Flavonoid

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Flavonoids (or bioflavonoids; from the Latin word flavus, meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants. Blackberry, black currant, chokeberry, and red cabbage are examples of plants with rich contents of flavonoids. In plant biology, flavonoids fulfill diverse functions, including attraction of pollinating insects, antioxidant protection against ultraviolet light, deterrence of environmental stresses and pathogens, and regulation of cell growth.<ref name="lpi-flav">Template:Cite web</ref><ref name="hollman">Template:Cite journal</ref>

Although commonly consumed in human and animal plant foods and in dietary supplements, flavonoids are not considered to be nutrients or biological antioxidants essential to body functions, and have no established effects on human health or prevention of diseases.<ref name=lpi-flav/><ref name=hollman/><ref name="efsa-2011">Template:Cite journal</ref>

Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and a heterocyclic ring (C, the ring containing the embedded oxygen).<ref name=lpi-flav/><ref name = "de_Souza_2021">Template:Cite journal</ref> This carbon structure can be abbreviated C6-C3-C6. According to the IUPAC nomenclature, they can be classified into flavonoids or bioflavonoids, isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure, and neoflavonoids, derived from 4-phenylcoumarin (4-phenyl-1,2-benzopyrone) structure.<ref name="iupac">Template:Citation</ref>

As ketone-containing compounds, the three flavonoid classes are grouped as anthoxanthins (flavones and flavonols).<ref name=lpi-flav/> 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.<ref name = "de_Souza_2021" />

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 later shown not to fulfil the criteria of a vitamin,<ref>Template:Cite book</ref> so that the term "vitamin P" is now obsolete.<ref>Template:Cite book</ref>

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

Biosynthesis

Template:Main 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.<ref name=lpi-flav/> Therefore, they are depicted as C6-C3-C6 compounds. Depending on the chemical structure, degree of oxidation, and unsaturation of the linking chain (C3), flavonoids can be classified into different groups, such as anthocyanidins, flavonols, flavanones, flavan-3-ols, flavanonols, flavones, and isoflavones.<ref name=lpi-flav/> Chalcones, also called 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.<ref name=lpi-flav/>

Functions in plants

Numbering some 5,000 individual compounds, flavonoids are widely distributed in plants, fulfilling numerous functions, including attraction of pollinating insects, deterrence of environmental stresses, and regulation of cell growth.<ref name=lpi-flav/> They are the most important plant pigments for flower coloration, producing yellow, red or blue pigmentation in petals evolved to attract pollinators.<ref name=lpi-flav/>

In higher plants, they are involved in antioxidant roles in plant cells, filtration of ultraviolet light, symbiotic nitrogen fixation, and defense against pathogens and pests. They also act as plant chemical messengers, physiological regulators, and cell cycle inhibitors.<ref name=lpi-flav/><ref name=hollman/> 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.<ref>Template:Cite journal</ref>

Subgroups

Flavonoids have been classified according to their chemical structure, and are usually subdivided into the following subgroups:<ref name=lpi-flav/><ref name="Ververidis">Template:Cite journal</ref>

Anthocyanidins

Anthocyanidins are the aglycones of anthocyanins; they use the flavylium (2-phenylchromenylium) ion skeleton.<ref name=lpi-flav/>

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

Anthoxanthins

Anthoxanthins are divided into two groups:<ref>Template:Cite journal</ref>

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
	Description	3-hydroxyl	2,3-dihydro	Structural formula
[[Flavones\|Template:Black Template:Red]]	Template:Black-Template:Red	✗	✗		Luteolin, Apigenin, Tangeritin
[[Flavonols\|Template:Black Template:Red Template:Green]] or [[Flavonols\|Template:Green Template:Black Template:Red]]	Template:Green-Template:Black-Template:Red	✓	✗		Quercetin, Kaempferol, Myricetin, Fisetin, Galangin, Isorhamnetin, Pachypodol, Rhamnazin, Pyranoflavonols, Furanoflavonols,

Flavanones

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
	Description	3-hydroxyl	2,3-dihydro	Structural formula
[[Flavanones\|Template:Black Template:Blue Template:Red]]	Template:Blue-Template:Black-Template:Red	✗	✓		Hesperetin, Naringenin, Eriodictyol, Homoeriodictyol

Flavanonols

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
	Description	3-hydroxyl	2,3-dihydro	Structural formula
[[Flavanonols\|Template:Black Template:Blue Template:Red Template:Green]] or Template:Green Template:Black Template:Blue Template:Red or Template:Blue Template:Black Template:Red Template:Green	Template:Green-Template:Blue-Template:Black-Template:Red	✓	✓		Taxifolin (or Dihydroquercetin), Dihydrokaempferol

Flavans

Include flavan-3-ols (flavanols), flavan-4-ols, and flavan-3,4-diols.

Skeleton	Name
	Flavan-3-ol (flavanol)
	Flavan-4-ol
	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: catechin (C), gallocatechin (GC), catechin 3-gallate (Cg), gallocatechin 3-gallate (GCg), epicatechins (EC), epigallocatechin (EGC), epicatechin 3-gallate (ECg), epigallocatechin 3-gallate (EGCg)
- Theaflavin
Examples: theaflavin-3-gallate, theaflavin-3'-gallate, theaflavin-3,3'-digallate
- Thearubigin
- Proanthocyanidins are dimers, trimers, oligomers, or polymers of the flavanols

Isoflavonoids

Isoflavonoids
- Isoflavones use the 3-phenylchromen-4-one skeleton (with no hydroxyl group substitution on carbon at position 2)
Examples: genistein, daidzein, glycitein

Dietary sources

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".<ref name=lpi-flav/><ref name=hollman/><ref>Template:Cite journal</ref> 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.<ref name=lpi-flav/><ref name=hollman/><ref name=efsa-2011/>

Foods with a high flavonoid content include blackberries, black currants, parsley, onions, blueberries and strawberries, red cabbage, black tea, dark chocolate, and citrus fruits.<ref name=lpi-flav/><ref name=hollman/><ref name="ars.usda">Template:Cite web</ref> One study found high flavonoid content in buckwheat.<ref>Template:Cite journal</ref>

Citrus flavonoids include hesperidin (a glycoside of the flavanone hesperetin), quercitrin, rutin (two glycosides of quercetin, and the flavone tangeritin.<ref name=lpi-flav/> 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).<ref>Template:Cite journal</ref>

Peanut (red) skin contains significant polyphenol content, including flavonoids.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Dietary intake

Food composition data for flavonoids were provided by the USDA database on flavonoids.<ref name="ars.usda" /> In the United States NHANES survey, mean flavonoid intake was 190 mg per day in adults, with flavan-3-ols as the main contributor.<ref name="Chun_2007">Template:Cite journal</ref> In the European Union, based on data from the European Food Safety Authority (EFSA), mean flavonoid intake was 140 mg/d, although there were considerable differences among individual countries.<ref name="Vogiatzoglou_2015">Template:Cite journal</ref> 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.<ref name=lpi-flav/><ref name=Vogiatzoglou_2015/><ref name=Chun_2007/>

Non-nutrient status in humans

Flavonoids are not considered as nutrients because there is no evidence for a cause-and-effect on specific cells or organs in vivo.<ref name=lpi-flav/><ref name=hollman/><ref name=efsa-2011/> The European Food Safety Authority determined that dietary flavonoids do not have the characteristics of nutrients, as they do not reduce disease risk, affect physiological or behavioral functions, improve satiety, contribute calories, or influence the growth and development of children.<ref name=efsa-2011/> The bioavailability of flavonoids is low because they are extensively metabolized in the stomach, small intestine and liver, and are rapidly excreted.<ref name=lpi-flav/><ref name=hollman/>

In the United States, flavonoids and other polyphenols are not included on the FDA list of nutrients.<ref name="fda-nutrients">Template:Cite web</ref>

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.<ref name=lpi-flav/><ref name=hollman/><ref name=EFSA2010/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name=lpi-flav/><ref name=hollman/><ref name=efsa-2011/> Microbial metabolism is a major contributor to the overall metabolism of dietary flavonoids.<ref name=lpi-flav/><ref name=hollman/><ref>Template:Cite journal</ref>

Safety

Likely due to the low bioavailability and rapid metabolism and excretion of flavonoids, there are no safety concerns and no adverse effects associated with high dietary intakes of flavonoids from plant foods.<ref name=lpi-flav/>

Regulatory status

Due to the absence of proof for flavonoid health effects in clinical research, neither the United States FDA nor the European Food Safety Authority has approved any flavonoids as prescription drugs.<ref name=lpi-flav/><ref name="EFSA2010">Template:Cite journal</ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref>

The 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.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>

From 2020 to 2023, the FDA issued 11 warning letters to American manufacturers of flavonoid dietary supplements for false advertising of health claims and illegal misbranding of products.<ref name="fda-warn">Template:Cite web</ref>

Research

Antioxidant research

Although flavonoids inhibit free radical activity in vitro, high dietary intakes in humans would be 100 to 1,000 times less than circulating concentrations of dietary and endogenous antioxidants, such as vitamin C, glutathione, and uric acid.<ref name=lpi-flav/><ref name=hollman/> Further, after digestion and metabolism in the body, flavonoid derivatives would have lower antioxidant activity than the parent flavonoid, rendering the smaller flavonoid metabolite with negligible antioxidant function.<ref name=lpi-flav/><ref name=hollman/><ref name=efsa-2011/>

Clinical research

Although numerous preliminary clinical studies have been conducted to assess the potential for dietary flavonoid intake to affect disease risk, research has been inconclusive due to limitations of experimental design and absence of cause-and-effect evidence.<ref name=lpi-flav/><ref name=hollman/><ref name=efsa-2011/>

Inflammation

Inflammation has been implicated as a possible origin of numerous local and systemic diseases, such as cancer,<ref>Template:Cite journal</ref> cardiovascular disorders,<ref>Template:Cite journal</ref> diabetes mellitus,<ref>Template:Cite journal</ref> and celiac disease.<ref>Template:Cite journal</ref> There is no clinical evidence that dietary flavonoids affect any of these diseases.<ref name=lpi-flav/>

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.<ref name=lpi-flav/><ref name="ReferenceA">Template:Cite journal</ref> There is little evidence to indicate that dietary flavonoids affect human cancer risk in general.<ref name=lpi-flav/>

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).<ref name=lpi-flav/> 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.<ref name=lpi-flav/><ref>Template:Cite journal</ref>

In 2013, the EFSA decided to permit health claims that 200 mg/day of cocoa flavanols "help[s] maintain the elasticity of blood vessels."<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> 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.<ref>Template:Cite report</ref><ref>Template:Cite news</ref>

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.<ref>Template:Cite book</ref>

Availability through microorganisms

Research has shown production of flavonoid molecules from genetically engineered microorganisms.<ref name="trantas09">Template:Cite journal</ref><ref name="Ververidis2">Template:Cite journal</ref>

Tests for detection

Shinoda test

Four pieces of magnesium filings are added to the ethanolic extract followed by few drops of concentrated hydrochloric acid. A pink or red colour indicates the presence of flavonoid.<ref>Template:Cite journal</ref> Colours varying from orange to red indicated flavones, red to crimson indicated flavonoids, crimson to magenta indicated 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Semi-synthetic alterations

Immobilized Candida antarctica lipase can be used to catalyze the regioselective acylation of flavonoids.<ref>Template:Cite journal</ref>

References

Template:Reflist

Flavonoid

Contents

History

Biosynthesis

Functions in plants