB signaling: impact on health span and the aging process. Current Opinion in Clinical Nutrition & Metabolic Care 15: 23–28.

Spencer JP, Vafeiadou K, Williams RJ and Vauzour D (2012) Neuroinflammation: Modulation by flavonoids and mechanisms of action. Molecular Aspects of Medicine 33: 83–97.

Taguchi K, Motohashi H and Yamamoto M (2011) Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes to Cells 16: 123–140.

Tian L, Pang YZ and Dixon RA (2008) Biosynthesis and genetic engineering of proanthocyanidins and (iso)flavonoids. Phytochemistry Reviews 7: 445–465.

Van der Heiden K, Cuhlmann S, Luong le A et al. (2010) Role of nuclear factor kappaB in cardiovascular health and disease. Clinical Science (London) 118: 593–605.

Xiao ZP, Peng ZY, Peng MJ et al. (2011) Flavonoids health benefits and their molecular mechanism. Mini‐Reviews in Medicinal Chemistry 11: 169–177.

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Miranda, Cristobal L, Maier, Claudia S, and Stevens, Jan F(Jun 2012) Flavonoids. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003068.pub2]