Flavonoid

For other uses, see Vitamin P (disambiguation) and Citrin.

Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their colour in nature), are a class of plant secondary metabolites.

Flavonoids were originally referred to as Vitamin P, likely due to the effect they had on the permeability of vascular capillaries, but this term is rarely used now. [1]

According to the IUPAC nomenclature,[2] they can be classified into:

The three flavonoid classes above are all ketone-containing compounds, and as such, are flavonoids and flavonols. This class was the first to be termed "bioflavonoids." The terms flavonoid and bioflavonoid have also been more loosely used to describe non-ketone polyhydroxy polyphenol compounds which are more specifically termed flavanoids, flavan-3-ols (or catechins).

Contents

Biosynthesis

Main article: Flavonoid biosynthesis

Functions of flavonoids in plants

Flavonoids are widely distributed in plants fulfilling many functions.

Flavonoids are the most important plant pigments for flower coloration producing yellow or red/blue pigmentation in petals designed to attract pollinator animals.

Flavonoids secreted by the root of their host plant help Rhizobia in the infection stage of their symbiotic relationship with legumes like peas, beans, clover, and soy. Rhizobia living in soil are able to sense the flavonoids and this triggers the secretion of Nod factors, which in turn are recognized by the host plant and can lead to root hair deformation and several cellular responses such as ion fluxes and the formation of a root nodule.

In addition, some flavonoids have inhibitory activity against organisms that cause plant disease eg. Fusarium oxysporum.[3]

Potential salutary effects on human health

Flavonoids (specifically flavanoids such as the catechins) are "the most common group of polyphenolic compounds in the human diet and are found ubiquitously in plants".[4] Flavonols, the original bioflavonoids such as quercetin, are also found ubiquitously, but in lesser quantities.

The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Preliminary research indicates that flavonoids may modify allergens, viruses, and carcinogens, and so may be biological "response modifiers". In vitro studies show that flavonoids also have anti-allergic, anti-inflammatory,[5] anti-microbial,[6][7] anti-cancer,[8] and anti-diarrheal activities.[9]

Antioxidant activity in vitro

Flavonoids (both flavonols and flavanols) are most commonly known for their antioxidant activity in vitro. At high experimental concentrations that would not exist in vivo, the antioxidant abilities of flavonoids in vitro may be stronger than those of vitamin C and E, depending on concentrations tested.[10]

Consumers and food manufacturers have become interested in flavonoids for their possible medicinal properties, especially their putative role in inhibiting cancer or cardiovascular disease. Although physiological evidence is not yet established, the beneficial effects of fruits, vegetables, tea, and red wine have sometimes been attributed to flavonoid compounds.

Negligible antioxidant properties of flavonoids in vivo

A research team at the Linus Pauling Institute and the European Food Safety Authority state that flavonoids, inside the human body, are of little or no direct antioxidant value.[11][12][13] Body conditions are unlike controlled test tube conditions, and the flavonoids are poorly absorbed (less than 5%), with most of what is absorbed being quickly metabolized and excreted.

The increase in antioxidant capacity of blood seen after the consumption of flavonoid-rich foods may not be caused directly by the flavonoids themselves, but most likely is due to increased production of uric acid resulting from excretion of flavonoids from the body.[14] According to Frei, "we can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them."

Potential anti-cancer activity

Flavonoids might induce mechanisms that affect cancer cells and inhibit tumor invasion.[14] In preliminary studies, UCLA cancer researchers proposed that smokers who ate foods containing certain flavonoids, such as the flavan-3-ols (catechins) found in strawberries and green and black teas, kaempferol from brussel sprouts and apples, and quercetin from beans, onions and apples, may have reduced risk of obtaining lung cancer.[15]

Potential deleterious effects on human health

Carcinogenic potential

Flavonoids were found to be strong topoisomerase inhibitors and induce DNA mutations in the MLL gene, which are common findings in neonatal acute leukemia.[16][17] The DNA changes were increased by treatment with flavonoids in cultured blood stem cells.[18] In one study, a high flavonoid-content diet in mothers seemed to increase risk of MLL+ acute myeloid leukemia in neonates. This result was not statistically significant though, and when the data on all types of leukiama in the study were taken together, a beneficial effect of the high-flavonoid diet was seen.[19][20][21]

Natural phenols (flavonoids in one set of experiments and delphinidin in another[22]) were found to be strong topoisomerase inhibitors, similar to some chemotherapeutic anticancer drugs including etoposide and doxorubicin.[23] This property may be responsible for both an anticarcinogenic-proapoptotic effect and a carcinogenic, DNA damaging potential of the substances.

Example flavonoids

Quercetin

Main article: quercetin

Quercetin, a flavonoid and more specifically a flavonol, is the aglycone form of other flavonoid glycosides, such as rutin and quercitrin, found in citrus fruit, buckwheat and onions. Quercetin forms the glycosides, quercitrin and rutin, together with rhamnose and rutinose, respectively.

Although there is preliminary evidence that asthma, lung cancer and breast cancer are lower among people consuming higher dietary levels of quercetin,[24] the U.S. Food and Drug Administration (FDA), EFSA and the American Cancer Society have concluded that no physiological role exists. The American Cancer Society states that dietary quercetin "is unlikely to cause any major problems or benefits."[25]

Epicatechin

Epicatechin may improve blood flow and has potential for cardiac health. Cocoa, the major ingredient of dark chocolate, contains relatively high amounts of epicatechin and has been found to have nearly twice the antioxidant content of red wine and up to three times that of green tea in vitro.[26][27] In the test outlined above, it appears the potential antioxidant effects in vivo are minimal as the antioxidants are rapidly excreted from the body.

Dietary sources

Good sources of flavonoids include all citrus fruits, berries, ginkgo biloba, onions[28][29] (particularly red onion[30]), parsley,[31] pulses,[32] tea (especially white and green tea), red wine, seabuckthorn, and dark chocolate (with a cocoa content of seventy percent or greater).

Citrus

The citrus bioflavonoids include hesperidin (a glycoside of the flavanone hesperetin), quercitrin, rutin (two glycosides of the flavonol quercetin), and the flavone tangeritin. In addition to possessing in vitro antioxidant activity and an ability to increase intracellular levels of vitamin C, rutin and hesperidin may have beneficial effects on capillary permeability and blood flow. They also exhibit anti-allergy and anti-inflammatory benefits of quercetin from in vitro studies. Quercetin can also inhibit reverse transcriptase, part of the replication process of retroviruses.[33] The therapeutic relevance of this inhibition has not been established. Hydroxyethylrutosides (HER) have potential for use in the treatment of abnormal capillary permeability, bruising, hemorrhoids, and varicose veins.

Tea

Main article: Polyphenols in tea

Wine

See also: Polyphenols in wine

Dark chocolate

Main article: Health effects of chocolate

Flavonoids exist naturally in cacao, but because they can be bitter, they are often removed from chocolate, even dark chocolate.[34] Although flavonoids are present in milk chocolate, milk may interfere with their absorption.[35][36]

Subgroups

Over 5000 naturally occurring flavonoids have been characterized from various plants. They have been classified according to their chemical structure, and are usually subdivided into the following subgroups (for further reading see [37]):

Flavones

Flavones are divided into four groups:[38]

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavone 2-phenylchromen-4-one ✗ ✗ Luteolin, Apigenin, Tangeritin
Flavonol
or
3-hydroxyflavone		 3-hydroxy-2-phenylchromen-4-one ✓ ✗ Quercetin, Kaempferol, Myricetin, Fisetin, Isorhamnetin, Pachypodol, Rhamnazin
Flavanone 2,3-dihydro-2-phenylchromen-4-one ✗ ✓ Hesperetin, Naringenin, Eriodictyol, Homoeriodictyol
Flavanonol
or
3-Hydroxyflavanone
or
2,3-dihydroflavonol		 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one ✓ ✓ Taxifolin (or Dihydroquercetin), Dihydrokaempferol

Isoflavones

Flavan-3-ols, Flavan-4-ols, Flavan-3,4-diols, and proanthocyanidins

Derivatives of flavan.

Skeleton Name
Flavan-3-ol
Flavan-4-ol
Flavan-3,4-diol (leucoanthocyanidin)

Anthocyanidins

Availability through microorganisms

Several recent research articles have demonstrated the efficient production of flavonoid molecules from genetically-engineered microorganisms.[39][40][41]

See also

References

  1. ^ Mobh, Shiro (1938). "Research for Vitamin P". The Journal of Biochemistry. 
  2. ^ Flavonoids (isoflavonoids and neoflavonoids)., IUPAC Compendium of Chemical Terminology
  3. ^ Galeotti, F; Barile, E; Curir, P; Dolci, M; Lanzotti, V (2008). "Flavonoids from carnation (Dianthus caryophyllus) and their antifungal activity". Phytochemistry Letters 1: 44. doi:10.1016/j.phytol.2007.10.001. 
  4. ^ Spencer, Jeremy P. E. (2008). "Flavonoids: modulators of brain function?". British Journal of Nutrition 99: ES60–77. doi:10.1017/S0007114508965776. PMID 18503736. 
  5. ^ "Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer". Yamamoto and Gaynor 107 (2): 135 -- Journal of Clinical Investigation. http://www.jci.org/cgi/content/full/107/2/135?ijkey=a1e09ce2dbca283cec170598f2410b15d5f4304f&keytype2=tf_ipsecsha. 
  6. ^ Cushnie TPT, Lamb AJ (2005). "Antimicrobial activity of flavonoids". International Journal of Antimicrobial Agents 26 (5): 343–356. doi:10.1016/j.ijantimicag.2005.09.002. PMID 16323269. 
  7. ^ Cushnie TPT, Lamb AJ (2011). "Recent advances in understanding the antibacterial properties of flavonoids". International Journal of Antimicrobial Agents 38 (2): 99–107. doi:10.1016/j.ijantimicag.2011.02.014. PMID 21514796. 
  8. ^ de Sousa RR, Queiroz KC, Souza AC, Gurgueira SA, Augusto AC, Miranda MA, Peppelenbosch MP, Ferreira CV, Aoyama H. (2007). "Phosphoprotein levels, MAPK activities and NFkappaB expression are affected by fisetin". J Enzyme Inhib Med Chem 22 (4): 439–444. doi:10.1080/14756360601162063. PMID 17847710. 
  9. ^ Schuier M, Sies H, Illek B, Fischer H (1 October 2005). "Cocoa-related flavonoids inhibit CFTR-mediated chloride transport across T84 human colon epithelia". J. Nutr. 135 (10): 2320–5. PMID 16177189. http://jn.nutrition.org/cgi/reprint/135/10/2320. 
  10. ^ Bagchi Manashi, Mark Milnes, Casey Williams, Jaya Balmoori, Xumei Ye, Sidney Stohs and Debasis Bagchi (1999). "Acute and chronic stress-induced oxidative gastrointestinal injury in rats, and the protective ability of a novel grape seed proanthocyanidin extract". Nutrition Research 19 (8): 1189–1199. doi:10.1016/S0271-5317(99)00080-9. 
  11. ^ Lotito SB, Frei B (2006). "Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon?". Free Radic. Biol. Med. 41 (12): 1727–46. doi:10.1016/j.freeradbiomed.2006.04.033. PMID 17157175. 
  12. ^ Scientific Opinion on the substantiation of health claims related to various food(s)/food constituent(s) and protection of cells from premature aging, antioxidant activity, antioxidant content and antioxidant properties, and protection of DNA, proteins and lipids from oxidative damage pursuant to Article 13(1) of Regulation (EC) No 1924/20061, EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)2, 3 European Food Safety Authority (EFSA), Parma, Italy, EFSA Journal 2010; 8(2):1489.
  13. ^ Williams RJ, Spencer JP, Rice-Evans C (April 2004). "Flavonoids: antioxidants or signalling molecules?". Free Radical Biology & Medicine 36 (7): 838–49. doi:10.1016/j.freeradbiomed.2004.01.001. PMID 15019969. 
  14. ^ a b "Studies force new view on biology of flavonoids", by David Stauth, EurekAlert!. Adapted from a news release issued by Oregon State University. URL accessed
  15. ^ UCLA news May 2008 - Fruits, vegetables, teas may protect smokers from lung cancer
  16. ^ Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H et al. (1993). "Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations". N Engl J Med 329 (13): 909–14. doi:10.1056/NEJM199309233291302. PMID 8361504. 
  17. ^ Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD (2000). "Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia". Proc Natl Acad Sci U S A 97 (9): 4790–5. doi:10.1073/pnas.070061297. PMC 18311. PMID 10758153. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10758153. 
  18. ^ Barjesteh van Waalwijk van Doorn-Khosrovani S, Janssen J, Maas LM, Godschalk RW, Nijhuis JG, van Schooten FJ (2007). "Dietary flavonoids induce MLL translocations in primary human CD34+ cells". Carcinogenesis 28 (8): 1703–9. doi:10.1093/carcin/bgm102. PMID 17468513. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&ired=17468513. 
  19. ^ Ross JA (1998). "Maternal diet and infant leukemia: a role for DNA topoisomerase II inhibitors?". Int J Cancer Suppl 11: 26–8. PMID 9876473. 
  20. ^ Ross JA (2000). "Dietary flavonoids and the MLL gene: A pathway to infant leukemia?". Proc Natl Acad Sci U S A 97 (9): 4411–3. doi:10.1073/pnas.97.9.4411. PMC 34309. PMID 10781030. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10781030. 
  21. ^ Spector LG, Xie Y, Robison LL, Heerema NA, Hilden JM, Lange B et al. (2005). "Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children's oncology group". Cancer Epidemiol Biomarkers Prev 14 (3): 651–5. doi:10.1158/1055-9965.EPI-04-0602. PMID 15767345. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15767345. 
  22. ^ Delphinidin Modulates the DNA-Damaging Properties of Topoisomerase II Poisons. Esselen, Jessica Fritz, Melanie Hutter and Doris Marko, Chem. Res. Toxicol., 2009, 22 (3), pp 554–564 doi:10.1021/tx800293v
  23. ^ Bandele, O.J.; Clawson, S.J.; Osheroff, N. (2008). "Dietary polyphenols as topoisomerase II poisons: B-ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement". Chemical Research in Toxicology (6): 1253–1260 doi:10.1021/tx8000785
  24. ^ Paul Knekt, Jorma Kumpulainen, Ritva Järvinen, Harri Rissanen, Markku Heliövaara, Antti Reunanen, Timo Hakulinen, and Arpo Aromaa (September 2002). "Flavonoid intake and risk of chronic diseases". Am J Clin Nutr 76 (3): 560–8. PMID 12198000. 
  25. ^ American Cancer Society, Quercetin
  26. ^ Lee KW, Kim YJ, Lee HJ, Lee CY (December 2003). "Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine". J. Agric. Food Chem. 51 (25): 7292–5. doi:10.1021/jf0344385. PMID 14640573. 
  27. ^ "Cocoa nutrient for 'lethal ills'". BBC News. http://news.bbc.co.uk/2/hi/health/.stm. 
  28. ^ Tsushida T., Suzuki, M. (1996) Content of flavonol glucosides and some properties of enzymes metabolizing the glucosides in onion. J. Jap. Soc. Food Sci. Technol., 43, 642-649.
  29. ^ Slimestad R, Fossen T, Vågen IM (December 2007). "Onions: a source of unique dietary flavonoids". J. Agric. Food Chem. 55 (25): 10067–80. doi:10.1021/jf0712503. PMID 17997520. 
  30. ^ Marotti, M.; Piccaglia, R. (2002). "Characterization of Flavonoids in Different Cultivars of Onion (Allium cepa L.)". Journal of Food Science 67 (3): 1229. doi:10.1111/j.1365-2621.2002.tb09482.x. 
  31. ^ Justesen U, Knuthsen P (2001). "Composition of flavonoids in fresh herbs and calculation of flavonoid intake by use of herbs in traditional Danish dishes". Food Chem. 73 (2): 245–50. doi:10.1016/S0308-8146(01)00114-5. 
  32. ^ Ewald C, Fjelkner-Modig S, Johansson K, Sjöholm I, Åkesson B (1999). "Effect of processing on major flavonoids in processed onions, green beans, and peas". Food Chem. 64 (2): 231–5. doi:10.1016/S0308-8146(98)00136-8. 
  33. ^ Spedding G, Ratty A, Middleton E (September 1989). "Inhibition of reverse transcriptases by flavonoids". Antiviral Res. 12 (2): 99–110. doi:10.1016/0166-3542(89)90073-9. PMID 2480745. 
  34. ^ The Lancet, (December 2007). "The devil in the dark chocolate". Lancet 370 (9605): 2070. doi:10.1016/S0140-6736(07)61873-X. PMID 18156011. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)61873-X. 
  35. ^ Serafini et al; Bugianesi, Rossana; Maiani, Giuseppe; Valtuena, Silvia; De Santis, Simone; Crozier, Alan (August 2003). "Plasma antioxidants from chocolate". Nature 424 (6952): 1013. doi:10.1038/4241013a. PMID 12944955. http://www.nature.com/nature/journal/v424/n6952/full/4241013a.html. 
  36. ^ Serafini, M., Crozier, A., Bugianesi, R., Maiani, G., Valtuena, S., and Santis, S.D. (2003). "Nutrition: milk and absorption of dietary flavanols". Nature 424 (6952): 1013. doi:10.1038/4241013a. PMID 12944955. 
  37. ^ Ververidis Filippos, F; Trantas Emmanouil, Douglas Carl, Vollmer Guenter, Kretzschmar Georg, Panopoulos Nickolas (October 2007). "Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: Chemical diversity, impacts on plant biology and human health". Biotechnology Journal 2 (10): 1214–34. doi:10.1002/biot.200700084. PMID 17935117. 
  38. ^ Phenolics:figure 4
  39. ^ Hwang EI, Kaneko M, Ohnishi Y, Horinouchi S (May 2003). "Production of plant-specific flavanones by Escherichia coli containing an artificial gene cluster". Appl. Environ. Microbiol. 69 (5): 2699–706. doi:10.1128/AEM.69.5.2699-2706.2003. PMC 154558. PMID 12732539. http://aem.asm.org/cgi/pmidlookup?view=long&pmid=12732539. 
  40. ^ Trantas Emmanouil, E; Panopoulos Nickolas, Ververidis Filippos (2009). "Metabolic engineering of the complete pathway leading to heterologous biosynthesis of various flavonoids and stilbenoids in Saccharomyces cerevisiae". Metabolic Engineering 11 (6): 355–366. doi:10.1016/j.ymben.2009.07.004. PMID 19631278. 
  41. ^ Ververidis Filippos, F; Trantas Emmanouil, Douglas Carl, Vollmer Guenter, Kretzschmar Georg, Panopoulos Nickolas (October 2007). "Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part II: Reconstruction of multienzyme pathways in plants and microbes". Biotechnology Journal 2 (10): 1235–49. doi:10.1002/biot.200700184. PMID 17935118. 

Further reading

External links

Antihemorrhoidals for topical use
Antivaricose therapy
Capillary stabilising agents

M: VAS

anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell/prot

noco/syva/cong/lyvd/tumr, sysi/epon, injr

proc, drug(C2s+n/3/4/5/7/8/9)
Phenylpropanoids
Types of Flavonoids
Flavonoids
Isoflavonoids
Neoflavonoids
Aurones
Other categories