Flavonoid

Molecular structure of the flavone backbone (2-phenyl-1,4-benzopyrone)

Isoflavan structure

Neoflavonoids structure

Flavonoids (or bioflavonoids), also collectively known as Vitamin P and citrin^[1], are a class of plant secondary metabolites. According to the IUPAC nomenclature,^[2] they can be classified into:

• flavonoids, derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure (examples: quercetin, rutin).
• isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
• neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure.

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 (although catechins are actually a subgroup of flavanoids).

Biosynthesis

Biological roles

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.

They also protect plants from attacks by microbes, fungi^[3] and insects.

Potential for biological activity

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. Both sets of compounds have evidence of health-modulating effects in animals which eat them.

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. Resulting from experimental evidence that they may modify allergens, viruses, and carcinogens, flavonoids have potential to be biological "response modifiers", such as anti-allergic, anti-inflammatory,^[5] anti-microbial^[6] and anti-cancer activities shown from in vitro studies.^[7]

Antioxidant activity in vitro

Flavonoids (both flavonols and flavanols) are most commonly known for their antioxidant activity in vitro.

Consumers and food manufacturers have become interested in flavonoids for their possible medicinal properties, especially their putative role in prevention of cancers and cardiovascular diseases. Although physiological evidence is not yet established, the beneficial effects of fruits, vegetables, tea, and red wine have sometimes been attributed to flavonoid compounds rather than to known micronutrients, such as vitamins and dietary minerals.^[8]

Alternatively, research conducted at the Linus Pauling Institute and evaluated by the European Food Safety Authority indicates that, following dietary intake, flavonoids themselves are of little or no direct antioxidant value.^[9][10] As body conditions are unlike controlled test tube conditions, flavonoids and other polyphenols 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 is not caused directly by flavonoids themselves, but most likely is due to increased uric acid levels that result from metabolism of flavonoids.^[11] 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."

Other potential health benefits

Cancer

Physiological processing of unwanted flavonoid compounds induces so-called Phase II enzymes that also help to eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention. Flavonoids could also induce mechanisms that may kill cancer cells and inhibit tumor invasion.^[11] UCLA cancer researchers have found that study participants who ate foods containing certain flavonoids, such as 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.^[12]

Research also indicated that only small amounts of flavonoids may be needed for possible benefits. Taking large dietary supplements likely provides no extra benefit and may pose risks. However, certainty of neither a benefit nor a risk has been proven yet in large-scale human intervention trials.^[11]

Diarrhea

A study done at Children's Hospital & Research Center Oakland, in collaboration with scientists at Heinrich Heine University in Germany, has shown that epicatechin, quercetin and luteolin can inhibit the development of fluids that result in diarrhea by targeting the intestinal cystic fibrosis transmembrane conductance regulator Cl– transport inhibiting cAMP-stimulated Cl– secretion in the intestine.^[13]

Capillary stabilizing agents

Bioflavonoids like rutin, monoxerutin, diosmin, troxerutin and hidrosmin have potential vasoprotective proprieties still under experimental evaluation.

Important flavonoids

Quercetin

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 clinical evidence that asthma, lung cancer and breast cancer are lower among people consuming higher dietary levels of quercetin,^[14] the consensus of scientists, regulatory authorities such as the FDA, and patient support organizations like the American Cancer Society is that no physiological role exists, stating that dietary quercetin "is unlikely to cause any major problems or benefits."^[15]

Epicatechin

Epicatechin (EC)

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.^[16][17] In the test outlined above, it appears the potential antioxidant effects in vivo are minimal as the antioxidants are rapidly excreted from the body.

Important dietary sources

Good sources of flavonoids include all citrus fruits, berries, ginkgo biloba, onions^[18][19], parsley^[20], (particularly red onion^[21]) pulses^[22], tea (especially white and green tea), red wine, seabuckthorn, and dark chocolate (with a cocoa content of seventy percent or greater).

Citrus

A variety of flavonoids are found in citrus fruits, including grapefruit.

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.^[23] 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

Green tea contains flavonoids

Green tea flavonoids are potent antioxidant compounds in vitro, with potential to reduce incidence of cancer ^[24][25] and heart disease. The major flavonoids in green tea are kaempferol and catechins (catechin, epicatechin, epicatechin gallate (ECG), and epigallocatechin gallate (EGCG)).

In producing teas such as oolong tea and black tea, the leaves are allowed to oxidize, during which enzymes present in the tea convert some or all of the catechins to larger molecules. However, green tea is produced by steaming the fresh-cut tea leaves, which deactivates these enzymes, and oxidation does not significantly occur. White tea is the least processed of teas and is shown to present the highest amount of catechins known to occur in Camellia sinensis.

Wine

Grape skins contain significant amounts of flavonoids as well as other polyphenols^[26]. Both red and white wine contain flavonoids; however, since red wine is produced by fermentation in the presence of the grape skins, red wine has been observed to contain higher levels of flavonoids, and other polyphenolics such as resveratrol.

Dark chocolate

Flavonoids exist naturally in cacao, but because they can be bitter, they are often removed from chocolate, even dark chocolate.^[27] Although flavonoids are present in milk chocolate, milk may interfere with their absorption.^[28]

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 ^[29]):

Flavones

Flavones are divided into four groups:^[30]

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

• Isoflavones

  Isoflavones use the 3-phenylchromen-4-one skeleton (with no hydroxyl group substitution on carbon at position 2).

  Examples: Genistein, Daidzein, Glycitein

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

Flavan structure

Derivatives of flavan.

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

• Flavan-3-ols (also known as flavanols) and Proanthocyanidins

  Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton.

  Catechins (Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg)), Epicatechins (Epicatechin (EC), Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg))

  Proanthocyanidins are dimers, trimers, oligomers, or polymers of the flavanols.

Anthocyanidins

Flavylium skeleton of anthocyanidins

• Anthocyanidins

  Anthocyanidins are the aglycones of anthocyanins. Anthocyanidins use the flavylium (2-phenylchromenylium) ion skeleton

  Examples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Availability through microorganisms

Several recent research articles have demonstrated the efficient production of flavonoid molecules from genetically-engineered microorganisms^[31][32][33].

See also

References

External links

• Instant insight considering the effect of flavonoids on memory and learning from the Royal Society of Chemistry
• USDA Database of Flavonoid content of food (pdf)
• Flavonoids (chemistry)
• Cornell news on Cocoa
• A Dark Chocolate a Day Keeps the Doctor Away
• Antioxidant in Green Tea may fight Alzheimer's-EGCG
• Yamamoto Y, Gaynor RB (January 2001). "Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer". J. Clin. Invest. 107 (2): 135–42. doi:10.1172/JCI11914. PMID 11160126. PMC 199180. http://www.jci.org/cgi/content/full/107/2/135. 
• Micronutrient Information Center - Flavonoids