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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.[1][2]

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.[1][2][3]

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).[1][4] 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.[5]

As ketone-containing compounds, the three flavonoid classes are grouped as anthoxanthins (flavones and 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.[4]

History

[edit]

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,[6] so that the term "vitamin P" is now obsolete.[7]

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

Biosynthesis

[edit]
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.[1] 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.[1] 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.[1]

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

Functions in plants

[edit]

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.[1] They are the most important plant pigments for flower coloration, producing yellow, red or blue pigmentation in petals evolved to attract pollinators.[1]

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.[1][2] 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.[8]

Subgroups

[edit]

Flavonoids have been classified according to their chemical structure, and are usually subdivided into the following subgroups:[1][9]

Anthocyanidins

[edit]
Flavylium skeleton of anthocyanidins

Anthocyanidins are the aglycones of anthocyanins; they use the flavylium (2-phenylchromenylium) ion skeleton.[1]

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

Anthoxanthins

[edit]

Anthoxanthins are divided into two groups:[10]

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, Galangin, Isorhamnetin, Pachypodol, Rhamnazin, Pyranoflavonols, Furanoflavonols,

Flavanones

[edit]

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

[edit]

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 ✓ ✓ Taxifolin (or Dihydroquercetin), Dihydrokaempferol

Flavans

[edit]
Flavan structure

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

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

Isoflavonoids

[edit]

Dietary sources

[edit]
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 catechins) are "the most common group of polyphenolic compounds in the human diet and are found ubiquitously in plants".[1][2][11] 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.[1][2][3]

Foods with a high flavonoid content include blackberries, black currants, parsley, onions, blueberries and strawberries, red cabbage, black tea, dark chocolate, and citrus fruits.[1][2][12] One study found high flavonoid content in buckwheat.[13]

Citrus flavonoids include hesperidin (a glycoside of the flavanone hesperetin), quercitrin, rutin (two glycosides of quercetin, and the flavone tangeritin.[1] 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]

Dietary intake

[edit]
Adult flavonoid intake (mg per day) in Europe; pie charts indicate the relative consumption of different flavonoid compounds[17]

Food composition data for flavonoids were provided by the USDA database on flavonoids.[12] In the United States NHANES survey, mean flavonoid intake was 190 mg per day in adults, with flavan-3-ols as the main contributor.[18] 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.[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]

Non-nutrient status in humans

[edit]

Flavonoids are not considered as nutrients because there is no evidence for a cause-and-effect on specific cells or organs in vivo.[1][2][3] 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.[3] The bioavailability of flavonoids is low because they are extensively metabolized in the stomach, small intestine and liver, and are rapidly excreted.[1][2]

In the United States, flavonoids and other polyphenols are not included on the FDA list of nutrients.[19]

Metabolism and excretion

[edit]

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][2][20][21][22] 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][2][3] Microbial metabolism is a major contributor to the overall metabolism of dietary flavonoids.[1][2][23]

Safety

[edit]

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.[1]

Regulatory status

[edit]

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.[1][20][24][25]

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.[26][27]

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.[28]

Research

[edit]

Antioxidant research

[edit]

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.[1][2] 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.[1][2][3]

Clinical research

[edit]

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.[1][2][3]

Inflammation

[edit]

Inflammation has been implicated as a possible origin of numerous local and systemic diseases, such as cancer,[29] cardiovascular disorders,[30] diabetes mellitus,[31] and celiac disease.[32] There is no clinical evidence that dietary flavonoids affect any of these diseases.[1]

Cancer

[edit]

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][33] There is little evidence to indicate that dietary flavonoids affect human cancer risk in general.[1]

Cardiovascular diseases

[edit]

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][34]

In 2013, the EFSA decided to permit health claims that 200 mg/day of cocoa flavanols "help[s] maintain the elasticity of blood vessels."[35][36] 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.[37][38]

Synthesis, detection, quantification, and semi-synthetic alterations

[edit]

Color spectrum

[edit]

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.[39]

Availability through microorganisms

[edit]

Research has shown production of flavonoid molecules from genetically engineered microorganisms.[40][41]

Tests for detection

[edit]

Shinoda test

[edit]

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.[42] Colours varying from orange to red indicated flavones, red to crimson indicated flavonoids, crimson to magenta indicated flavonones.

Sodium hydroxide test

[edit]

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.[43]

p-Dimethylaminocinnamaldehyde test

[edit]

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.[44]

Quantification

[edit]

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.[45][46]

Semi-synthetic alterations

[edit]

Immobilized Candida antarctica lipase can be used to catalyze the regioselective acylation of flavonoids.[47]

See also

[edit]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Flavonoid

View on Grokipedia
from Grokipedia
Flavonoids are a large and diverse group of naturally occurring polyphenolic compounds, characterized by a basic 15-carbon skeleton consisting of two phenyl rings (A and B) connected by a three-carbon linking chain that forms a heterocyclic ring (C), and they are widely distributed in the plant kingdom. These secondary metabolites, often hydroxylated and glycosylated, serve essential roles in while offering potential health-promoting effects in humans through dietary consumption. Flavonoids are classified into several subclasses based on variations in their chemical structure, with the six primary classes being flavones, , flavanones, flavan-3-ols, , and anthocyanidins; additional subclasses include aurones, chalcones, and dihydrochalcones, bringing the total to over 12 recognized groups. This structural diversity—exemplified by the between carbons 2 and 3 in flavones and , or the absence thereof in flavanones—underlies their varied biological activities and occurrence in different plant tissues. In , flavonoids function primarily as pigments, antioxidants, and signaling molecules, attracting pollinators through coloration in flowers and fruits, protecting against radiation, and defending against pathogens and herbivores via and anti-feedant properties. They are synthesized through the phenylpropanoid pathway and accumulate in vacuoles, , and other tissues, contributing to plant stress tolerance and reproduction. Dietary sources of flavonoids are abundant in everyday foods, including fruits (e.g., apples, berries, ), vegetables (e.g., onions, ), grains, teas, , and , with average daily intake in Western diets estimated at 200–300 mg, though varies due to and gut metabolism. Prominent examples include (a flavonol in onions and apples), catechins (flavan-3-ols in ), and anthocyanins (in berries and red grapes), which contribute to the sensory qualities and nutritional value of these plant-based foods. In human health, flavonoids exhibit a range of bioactivities, including potent and free radical-scavenging effects that mitigate , alongside , cardioprotective, and anticancer properties supported by epidemiological and studies. Diets rich in flavonoids are associated with reduced risks of , improved endothelial function, and potential benefits in managing and neurodegeneration, though clinical evidence remains mixed due to factors like absorption and . Ongoing emphasizes their role as nutraceuticals, with over 10,000 identified compounds highlighting their significance in preventive .

Overview

Definition and Biological Significance

Flavonoids constitute a diverse class of secondary metabolites characterized by polyphenolic structures, with more than 10,000 distinct compounds identified to date. These compounds are predominantly synthesized by , where they accumulate in various tissues such as fruits, , flowers, and roots, but they have also been detected in certain fungi and through biosynthetic pathways. As plant secondary metabolites, flavonoids play essential roles beyond primary , contributing to the and of producing organisms in their environments. In , flavonoids exhibit multifaceted biological significance, including potent activity that helps neutralize generated under stress conditions. They serve as pigments, particularly through anthocyanins, imparting colors to flowers, fruits, and leaves to attract pollinators and seed dispersers, thereby facilitating reproduction and ecological interactions. Additionally, flavonoids provide (UV) protection by absorbing harmful UV radiation, shielding tissues from photodamage, and act as signaling molecules in symbiotic relationships, such as nodulation with nitrogen-fixing . From an evolutionary perspective, flavonoids are derived from the phenylpropanoid pathway, originating from the , which enables their production in response to environmental stresses like , pathogens, and herbivory. This biosynthetic route underscores their role in plant defense and interspecies signaling, enhancing resilience and promoting beneficial microbial associations within ecosystems. In human diets, flavonoids from plant sources contribute to health through their antioxidant properties, with higher intakes linked to improved vascular function and reduced risk of chronic conditions.

Basic Chemical Structure

Flavonoids are characterized by a fundamental 15-carbon skeleton known as flavan, structured as C6–C3–C6, comprising two benzene rings labeled A and B linked by a three-carbon chain that cyclizes to form a central heterocyclic pyran ring designated as C. Ring A is a benzene ring fused to the pyran ring C at positions 5–10, while ring B is attached to ring C at position 2, creating a diphenylpropane-derived framework that underpins all flavonoid variants. This core architecture is visually represented in standard diagrams as a tricyclic system, with ring A positioned on the bottom left, the oxygen-containing ring C in the center featuring a pyrone ring motif, and ring B extending from the top right, often annotated with numbered carbon positions to indicate substitution sites. A defining feature of the flavonoid structure involves multiple hydroxyl groups attached primarily to rings A and B, typically at positions such as 5, 7 on ring A and 3', 4' on ring B, which impart polarity, enhance , and facilitate bonding interactions central to their chemical reactivity. These phenolic hydroxyls are prone to modifications, most notably glycosidation, where or units (e.g., glucose or ) are esterified to the oxygen of a hydroxyl group, forming O-glycosides that predominate in tissues and boost compound stability against oxidation and enzymatic degradation. Less commonly, C-glycosides occur via direct carbon-carbon bonding to the aglycone core, further diversifying profiles. Structural diversity within flavonoids stems from modifications to the central ring C, including the presence or absence of a (carbonyl) group at carbon 4, which influences planarity and conjugation; a between carbons 2 and 3, promoting in the pyrone ring; and stereochemical arrangements at asymmetric carbons (e.g., C2 or C3 in partially saturated forms), which dictate molecular conformation and subclass affiliation without altering the overarching C6–C3–C6 motif. These variations modulate electronic properties and hydrogen-bonding capacity while preserving the essential bicyclic aromatic system connected by the heterocyclic linker.

History

Early Discovery

The early discovery of flavonoids traces back to the late , when plant extracts rich in these compounds were utilized as natural yellow dyes. Quercitron bark, derived from the black oak (), was introduced as a commercial source of yellow pigment in 1775 by American physician , who recognized its dyeing potential for textiles. The active principle, —a flavonol—was first isolated in pure form in 1814 by French chemist from onion skins and other plant sources, though its structure remained undetermined for decades. By the mid-19th century, chemists began systematically extracting and naming these substances from various , often referring to them as "yellow dyes" or flavins due to their coloration. , obtained from quercitron bark through acid hydrolysis, became a prototypical example, yielding a brilliant yellow hue valued in the dye industry. These compounds were initially studied for their practical applications in coloring rather than their chemical identity. In the 1890s, structural elucidation advanced significantly through the work of Polish-Swiss chemist Stanisław Kostanecki and British chemist Arthur George Perkin. Kostanecki, collaborating with J. Tambor, first proposed the term "" in 1895 to describe the core structure of these oxygen-containing heterocyclic compounds, based on degradative analyses of natural isolates like from bee propolis. This marked a pivotal shift from empirical extraction to understanding their polyphenolic backbone. Perkin, building on this, isolated and elucidated the structures of several flavones and flavonols from floral sources, such as from , using and oxidation techniques that confirmed the diphenylpyrone skeleton. Flavonoids were soon recognized as key plant pigments contributing to flower colors, particularly yellows from flavones and , and reds/blues from anthocyanidins, while certain polymeric forms were identified as condensed used in processing. This early appreciation highlighted their roles in pigmentation and astringency, predating deeper biosynthetic insights.

Key Developments and Nomenclature

In the mid-20th century, significant breakthroughs in flavonoid research advanced the understanding of their chemical diversity and . A pivotal contribution was T.A. Geissman's 1962 edited volume, The Chemistry of Flavonoid Compounds, which compiled comprehensive reviews on the synthesis, , and reactions of flavonoids, establishing a foundational framework for their systematic based on structural variations. Concurrently, the full elucidation of structures, key flavonoid pigments responsible for plant coloration, was achieved through detailed chemical analyses, confirming their flavylium cation backbone and glycosylated forms, which had been progressively refined since early proposals in the . Nomenclature for flavonoids evolved to provide clarity amid growing structural complexity, with the International Union of Pure and Applied Chemistry (IUPAC) playing a central role in standardization during the 1970s and beyond. Early efforts distinguished flavonoids, characterized by the 2-phenylchromen-4-one core, from related classes like isoflavonoids (3-phenylchromen-4-one), using the diphenylpropane descriptor C6-C3-C6 to denote the basic 15-carbon skeleton linking two aromatic rings via a three-carbon bridge. These IUPAC guidelines, building on semi-systematic , facilitated precise identification of substituents and , addressing ambiguities in earlier trivial names and enabling consistent reporting across chemical literature. In the 2000s, genomic approaches revolutionized the study of flavonoid biosynthesis, identifying key regulatory genes and enzymes through whole-genome sequencing of model plants like Arabidopsis thaliana. Milestones included the mapping of phenylpropanoid pathway genes, such as chalcone synthase and flavonoid hydroxylases, which revealed evolutionary conservation and tissue-specific expression patterns. By the 2020s, advances in mass spectrometry, particularly high-resolution LC-MS/MS, enabled the identification of over 10,000 distinct flavonoid compounds across plant species, expanding the known chemical repertoire and linking structural diversity to ecological roles. Modern taxonomy has addressed historical gaps by incorporating neoflavonoids (4-phenylcoumarin derivatives) and homoisoflavonoids (3-benzylidenechromanones) into the broader flavonoid superfamily, recognizing their biosynthetic origins from the same phenylpropanoid pathway despite structural deviations from the classic C6-C3-C6 motif. This inclusion, formalized in IUPAC definitions, reflects phylogenetic evidence from genomic studies showing shared ancestry, while maintaining subclass distinctions to account for unique distributions in families like and .

Classification

Flavones and Flavonols

Flavones constitute a subclass of flavonoids characterized by a 2-phenylchromen-4-one backbone, featuring a between carbons 2 and 3 and a group at position 4. This core structure imparts stability and aromatic properties to flavones, which often appear as yellow pigments in various herbs and plants. Representative examples include , a 4',5,7-trihydroxyflavone abundant in , , and , and , a 3',4',5,7-tetrahydroxyflavone found in , , and green peppers. Flavonols, in contrast, are distinguished by the addition of a hydroxyl group at the 3-position of the flavone skeleton, resulting in a 3-hydroxyflavone core that enhances their polarity and reactivity. These compounds are ubiquitous in fruits, vegetables, and leaves, contributing to pigmentation and sometimes bitterness in foods like apples and onions. Key examples are quercetin, a 3,3',4',5,7-pentahydroxyflavone prevalent in onions, berries, and capers, and kaempferol, a 3,4',5,7-tetrahydroxyflavone common in kale, tea, and broccoli. The primary structural difference between flavones and lies in the presence of the 3-hydroxyl group in the latter, which influences patterns across the rings and thereby affects and . Flavones typically exhibit fewer hydroxyl substitutions, rendering them less polar, while ' additional hydroxyls increase water , particularly when combined with —a prevalent modification where sugar moieties attach to hydroxyl groups, further enhancing and stability in tissues. Varying degrees of , such as in the B-ring (e.g., moiety in and ), modulate these properties, with more hydroxyl groups generally promoting greater aqueous .

Flavanones and Flavanonols

Flavanones represent a subclass of flavonoids defined as 2,3-dihydroflavones, distinguished by the saturation of the double bond between carbons 2 and 3 in the central heterocyclic C ring, which imparts a partially reduced structure compared to fully aromatic flavones. This structural modification results in a single chiral center at C-2, enabling the existence of enantiomers that influence their biological interactions. Flavanones commonly occur in both aglycone and glycoside forms, with glycosylation often enhancing their solubility and stability in plant tissues. Prominent examples of flavanones include naringenin and as aglycones, alongside their corresponding glycosides and , which are neohesperidosides prevalent in species. These compounds are particularly abundant in fruits, such as sweet oranges (), grapefruits (Citrus paradisi), and lemons (Citrus limon), where they contribute to the characteristic bitterness and astringency of the fruit. For instance, predominates in sweet oranges and mandarins, while is a major constituent in grapefruits, often comprising the bulk of total flavonoid content in these sources. Flavanonols, closely related to flavanones, are characterized as 3-hydroxyflavanones, featuring an additional hydroxyl group at C-3 alongside the saturated C2-C3 bond in the C ring. This substitution introduces a second chiral center at C-3, yielding diastereomers with distinct stereochemical configurations that affect their reactivity and function in plants. Like flavanones, flavanonols exist as aglycones or glycosides, though aglycone forms are more commonly studied for their roles in metabolic pathways. A key example of a flavanonol is , also termed dihydroquercetin, which is widely distributed in plants including like Taxus species, as well as in onions and certain fruits. acts as an important intermediate in flavonoid , serving as a precursor to flavan-3-ols such as catechins through subsequent enzymatic modifications. Its presence in glycosylated forms further supports its incorporation into plant defense mechanisms and nutritional profiles.

Flavan-3-ols and Anthocyanidins

Flavan-3-ols, also known as flavanols, represent a subclass of flavonoids characterized by a saturated C-ring with a hydroxyl group at the C-3 position, distinguishing them from other flavonoids by the absence of a between C-2 and C-3. These compounds are typically found as monomers such as (+)- and (-)-epicatechin, which feature multiple hydroxyl groups on the A, B, and C rings, contributing to their reactivity and biological interactions. The hydroxyl groups, particularly the ortho-dihydroxy configuration on the B-ring in catechins, enable strong binding to proteins, resulting in the sensory property of astringency observed in foods rich in these compounds. Monomeric flavan-3-ols can undergo polymerization through carbon-carbon linkages, primarily between the C-4 position of one unit and the C-8 or C-6 position of another, forming oligomeric and polymeric structures known as proanthocyanidins or condensed tannins. Proanthocyanidins, such as those composed of epicatechin units (procyanidins), exhibit increased astringency with higher degrees of polymerization due to enhanced protein-binding capacity, while bitterness tends to decrease as chain length grows. In plants, these polymers play protective roles by deterring herbivores through their bitter and astringent taste and by contributing to structural integrity in tissues like seeds and bark. Anthocyanidins, in contrast, form the colored subgroup of flavonoids, existing primarily as flavylium cations—a positively charged in the C-ring that imparts vibrant hues to plant tissues. Key examples include , with five hydroxyl groups at positions 3, 5, 7, 3', and 4', and , which has an additional hydroxyl at 5' for a total of six, influencing their pigmentation intensity and stability. The color of anthocyanidins is highly -dependent: at acidic (below 3), the flavylium cation dominates, producing red-orange shades, while at neutral to slightly alkaline (4-6), transformation to the quinonoidal base yields to colors, enabling dynamic visual signaling in flowers and fruits. To enhance stability against degradation from light, heat, or pH shifts, anthocyanidins are commonly glycosylated at the 3-position or other hydroxyl sites, forming anthocyanins that benefit from intramolecular between moieties and the . not only improves and resistance to oxidation but also modulates color expression, with acylated glycosides showing greater resilience in vacuoles where these pigments accumulate. In ecological contexts, anthocyanidins serve visual functions by attracting pollinators and dispersers through vivid and coloration, while also providing photoprotection against UV radiation.

Isoflavonoids and Other Subclasses

Isoflavonoids represent a significant subclass of flavonoids characterized by a rearranged carbon skeleton, specifically a 3-phenylchromen-4-one backbone, which differs from the typical 2-phenylchromen-4-one structure of most flavonoids. This structural isomerism arises biogenetically from the standard flavonoid framework through a 1,2-aryl migration, resulting in the attachment of the B-ring at the C-3 position of the central pyrone ring. Predominantly found in leguminous plants, isoflavonoids serve as phytoalexins, contributing to defense against pathogens and herbivores. Prominent examples include genistein and daidzein, which are aglycones abundant in soybeans and exhibit phytoestrogenic properties due to their ability to bind estrogen receptors, mimicking endogenous estrogens. These compounds play roles in plant signaling and symbiosis, particularly with nitrogen-fixing bacteria in legumes. Beyond isoflavonoids, other flavonoid subclasses feature distinct structural modifications, often involving reduced, open-chain, or alternatively rearranged skeletons. Flavan-3,4-diols, also known as leucoanthocyanidins, possess a flavan skeleton with hydroxyl groups at both the 3 and 4 positions, lacking the carbonyl at C-4 typical of many flavonoids; they serve as key intermediates in the formation of condensed tannins and proanthocyanidins. Aurones, a less common group, exhibit a five-membered benzofuranone core with a 2-benzylidene substituent, making them structural isomers of flavones and responsible for yellow pigmentation in certain flowers and leaves. Chalcones, considered acyclic precursors in the flavonoid biosynthetic pathway, feature an open-chain α,β-unsaturated ketone linking two aromatic rings, and they can cyclize to form flavanones or other cyclic flavonoids. Dihydrochalcones, related to chalcones but with a saturated three-carbon bridge connecting two aromatic rings, represent another subclass; prominent examples include phloretin and its glycoside phloridzin, which are abundant in apples and contribute to the plant's defense and sensory properties like sweetness. Neoflavonoids, another rearranged variant, are defined by a 4-phenylchromen backbone where the B-ring attaches at the C-4 position, distinguishing them from the standard C-2 attachment; they are rare and primarily occur in families such as Moraceae and Fabaceae, with examples like neoflavone demonstrating antimicrobial potential. These subclasses highlight the diversity of flavonoid rearrangements, enabling specialized biological niches such as pigmentation, precursor roles, and defense mechanisms in . In some cases, microbial associations influence the accumulation or modification of these compounds, enhancing their ecological functions.

Biosynthesis

Pathway in

The of flavonoids in initiates within the phenylpropanoid pathway, starting from the aromatic amino acid . The first committed step is catalyzed by (PAL), which deaminates to form trans-cinnamic acid, releasing in the process. This reaction represents the entry point into phenylpropanoid metabolism, shared with other . Trans-cinnamic acid is then hydroxylated at the 4-position by cinnamate 4-hydroxylase (C4H), a P450-dependent monooxygenase, yielding . Subsequently, 4-coumarate:CoA (4CL) activates through adenylation and thioesterification with , producing 4-coumaroyl-CoA, the key intermediate for flavonoid assembly. These early steps, involving PAL, C4H, and 4CL, are tightly coordinated in the and of cells. The flavonoid-specific branch diverges from 4-coumaroyl-CoA via chalcone synthase (CHS), a that performs three sequential condensations with (derived from via ), followed by a Claisen-type cyclization to generate naringenin . Chalcone isomerase (CHI) then catalyzes the stereospecific cyclization of naringenin to the flavanone naringenin, establishing the central C6-C3-C6 scaffold of flavonoids. This core sequence can be summarized as: Phenylalanine →PAL trans-Cinnamic acid →C4H p-Coumaric acid →4CL 4-Coumaroyl-CoA →CHS Naringenin chalcone →CHI Naringenin (flavanone). Downstream from naringenin, the pathway branches to produce diverse flavonoid subgroups through specific enzymes. Flavones arise directly from flavanones via flavone synthases, which exist in two forms: FNS I (a 2-oxoglutarate-dependent dioxygenase) or FNS II (a cytochrome P450). Flavonols are synthesized by sequential action of flavanone 3-hydroxylase (F3H), which introduces a hydroxyl group at the 3-position to form dihydroflavonols like dihydrokaempferol, followed by flavonol synthase (FLS), another 2-oxoglutarate-dependent dioxygenase that dehydrates and aromatizes the C-ring to yield flavonols such as kaempferol. Additional branch points include isoflavonoid formation via isoflavone synthase (IFS) on naringenin or liquiritigenin, and proanthocyanidin/anthocyanin pathways via dihydroflavonol 4-reductase (DFR), enabling specialization across plant species and tissues.

Regulation and Variations

The regulation of flavonoid biosynthesis in plants is primarily orchestrated by the MBW transcriptional complex, comprising R2R3-MYB, basic helix-loop-helix (bHLH), and -repeat (WDR) proteins, which binds to promoters of structural genes to activate their expression. This complex plays a pivotal role in controlling the early steps of the pathway, particularly the upregulation of chalcone synthase (), the first committed , thereby fine-tuning flavonoid production in response to developmental and stress cues. For instance, MYB factors often act as activators or repressors within the MBW assembly, with subgroup IIIf bHLHs providing specificity for and branches, while proteins stabilize the complex for efficient gene regulation. Environmental triggers significantly modulate flavonoid biosynthesis through signaling cascades that intersect with the MBW complex. (UV) light, particularly UV-B radiation, induces rapid accumulation of flavonoids by activating photoreceptors that enhance transcription of biosynthetic genes, serving as a protective response against oxidative damage. Similarly, attacks stimulate the pathway via (JA) signaling, where JA acts as a mediator to upregulate CHS and downstream enzymes, promoting flavonoid-derived phytoalexins for defense; this is evident in responses to fungal infections like Magnaporthe oryzae. These abiotic and biotic cues highlight the pathway's adaptability, with JA often synergizing with other s to amplify MBW activity under stress. Species-specific variations in flavonoid regulation underscore evolutionary diversification, particularly in enzyme recruitment and tissue-specific accumulation. In legumes, isoflavone synthase (IFS), a cytochrome P450 enzyme unique to this family, catalyzes the conversion of flavanones to isoflavones, branching the pathway toward bioactive compounds essential for nodulation and defense; this specialization is absent in non-legumes, reflecting gene duplication events in Fabaceae. In legumes like red clover, CRISPR/Cas9-mediated deletion of the IFS1 gene has reduced isoflavone levels and altered nodulation, illustrating their role in symbiosis. Anthocyanin accumulation in fruits, conversely, exhibits temporal and genotypic variations, often peaking during ripening due to MBW-mediated activation in vacuolar compartments, as seen in berries where altitude and developmental stage influence profiles through differential gene expression. These variations enable tailored ecological roles, such as UV protection in high-altitude fruits or microbial signaling in legumes. Recent advances in /Cas9-based pathway engineering have illuminated regulatory mechanisms and enabled precise modifications. Studies from the 2020s have targeted MBW components and structural genes, such as editing CHS2 in horticultural crops to redirect flux from flavonoids to stilbenoids, revealing competitive branch-point dynamics. Multiplexed CRISPR activation has enhanced flavonol production in a cell-type-specific manner. These efforts demonstrate CRISPR's utility in dissecting variations and engineering resilient varieties without off-target effects.

Natural Functions

Roles in Plants

Flavonoids play crucial physiological roles in plant pigmentation, primarily through subclasses like , which impart red, purple, and blue hues to flowers, fruits, and vegetative tissues. These pigments attract by providing visual cues that enhance reproductive success, as demonstrated in where anthocyanin accumulation influences pollinator preference in field conditions. Anthocyanins also contribute to by signaling to animals, though their primary internal function lies in modulating light absorption within plant cells. In contrast, such as and accumulate in epidermal layers and act as UV-B screens, absorbing radiation to protect underlying photosynthetic tissues from damage and . This screening function is particularly vital in high-altitude or open environments, where flavonol levels increase in response to UV exposure to maintain cellular integrity. Beyond pigmentation, flavonoids function as key components of the plant's antioxidant defense system, scavenging (ROS) produced during abiotic stresses like , , and excess light. Under such conditions, flavonoids such as and flavones neutralize ROS through their phenolic hydroxyl groups, which donate electrons or hydrogen atoms to stabilize free radicals and prevent oxidative damage to membranes and proteins. This ROS-scavenging activity supplements enzymatic antioxidants like , forming a secondary line of defense when primary systems are overwhelmed. Additionally, flavonoids chelate transition metals such as iron and , inhibiting Fenton-type reactions that generate highly reactive hydroxyl radicals and thereby mitigating metal-induced in plant cells. Flavonoids also regulate plant development, notably by modulating transport, which controls root architecture and tropisms. Flavonols, including glycosides, inhibit polar auxin efflux carriers like PIN proteins, leading to localized accumulation that influences emergence and root gravitropism in species such as . This inhibition fine-tunes developmental responses to environmental cues, ensuring adaptive growth patterns. A specific example is role in reproductive tissues, where it supports viability and tube growth by maintaining and stabilizing cellular structures during . In pollen tubes, quercetin modulates signaling pathways to sustain integrity and directed growth toward the .

Ecological and Protective Functions

Flavonoids serve as key defensive compounds in , particularly through their role as phytoalexins that combat fungal and bacterial . Isoflavonoids, a subclass of flavonoids, accumulate in response to and inhibit the growth of fungi such as species by disrupting pathogen cell membranes and enzymatic activities. For instance, in , novel phytoalexins like triticein (5-hydroxy-2′,4′,7-trimethoxyisoflavone) are induced upon fungal challenge, providing broad-spectrum resistance. Similarly, in , phytoalexins such as medicarpin exhibit properties against root pathogens, enhancing plant survival in microbe-rich soils. Beyond direct antimicrobial action, flavonoids contribute to , where root exudates inhibit the growth of neighboring through chemical interference. , a flavonol commonly exuded from roots of species like ( esculentum), suppresses seedling elongation in competing weeds by interfering with and nutrient uptake. In (Hordeum vulgare), flavonoids such as and in root exudates exhibit phytotoxic effects, reducing radicle growth in sensitive species and thus conferring a in crop fields. These exudate-mediated interactions highlight flavonoids' role in shaping dynamics in natural and agricultural ecosystems. In symbiotic relationships, flavonoids act as signaling molecules that facilitate beneficial interactions with soil microbes, particularly in nitrogen-fixing symbioses. roots exude specific flavonoids like , a , which binds to the NodD receptor protein in rhizobial bacteria, triggering the expression of nodulation (nod) genes essential for nodule formation. This induction enables species to produce Nod factors, lipo-chitooligosaccharides that promote root cortical and infection thread development in hosts like (). Such flavonoid-rhizobia crosstalk ensures efficient , enhancing productivity in nitrogen-poor soils. Flavonoids also provide protection against herbivory by imparting bitterness and astringency, sensory properties that deter feeding by insects and mammals. Condensed tannins, polymeric flavonoids abundant in leaves and bark, bind to proteins in the 's mouth, causing a dry, puckering sensation that discourages consumption; for example, in forage crops like birdsfoot trefoil (), high tannin levels reduce palatability to grazing animals. Certain monomeric flavonoids, such as quercetin glycosides, contribute to bitter taste via activation of taste receptors, signaling toxicity and thereby reducing damage in species like (). These deterrent effects are amplified under herbivore attack, where flavonoid is upregulated. Conversely, flavonoids play a protective role in reproduction by serving as visual cues for pollinators through flower pigmentation. Anthocyanins and absorb UV and visible light, producing colors from red to blue that attract and birds; in bee-pollinated flowers like those of snapdragon (), pelargonidin-derived anthocyanins enhance visibility against green foliage, increasing visitation rates. These pigments not only guide pollinators but also protect reproductive tissues from UV damage during , ensuring successful in exposed environments. Under abiotic stresses like and UV radiation, upregulate flavonol production as an adaptive response to mitigate oxidative damage. In grapevines (), moderate induces the transcription factor VviMYB24, boosting flavonol synthase activity and accumulating and glycosides that scavenge (ROS) in leaves. Recent studies on () show UV-B pre-exposure elevates flavonol levels via CsHY5-mediated pathways, improving membrane stability and during subsequent water deficits. In desert shrubs like Artemisia species, combined and UV stress correlate with 2-3-fold increases in flavonol content, enhancing tolerance through reinforcement and osmotic adjustment. These adaptations underscore flavonoids' contributions to in vascular .

Occurrence and Dietary Sources

Plant Sources and Distribution

Flavonoids are ubiquitous secondary metabolites found in a wide array of species, with over 6,000 distinct structures identified across vascular , contributing to pigmentation, flavor, and defense mechanisms. Common sources include fruits such as berries (e.g., blueberries, strawberries) and (e.g., oranges, lemons), vegetables like onions and , beverages derived from leaves and grapes (wine), and herbs such as . These compounds are particularly abundant in edible parts, including grains, bark, , stems, flowers, and , reflecting their role in . Within plants, flavonoids exhibit tissue-specific accumulation patterns, often concentrating in protective outer layers. High levels are typically observed in fruit skins and seeds, where they serve as barriers against environmental stressors; for instance, proanthocyanidins accumulate in skins and seeds. Anthocyanins, responsible for , , and hues, are predominantly found in the skins and flesh of colored produce like berries, , and . In contrast, flavonols such as and are more prevalent in leaves and outer tissues of vegetables, including leaves and skins, as well as in apples and leaves. This distribution varies by plant organ, with shoots and external structures like glandular hairs showing higher concentrations compared to roots in many species. Global variations highlight subclass-specific sources, with isoflavonoids like and concentrated in , particularly soybeans, which are a in Asian flora. Flavan-3-ols, including catechins and epicatechins, are notably abundant in cocoa beans from trees native to tropical regions. Flavonoids have been documented in over 9,000 plant species worldwide, underscoring their evolutionary conservation across angiosperms, gymnosperms, and even some ferns. Emerging research in the 2020s has revealed flavonoids in marine algae, such as brown seaweeds (e.g., species) and green seaweeds (e.g., ), expanding their known distribution beyond terrestrial plants to aquatic environments.

Human Dietary Intake Patterns

Human dietary intake of flavonoids typically ranges from 200 to 500 mg per day in Western populations, with studies reporting means such as 176 mg/day in a large and 225 mg/day in U.S. adults. In Asian diets, intake is often higher, averaging around 318 mg/day in Korean adults, largely due to soy-based sources. Mediterranean diets show similar levels, approximately 370 mg/day, supported by consumption of fruits, , and moderate wine intake. Major contributors to flavonoid intake include , which provides the bulk of flavan-3-ols at about 157 mg/day on average, followed by fruit juices (8 mg/day, primarily flavanones like ), wine (4 mg/day), and fruits (3 mg/day). such as are predominantly sourced from onions and apples, while berries and soy products contribute anthocyanidins and , respectively. These sources account for over 50% of total intake in most diets, with fruits and comprising 54% and adding another 33%. Intake patterns have shown a decline in diets high in ultra-processed foods, where total flavonoid consumption decreases by 50-70% compared to minimally processed diets. Concurrently, the use of flavonoid-containing supplements has risen in the , driven by concerns over declining nutrient density in modern food supplies. Global surveys reveal variations by region, with the European Prospective Investigation into Cancer and Nutrition (EPIC) study showing differences between Mediterranean and non-Mediterranean European countries and no significant gender differences. U.S. surveys indicate higher intakes among non-Hispanic Asian adults compared to other groups. Recent cohort analyses as of 2025 suggest median intakes up to 792 mg/day in diverse, flavonoid-rich diets. Intake tends to be lower in the elderly, potentially due to reduced and consumption.

Metabolism and Bioavailability

Absorption and Metabolism in Humans

Flavonoids in the diet are predominantly present as glycosides, which exhibit limited direct absorption in their conjugated form. Upon , these compounds reach the , where absorption primarily occurs via passive of the aglycone moiety after deglycosylation. The lactase-phlorizin hydrolase (LPH), located in the of enterocytes, can hydrolyze β-glycosides such as quercetin-4'-glucoside, facilitating uptake into epithelial cells. However, the majority of flavonoid glycosides, especially those with more complex sugar attachments, resist small intestinal hydrolysis and proceed to the colon, where play a crucial role in deconjugation through microbial β-glucosidases, releasing free aglycones for potential absorption across the colonic . Once absorbed, flavonoids undergo extensive phase I and phase II , primarily in the enterocytes and liver, transforming them into more polar conjugates for efficient transport and elimination. Phase I involves (CYP450) enzymes, such as and , which perform oxidation reactions on certain flavonoids like , generating hydroxylated derivatives. Phase II conjugation follows, mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and catechol-O-methyltransferases (COMT), producing glucuronides, sulfates, and methylated metabolites, respectively. A major circulating metabolite of , for instance, is quercetin-3-glucuronide, which predominates in plasma after dietary intake. This process can be represented as: Aglycone+UDPGA→UGT[Glucuronide](/page/Glucuronide) conjugate+UDP\text{Aglycone} + \text{UDPGA} \xrightarrow{\text{UGT}} \text{[Glucuronide](/page/Glucuronide) conjugate} + \text{UDP}
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