flavonoid

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

The term flavonoid refers to a class of plant secondary metabolites. According to the IUPAC nomenclature,^[1] they can be classified into:

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

Flavonoids are most commonly known for their antioxidant activity. However, it is now known that the health benefits they provide against cancer and heart disease are the result of other mechanisms.^[2] Flavonoids are also commonly referred to as bioflavonoids in the media – the terms are equivalent and interchangeable, for flavonoids are biological in origin.

Biosynthesis

Flavonoids are synthesized by the phenylpropanoid metabolic pathway in which the amino acid phenylalanine is used to produce 4-coumaroyl-CoA. This can be combined with malonyl-CoA to yield the true backbone of flavonoids, a group of compounds called chalcones which contain two phenyl rings (see polyphenols). Conjugate ring-closure of chalcones results in the familiar form of flavonoids, the three-ringed structure of a flavone. The metabolic pathway continues through a series of enzymatic modifications to yield flavanones → dihydroflavonols → anthocyanins. Along this pathway many products can be formed, including the flavonols, flavan-3-ols, proanthocyanidins (tannins) and a host of other polyphenolics.

Biological effects

Flavonoids are widely distributed in plants fulfilling many functions including producing yellow or red/blue pigmentation in flowers and protection from attack by microbes and insects. 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. Flavonoids have been referred to as "nature's biological response modifiers" because of strong experimental evidence of their inherent ability to modify the body's reaction to allergens, viruses, and carcinogens. They show anti-allergic, anti-inflammatory^[3] , anti-microbial and anti-cancer activity.

Consumers and food manufacturers have become interested in flavonoids for their medicinal properties, especially their potential role in the prevention of cancers and cardiovascular disease. The beneficial effects of fruit, vegetables, and tea or even red wine have been attributed to flavonoid compounds rather than to known nutrients and vitamins.

Health benefit not due to direct antioxidant value

In 2007, research conducted at the Linus Pauling Institute and published in Free Radical Biology and Medicine indicates that inside the human body, flavonoids themselves are of little or no direct antioxidant value. Unlike in the controlled conditions of a test tube, flavonoids are poorly absorbed by the human body (less than 5%), and most of what is absorbed is quickly metabolized and excreted from the body.

The huge increase in antioxidant capacity of blood seen after the consumption of flavonoid-rich foods is not caused directly by the flavonoids themselves, but most likely is due to increased uric acid levels that result from expelling flavonoids from the body.^[2] 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. But this process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention... Flavonoids could also induce mechanisms that help kill cancer cells and inhibit tumor invasion."^[2]

Their research also indicated that only small amounts of flavonoids are necessary to see these medical benefits. Taking large dietary supplements provides no extra benefit and may pose some risks.^[2]

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.^[4]

Important flavonoids

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Quercetin

Quercetin is a flavonoid and more specifically a flavonol (see below), that constitutes the aglycone of the glycoside rutin. In studies, quercetin is found to be the most active of the flavonoids, and many medicinal plants owe much of their activity to their high quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation. For example, it inhibits both the production and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action. It has been found to be anti-cancer. Quercetin can be found in the herbal products based on Hawthorn which are used for acute symptoms of Congestive Heart Failure.

Epicatechin

Epicatechin improves blood flow and thus seems good 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 in-vitro tests.^{[5] [6]} But in the test outlined above it now appears the beneficial antioxidant effects are minimal as the antioxidants are rapidly excreted from the body.

Oligomeric proanthocyanidins

Proanthocyanidins extracts demonstrate a wide range of pharmacological activity. Their effects include increasing intracellular vitamin C levels, decreasing capillary permeability and fragility, scavenging oxidants and free radicals, and inhibiting destruction of collagen, the most abundant protein in the body.

Important dietary sources

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Good sources of flavonoids include all citrus fruits, berries, onions, parsley, legumes, green tea, red wine, seabuckthorn, and dark chocolate (that with a cocoa content of seventy percent or greater).

Citrus

The citrus bioflavonoids include hesperidin, quercetin, rutin (a glycoside of quercetin), and tangeritin. In addition to possessing antioxidant activity and an ability to increase intracellular levels of vitamin C, rutin and hesperidin exert beneficial effects on capillary permeability and blood flow. They also exhibit some of the anti-allergy and anti-inflammatory benefits of quercetin. Quercetin can also inhibit reverse transcriptase, part of the replication process of retroviruses.^[7] The therapeutical relevance of this inhibition has not been established. Hydroxyethylrutosides (HER) have been used in the treatment of capillary permeability, easy bruising, hemorrhoids, and varicose veins.

Tea

Green tea flavonoids are potent antioxidant compounds, thought to reduce incidence of cancer and heart disease. The major flavonoids in green tea are the catechins (catechin, epicatechin, epicatechin gallate, 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. White tea is the least processed of teas and is shown to present the highest amount of catechins known to occur in camellia sinensis.However, green tea is produced by steaming the fresh-cut leaf, which inactivates these enzymes, and oxidation does not significantly occur.

Wine

Grape skins contain significant amounts of flavonoids as well as other polyphenols^[8]. 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.

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:

Flavones

Flavones are divided into four groups:^[9]

• Flavones

  Flavones use the 2-phenylchromen-4-one skeleton.

  Examples: Luteolin, Apigenin, Tangeritin

• Flavonols

  Flavonols or 3-hydroxyflavones use the 3-hydroxy-2-phenylchromen-4-one skeleton.

  Examples: Quercetin, Kaempferol, Myricetin, Fisetin, Isorhamnetin, Pachypodol, Rhamnazin

• Flavanones

  Flavanones use the 2,3-dihydro-2-phenylchromen-4-one skeleton.

  Examples: Hesperetin, Naringenin, Eriodictyol

• 3-Hydroxyflavanones or 2,3-dihydroflavonols

  3-Hydroxyflavanones use the 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one skeleton.

  Examples: Dihydroquercetin, Dihydrokaempferol

Isoflavones

• Isoflavones

  Isoflavones use the 3-phenylchromen-4-one skeleton.

  Examples: Genistein, Daidzein, Glycitein

Flavan-3-ols and Anthocyanidins

• Flavan-3-ols

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

  Examples: 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))

• 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

A number of recent research articles have demonstrated the efficient production of flavonoid molecules from genetically-engineered microorganisms^[10].

See also

• Phytochemistry

References

1. ^ Flavonoids (isoflavonoids and neoflavonoids)., IUPAC Compendium of Chemical Terminology
2. ^ ^{a b c d} "Studies force new view on biology of flavonoids", by David Stauth, EurekAlert!. Adapted from a news release issued by Oregon State University. URL accessed 2007-03-06.
3. ^ 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. Retrieved on 2006-08-30.
4. ^ Schuier, Maximilian; Helmut Sies, Beate Illek, and Horst Fischer (October 2005). "Cocoa-Related Flavonoids Inhibit CFTR-Mediated Chloride Transport across T84 Human Colon Epithelia" (PDF). Journal of Nutrition 135 (10): 2320-2325. Retrieved on 2007-05-02. 
5. ^ J. Agric.Food Chem. (2003) 51:7292-7295 Lee et al.
6. ^ Cocoa nutrient for 'lethal ills'. BBC News. Retrieved on 2007-03-11.
7. ^ Spedding, G., Ratty, A., Middleton, E. Jr. (1989) Inhibition of reverse transcriptases by flavonoids. Antiviral Res 12 (2), 99-110. PMID 2480745
8. ^ James A. Kennedy, Mark A. Matthews, and Andrew L. Waterhouse, Effect of Maturity and Vine Water Status on Grape Skin and Wine Flavonoids Am. J. Enol. Vitic. 53:4:268-274 (2002) (abstract)
9. ^ http://www.ars.usda.gov/is/np/phenolics/illus/phenfig4.htm
10. ^ Hwang EI, Kaneko M, Ohnishi Y, Horinouchi S. Production of plant-specific flavanones by Escherichia coli containing an artificial gene cluster. Appl Environ Microbiol. 2003 May;69(5):2699-706 PMID 12732539

• Balch, J. F., & Balch, P. A. (2000). Prescription for Nutritional Healing. New York: Avery, Penguin Putnam Inc.
• Murray, M. T. (1996). Encyclopedia of Nutritional Supplements. Roseville: Prima Publishing.

External links

• USDA Database of Flavonoid content of food (pdf)
• Flavonoids (chemistry)
• Flavonoids (chemistry)
• Cornell news on Cocoa
• A Dark Chocolate a Day Keeps the Doctor Away
• Antioxidant in Green Tea may fight Alzheimer's-EGCG
• Therapeutic potential of the NF-kB pathway in the treatment of inflammatory disorders

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