Flavonoid

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"Vitamin P" redirects here. For other uses, see Vitamin P (disambiguation).
Molecular structure of the flavone backbone (2-phenyl-1,4-benzopyrone)
Isoflavan structure
Neoflavonoids structure

Flavonoids (or bioflavonoids; from the Latin word flavus, meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.[1]

Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two

IUPAC nomenclature,[3][4]
they can be classified into:

The three flavonoid classes above are all

flavonols).[1] 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. The three cycles or heterocycles in the flavonoid backbone are generally called ring A, B, and C.[2] Ring A usually shows a phloroglucinol
substitution pattern.

History

In the 1930s, Albert Szent-Györgyi and other scientists discovered that Vitamin C alone was not as effective at preventing scurvy as the crude yellow extract from oranges, lemons or paprika. They attributed the increased activity of this extract to the other substances in this mixture, which they referred to as "citrin" (referring to citrus) or "Vitamin P" (a reference to its effect on reducing the permeability of capillaries). The substances in question (hesperidin, eriodictyol, hesperidin methyl chalcone and neohesperidin) were however later shown not to fulfil the criteria of a vitamin,[5] so that this term is now obsolete.[6]

Biosynthesis

Main article: Flavonoid biosynthesis

Flavonoids are secondary metabolites synthesized mainly by plants. The general structure of flavonoids is a fifteen-carbon skeleton, containing two benzene rings connected by a three-carbon linking chain.

chalconoids, although lacking the heterocyclic ring, are also classified as flavonoids. Furthermore, flavonoids can be found in plants in glycoside-bound and free aglycone forms. The glycoside-bound form is the most common flavone and flavonol form consumed in the diet.[1]

A biochemical diagram showing the class of flavonoids and their source in nature through various inter-related plant species.

Functions of flavonoids in plants

Flavonoids are widely distributed in plants, fulfilling many functions.[1] They are the most important plant pigments for flower coloration, producing yellow or red/blue pigmentation in petals designed to attract pollinator animals. In higher plants, they are involved in UV filtration, symbiotic nitrogen fixation, and floral pigmentation. They may also act as chemical messengers, physiological regulators, and cell cycle inhibitors. 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 diseases, e.g. Fusarium oxysporum.[7]

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[8]):

Flavonoids


Anthocyanidins

Flavylium skeleton of anthocyanidins

flavylium (2-phenylchromenylium) ion skeleton.[1]

Examples: cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin

Anthoxanthins

Anthoxanthins are divided into two groups:[9]

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavone 2-phenylchromen-4-one ✗ ✗
Tangeritin
Flavonol
or
3-hydroxyflavone 		3-hydroxy-2-phenylchromen-4-one ✓ ✗
Furanoflavonols
,

Flavanones

Flavanones

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavanone
 		2,3-dihydro-2-phenylchromen-4-one ✗ ✓ Hesperetin, Naringenin, Eriodictyol, Homoeriodictyol

Flavanonols

Flavanonols

Group Skeleton Examples
Description Functional groups Structural formula
3-hydroxyl 2,3-dihydro
Flavanonol

or
3-Hydroxyflavanone
or
2,3-dihydroflavonol 		3-hydroxy-2,3-dihydro-2-phenylchromen-4-one ✓ ✓
Dihydrokaempferol

Flavans

Flavan structure

Include

flavan-3,4-diols
.

Skeleton Name
Flavan-3ol Flavan-3-ol (flavanol)
Flavan-4ol Flavan-4-ol
Flavan-3,4-diol
Flavan-3,4-diol
(leucoanthocyanidin)
  • Flavan-3-ols
    (flavanols)
    • Flavan-3-ols
      use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton
    Examples:
    Epigallocatechin 3-gallate
    (EGCg)
    Examples:
    Theaflavin-3,3'-digallate
    • Thearubigin
    • Proanthocyanidins
      are dimers, trimers, oligomers, or polymers of the flavanols

Isoflavonoids

Dietary sources

Parsley is a source of flavones
Blueberries are a source of dietary anthocyanins
Flavonoids are found in citrus fruits, including red grapefruit

Flavonoids (specifically flavanoids such as the

alkaloids) mean that many animals, including humans, ingest significant quantities in their diet.[1]

Foods with a high flavonoid content include

oolong tea,[11] bananas, all citrus fruits, Ginkgo biloba, red wine, sea-buckthorns, buckwheat,[12] and dark chocolate with a cocoa content of 70% or greater. As flavonoids in cocoa have a bitter taste, they may be removed during chocolate manufacturing.[13]

Citrus flavonoids include

tangeritin. The flavonoids are less concentrated in the pulp than in the peels (for example, 165 versus 1156 mg/100 g in pulp versus peel of satsuma mandarin, and 164 vis-à-vis 804 mg/100 g in pulp versus peel of clementine).[14]

Peanut (red) skin contains significant polyphenol content, including flavonoids.[15][16]

Flavonoid content in food (mg/100 g)[1]
Food source Flavones Flavonols Flavanones
Red onion 0 4–100 0
Parsley, fresh 24–634 8–10 0
Thyme, fresh 56 0 0
Lemon juice, fresh 0 0–2 2–175

Dietary intake

Mean flavonoid intake in mg/d per country, the pie charts show the relative contribution of different types of flavonoids.[17]

EFSA, mean flavonoid intake was 140 mg/d, although there were considerable differences among individual countries.[17] The main type of flavonoids consumed in the EU and USA were flavan-3-ols (80% for USA adults), mainly from tea or cocoa in chocolate, while intake of other flavonoids was considerably lower.[1][17][18]

Data are based on mean flavonoid intake of all countries included in the 2011 EFSA Comprehensive European Food Consumption Database.[17]

Research

Neither the United States Food and Drug Administration (FDA) nor the European Food Safety Authority (EFSA) has approved any flavonoids as prescription drugs.[1][19][20][21] The U.S. FDA has warned numerous dietary supplement and food manufacturers, including Unilever, producer of Lipton tea in the U.S., about illegal advertising and misleading health claims regarding flavonoids, such as that they lower cholesterol or relieve pain.[22][23]

Metabolism and excretion

Flavonoids are poorly absorbed in the human body (less than 5%), then are quickly metabolized into smaller fragments with unknown properties, and rapidly excreted.[1][21][24][25] Flavonoids have negligible antioxidant activity in the body, and the increase in antioxidant capacity of blood seen after consumption of flavonoid-rich foods is not caused directly by flavonoids, but by production of uric acid resulting from flavonoid depolymerization and excretion.[1] Microbial metabolism is a major contributor to the overall metabolism of dietary flavonoids.[1][26] The effect of habitual flavonoid intake on the human gut microbiome is unknown.[1][27]

Inflammation

diabetes mellitus,[30] and celiac disease.[31] There is no clinical evidence that dietary flavonoids affect any of these diseases.[1]

Cancer

Clinical studies investigating the relationship between flavonoid consumption and cancer prevention or development are conflicting for most types of cancer, probably because most human studies have weak designs, such as a small sample size.[1][32] There is little evidence to indicate that dietary flavonoids affect human cancer risk in general.[1]

Cardiovascular diseases

Although no significant association has been found between flavan-3-ol intake and cardiovascular disease mortality, clinical trials have shown improved endothelial function and reduced blood pressure (with a few studies showing inconsistent results).[1] Reviews of cohort studies in 2013 found that the studies had too many limitations to determine a possible relationship between increased flavonoid intake and decreased risk of cardiovascular disease, although a trend for an inverse relationship existed.[1][33]

In 2013, the EFSA decided to permit health claims that 200 mg/day of cocoa flavanols "help[s] maintain the elasticity of blood vessels."[34][35] The FDA followed suit in 2023, stating that there is "supportive, but not conclusive" evidence that 200 mg per day of cocoa flavanols can reduce the risk of cardiovascular disease. This is greater than the levels found in typical chocolate bars, which can also contribute to weight gain, potentially harming cardiovascular health.[36][37]

Synthesis, detection, quantification, and semi-synthetic alterations

Color spectrum

Flavonoid synthesis in plants is induced by light color spectrums at both high and low energy radiations. Low energy radiations are accepted by phytochrome, while high energy radiations are accepted by carotenoids, flavins, cryptochromes in addition to phytochromes. The photomorphogenic process of phytochrome-mediated flavonoid biosynthesis has been observed in Amaranthus, barley, maize, Sorghum and turnip. Red light promotes flavonoid synthesis.[38]

Availability through microorganisms

Research has shown production of flavonoid molecules from genetically engineered microorganisms.[39][40]

Tests for detection

Shinoda test

Four pieces of magnesium filings are added to the ethanolic extract followed by few drops of concentrated

flavonones
.

Sodium hydroxide test

About 5 mg of the compound is dissolved in water, warmed, and filtered. 10% aqueous sodium hydroxide is added to 2 ml of this solution. This produces a yellow coloration. A change in color from yellow to colorless on addition of dilute hydrochloric acid is an indication for the presence of flavonoids.[42]

p-Dimethylaminocinnamaldehyde test

A colorimetric assay based upon the reaction of A-rings with the chromogen

p-dimethylaminocinnamaldehyde (DMACA) has been developed for flavanoids in beer that can be compared with the vanillin procedure.[43]

Quantification

Lamaison and Carnet have designed a test for the determination of the total flavonoid content of a sample (AlCI3 method). After proper mixing of the sample and the reagent, the mixture is incubated for ten minutes at ambient temperature and the absorbance of the solution is read at 440 nm. Flavonoid content is expressed in mg/g of quercetin.[44]

Semi-synthetic alterations

Immobilized

Candida antarctica lipase can be used to catalyze the regioselective acylation of flavonoids.[45]

See also

References

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  36. ^ Kavanaugh C (February 1, 2023). RE: Petition for a Qualified Health Claim – for Cocoa Flavanols and Reduced Risk of Cardiovascular Disease (Docket No. FDA-2019-Q-0806) (Report). FDA.
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  44. ^ Lamaison JL, Carnet A (1991). "Teneurs en principaux flavonoïdes des fleurs de Cratageus monogyna Jacq. et de Cratageus laevigata (Poiret D.C.) en fonction de la végétation" [Principal flavonoid content of flowers of Cratageus monogyna Jacq. and Cratageus laevigata (Poiret D.C.) dependent on vegetation]. Plantes Medicinales: Phytotherapie (in French). 25: 12–16.
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Further reading

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