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Polyphenol
Polyphenol
Polyphenol
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Representative chemical structure of one of many plant-derived polyphenols that comprise tannic acid. Such compounds are formed by esterification of phenylpropanoid-derived gallic acid to a monosaccharide (glucose) core.

Polyphenols (/ˌpɒliˈfiːnoʊl, -nɒl/) are a large family of naturally occurring phenols.[1] They are abundant in plants and structurally diverse.[1][2][3] Polyphenols include phenolic acids, flavonoids, tannic acid, and ellagitannin, some of which have been used historically as dyes and for tanning garments.

Curcumin, a bright yellow component of turmeric (Curcuma longa), is a well-studied polyphenol.

Etymology

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The name derives from the Ancient Greek word πολύς (polus, meaning "many, much") and the word 'phenol' which refers to a chemical structure formed by attachment of an aromatic benzenoid (phenyl) ring to a hydroxyl (-OH) group (hence the -ol suffix). The term "polyphenol" has been in use at least since 1894.[4]

Definition

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Ellagic acid, a polyphenol

Polyphenols are natural products with "several hydroxyl groups on aromatic rings", including four principal classes: phenolic acids, flavonoids, stilbenes, and lignans.[2][5] Flavonoids can be grouped as flavones, flavonols, flavanols, flavanones, isoflavones, proanthocyanidins, and anthocyanins.[2] Particularly abundant flavanoids in foods are catechin (tea, fruits), hesperetin (citrus fruits), cyanidin (red fruits and berries), daidzein (soybean), proanthocyanidins (apple, grape, cocoa), and quercetin (onion, tea, apples).[2] Polyphenols also include phenolic acids, such as caffeic acid, and lignans, which are derived from phenylalanine present in flax seed and other cereals.[2]

WBSSH definition

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The White–Bate-Smith–Swain–Haslam (WBSSH) definition[6] characterized structural characteristics common to plant phenolics used in tanning (i.e., the tannins).[7]

In terms of properties, the WBSSH describes the polyphenols as follows:

  • generally moderately water-soluble compounds
  • with molecular weight of 500–4000 Da
  • with >12 phenolic hydroxyl groups
  • with 5–7 aromatic rings per 1000 Da

In terms of structures, the WBSSH recognizes two structural family that have these properties:

  • proanthocyanidins and its derivatives
  • galloyl and hexahydroxydiphenoyl esters and their derivatives

Quideau definition

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Raspberry ellagitannin, a tannin composed of 14 gallic acid units around a core of three units of glucose, with two gallic acids as simple esters, and the remaining 12 appearing in 6 ellagic acid-type units. Ester, ether, and biaryl linkages are present, see below.

According to Stéphane Quideau, the term "polyphenol" refers to compounds derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functions.[8]

Ellagic acid, a molecule at the core of naturally occurring phenolic compounds of varying sizes, is itself not a polyphenol by the WBSSH definition, but is by the Quideau definition. The raspberry ellagitannin,[9] on the other hand, with its 14 gallic acid moieties (most in ellagic acid-type components), and more than 40 phenolic hydroxyl groups, meets the criteria of both definitions of a polyphenol. Other examples of compounds that fall under both the WBSSH and Quideau definitions include the black tea theaflavin-3-gallate shown below, and the hydrolyzable tannin, tannic acid.[citation needed]

Chemistry

[edit]
Theaflavin-3-gallate, a plant-derived polyphenol, an ester of gallic acid and a theaflavin core. There are nine phenolic hydroxyl groups and two phenolic ether linkages.

Polyphenols are reactive species toward oxidation, hence their description as antioxidants in vitro.[10]

Structure

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Polyphenols, such as lignin, are larger molecules (macromolecules). Their upper molecular weight limit is about 800 daltons, which allows for the possibility to rapidly diffuse across cell membranes so that they can reach intracellular sites of action or remain as pigments once the cell senesces. Hence, many larger polyphenols are biosynthesized in situ from smaller polyphenols to non-hydrolyzable tannins and remain undiscovered in the plant matrix. Most polyphenols contain repeating phenolic moieties of pyrocatechol, resorcinol, pyrogallol, and phloroglucinol connected by esters (hydrolyzable tannins) or more stable C-C bonds (nonhydrolyzable condensed tannins). Proanthocyanidins are mostly polymeric units of catechin and epicatechin.

The C-glucoside substructure of polyphenols is exemplified by the phenol-saccharide conjugate puerarin, a midmolecular-weight plant natural product. The attachment of the phenol to the saccharide is by a carbon-carbon bond. The isoflavone and its 10-atom benzopyran "fused ring" system, also a structural feature here, is common in polyphenols.

Polyphenols often have functional groups beyond hydroxyl groups. Ether ester linkages are common, as are carboxylic acids.

An example of a synthetically achieved small ellagitannin, tellimagrandin II, derived biosynthetically and sometimes synthetically by oxidative joining of two of the galloyl moieties of 1,2,3,4,6-pentagalloyl-glucose

Analytical chemistry

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The analysis techniques are those of phytochemistry: extraction, isolation, structural elucidation,[11] then quantification.[citation needed]

Reactivity

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Polyphenols readily react with metal ions to form coordination complexes, some of which form metal-phenolic networks.[12]

Extraction

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Extraction of polyphenols[13] can be performed using a solvent like water, hot water, methanol, methanol/formic acid, methanol/water/acetic or formic acid. Liquid–liquid extraction can be also performed or countercurrent chromatography. Solid phase extraction can also be made on C18 sorbent cartridges. Other techniques are ultrasonic extraction, heat reflux extraction, microwave-assisted extraction,[14] critical carbon dioxide,[15][16] high-pressure liquid extraction[17] or use of ethanol in an immersion extractor.[18] The extraction conditions (temperature, extraction time, ratio of solvent to raw material, particle size of the sample, solvent type, and solvent concentrations) for different raw materials and extraction methods have to be optimized.[19][20]

Mainly found in the fruit skins and seeds, high levels of polyphenols may reflect only the measured extractable polyphenol (EPP) content of a fruit which may also contain non-extractable polyphenols. Black tea contains high amounts of polyphenol and makes up for 20% of its weight.[21]

Concentration can be made by ultrafiltration.[22] Purification can be achieved by preparative chromatography.

Analysis techniques

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Reversed-phase HPLC plot of separation of phenolic compounds. Smaller natural phenols formed individual peaks while tannins form a hump.

Phosphomolybdic acid is used as a reagent for staining phenolics in thin layer chromatography. Polyphenols can be studied by spectroscopy, especially in the ultraviolet domain, by fractionation or paper chromatography. They can also be analysed by chemical characterisation.

Instrumental chemistry analyses include separation by high performance liquid chromatography (HPLC), and especially by reversed-phase liquid chromatography (RPLC), can be coupled to mass spectrometry.[15]

Microscopy analysis
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The DMACA reagent is an histological dye specific to polyphenols used in microscopy analyses. The autofluorescence of polyphenols can also be used, especially for localisation of lignin and suberin. Where fluorescence of the molecules themselves is insufficient for visualization by light microscopy, DPBA (diphenylboric acid 2-aminoethyl ester, also referred to as Naturstoff reagent A) has traditionally been used, at least in plant science, to enhance the fluorescence signal.[23]

Quantification

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Polyphenolic content in vitro can be quantified by volumetric titration. An oxidizing agent, permanganate, is used to oxidize known concentrations of a standard tannin solution, producing a standard curve. The tannin content of the unknown is then expressed as equivalents of the appropriate hydrolyzable or condensed tannin.[24]

Some methods for quantification of total polyphenol content in vitro are based on colorimetric measurements. Some tests are relatively specific to polyphenols (for instance the Porter's assay). Total phenols (or antioxidant effect) can be measured using the Folin–Ciocalteu reaction.[15] Results are typically expressed as gallic acid equivalents. Polyphenols are seldom evaluated by antibody technologies.[25]

Other tests measure the antioxidant capacity of a fraction. Some make use of the ABTS radical cation which is reactive towards most antioxidants including phenolics, thiols and vitamin C.[26] During this reaction, the blue ABTS radical cation is converted back to its colorless neutral form. The reaction may be monitored spectrophotometrically. This assay is often referred to as the Trolox equivalent antioxidant capacity (TEAC) assay. The reactivity of the various antioxidants tested are compared to that of Trolox, which is a vitamin E analog.

Other antioxidant capacity assays which use Trolox as a standard include the diphenylpicrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC),[27] ferric reducing ability of plasma (FRAP)[28] assays or inhibition of copper-catalyzed in vitro human low-density lipoprotein oxidation.[29]

New methods including the use of biosensors can help monitor the content of polyphenols in food.[30]

Quantitation results produced by the mean of diode array detector–coupled HPLC are generally given as relative rather than absolute values as there is a lack of commercially available standards for all polyphenolic molecules.[citation needed]

Applications

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Some polyphenols are traditionally used as dyes in leather tanning. For instance, in the Indian subcontinent, pomegranate peel, high in tannins and other polyphenols, or its juice, is employed in the dyeing of non-synthetic fabrics.[31]

Of some interest in the era of silver-based photography, pyrogallol and pyrocatechin are among the oldest photographic developers.[32][33]

Aspirational use as green chemicals

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Natural polyphenols have long been proposed as renewable precursors to produce plastics or resins by polymerization with formaldehyde,[34] as well as adhesives for particleboards.[35] The aims are generally to make use of plant residues from grape, olive (called pomaces), or pecan shells left after processing.[15][better source needed]

Occurrence

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The most abundant polyphenols are the condensed tannins, found in virtually all families of plants. Larger polyphenols are often concentrated in leaf tissue, the epidermis, bark layers, flowers and fruits but also play important roles in the decomposition of forest litter, and nutrient cycles in forest ecology. Absolute concentrations of total phenols in plant tissues differ widely depending on the literature source, type of polyphenols and assay; they are in the range of 1–25% total natural phenols and polyphenols, calculated with reference to the dry green leaf mass.[36]

Polyphenols are also found in animals. In arthropods, such as insects,[37] and crustaceans[38] polyphenols play a role in epicuticle hardening (sclerotization). The hardening of the cuticle is due to the presence of a polyphenol oxidase.[39] In crustaceans, there is a second oxidase activity leading to cuticle pigmentation.[40] There is apparently no polyphenol tanning occurring in arachnids cuticle.[41]

Biochemistry

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Polyphenols are thought to play diverse roles in the ecology of plants. These functions include:[42]

  • Release and suppression of growth hormones such as auxin.
  • UV screens to protect against ionizing radiation and to provide coloration (plant pigments).[5]
  • Deterrence of herbivores (sensory properties).
  • Prevention of microbial infections (phytoalexins).[5][43]
  • Signaling molecules in ripening and other growth processes.
  • In some woods can explain their natural preservation against rot.[44]

Flax and Myriophyllum spicatum (a submerged aquatic plant) secrete polyphenols that are involved in allelopathic interactions.[45][46]

Biosynthesis and metabolism

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Polyphenols incorporate smaller parts and building blocks from simpler natural phenols, which originate from the phenylpropanoid pathway for the phenolic acids or the shikimic acid pathway for gallotannins and analogs. Flavonoids and caffeic acid derivatives are biosynthesized from phenylalanine and malonyl-CoA. Complex gallotannins develop through the in vitro oxidation of 1,2,3,4,6-pentagalloylglucose or dimerization processes resulting in hydrolyzable tannins. For anthocyanidins, precursors of the condensed tannin biosynthesis, dihydroflavonol reductase and leucoanthocyanidin reductase (LAR) are crucial enzymes with subsequent addition of catechin and epicatechin moieties for larger, non-hydrolyzable tannins.[47]

The glycosylated form develops from glucosyltransferase activity and increases the solubility of polyphenols.[48]

Polyphenol oxidase (PPO) is an enzyme that catalyses the oxidation of o-diphenols to produce o-quinones. It is the rapid polymerisation of o-quinones to produce black, brown or red polyphenolic pigments that causes fruit browning. In insects, PPO is involved in cuticle hardening.[49]

Occurrence in food

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See also: List of phytochemicals in food
Main articles: Natural phenols and polyphenols in wine and Natural phenols and polyphenols in tea

Polyphenols comprise up to 0.2–0.3% fresh weight for many fruits. Consuming common servings of wine, chocolate, legumes or tea may also contribute to about one gram of intake per day.[2][50] According to a 2005 review on polyphenols:

The most important food sources are commodities widely consumed in large quantities such as fruit and vegetables, green tea, black tea, red wine, coffee, chocolate, olives, and extra virgin olive oil. Herbs and spices, nuts and algae are also potentially significant for supplying certain polyphenols. Some polyphenols are specific to particular food (flavanones in citrus fruit, isoflavones in soya, phloridzin in apples); whereas others, such as quercetin, are found in all plant products such as fruit, vegetables, cereals, leguminous plants, tea, and wine.[51]

Some polyphenols are considered antinutrients – compounds that interfere with the absorption of essential nutrients – especially iron and other metal ions, which may bind to digestive enzymes and other proteins, particularly in ruminants.[52]

In a comparison of cooking methods, phenolic and carotenoid levels in vegetables were retained better by steaming compared to frying.[53] Polyphenols in wine, beer and various nonalcoholic juice beverages can be removed using finings, substances that are usually added at or near the completion of the processing of brewing.[citation needed]

Astringency

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With respect to food and beverages, the cause of astringency is not fully understood, but it is measured chemically as the ability of a substance to precipitate proteins.[54]

Astringency increases and bitterness decrease with the mean degree of polymerization. For water-soluble polyphenols, molecular weights between 500 and 3000 were reported to be required for protein precipitation. However, smaller molecules might still have astringent qualities likely due to the formation of unprecipitated complexes with proteins or cross-linking of proteins with simple phenols that have 1,2-dihydroxy or 1,2,3-trihydroxy groups.[55] Flavonoid configurations can also cause significant differences in sensory properties, e.g., epicatechin, is more bitter and astringent than its chiral isomer catechin. In contrast, hydroxycinnamic acids do not have astringent qualities, but are bitter.[56]

Research

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Polyphenols are a large, diverse group of compounds, which makes it challenging to determine their biological effects.[57] They are not considered nutrients, as they do not contribute to growth, survival, or reproduction, nor do they provide dietary energy. Therefore, they do not have recommended recommended daily intake levels, such as those for vitamins, minerals, and fiber.[58][59][60] In the United States, the Food and Drug Administration issued guidance to manufacturers that polyphenols cannot be mentioned on food labels as antioxidant nutrients unless physiological evidence exists to verify such a qualification and a Dietary Reference Intake value has been established – characteristics which have not been determined for polyphenols.[61][62]

In the European Union, two health claims were authorized between 2012 and 2015: 1) flavanols in cocoa solids at doses exceeding 200 mg per day may contribute to maintenance of vascular elasticity and normal blood flow;[63][64] and 2) olive oil polyphenols (5 mg of hydroxytyrosol and its derivatives such as oleuropein complex and tyrosol) may "contribute to the protection of blood lipids from oxidative damage", if consumed daily.[65][66]

As of 2022, clinical trials that assessed the effect of polyphenols on health biomarkers are limited, with results difficult to interpret due to the wide variation of intake values for both individual polyphenols and total polyphenols.[67]

Polyphenols were once considered as antioxidants, but this concept is obsolete.[68] Most polyphenols are metabolized by catechol-O-methyltransferase, and therefore do not have the chemical structure allowing antioxidant activity in vivo; they may exert biological activity as signaling molecules.[2][62][68] Some polyphenols are considered to be bioactive compounds[69] for which development of dietary recommendations was under consideration in 2017.[70]

Cardiovascular diseases

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In the 1930s, polyphenols (then called vitamin P) were considered as a factor in capillary permeability, followed by various studies through the 21st century of a possible effect on cardiovascular diseases. For most polyphenols, there is no evidence for an effect on cardiovascular regulation, although there are some reviews showing a minor effect of consuming polyphenols, such as chlorogenic acid or flavan-3-ols, on blood pressure.[71][72][73]

Cancer

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Higher intakes of soy isoflavones may be associated with reduced risks of breast cancer in postmenopausal women and prostate cancer in men.[2]

A 2019 systematic review found that intake of soy and soy isoflavones is associated with a lower risk of mortality from gastric, colorectal, breast and lung cancers.[74] The study found that an increase in isoflavone consumption by 10 mg per day was associated with a 7% decrease in risk from all cancers, and an increase in consumption of soy protein by 5 grams per day produced a 12% reduction in breast cancer risk.[74]

Cognitive function

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Polyphenols are under preliminary research for possible cognitive effects in healthy adults.[75][76]

Phytoestrogens

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Isoflavones, which are structurally related to 17β-estradiol, are classified as phytoestrogens.[77] A risk assessment by the European Food Safety Authority found no cause for concern when isoflavones are consumed in a normal diet.[78]

Phlebotonic

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Main article: Diosmin § Phlebotonics

Phlebotonics of heterogeneous composition, consisting partly of citrus peel extracts (flavonoids, such as hesperidin) and synthetic compounds, are used to treat chronic venous insufficiency and hemorrhoids.[79] Some are non-prescription dietary supplements, such as diosmin,[79] while one other – Vasculera (Diosmiplex) – is a prescription medical food intended for treating venous disorders.[80] Their mechanism of action is undefined,[79] and clinical evidence of benefit for using phlebotonics to treat venous diseases is limited.[79]

Gut microbiome

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Polyphenols are extensively metabolized by the gut microbiota and are investigated as a potential metabolic factor in function of the gut microbiota.[81][82]

Toxicity and adverse effects

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Adverse effects of polyphenol intake range from mild (e.g., gastrointestinal tract symptoms)[2] to severe (e.g., hemolytic anemia or hepatotoxicity).[83] In 1988, hemolytic anemia following polyphenol consumption was documented, resulting in the withdrawal of a catechin-containing drug.[84] Polyphenols, particularly in beverages that contain them in high concentrations (tea, coffee, etc), inhibit the absorption of non-haem iron when consumed together in a single meal.[2][85][86][87] Research is limited on the effect of this inhibition on iron status.[88]

Metabolism of polyphenols can result in flavonoid-drug interactions, such as in grapefruit–drug interactions, which involves inhibition of the liver enzyme, CYP3A4, likely by grapefruit furanocoumarins, a class of polyphenol.[2][83] The European Food Safety Authority established upper limits for some polyphenol-containing supplements and additives, such as green tea extract or curcumin.[89][90] For most polyphenols found in the diet, an adverse effect beyond nutrient-drug interactions is unlikely.[2]

See also

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Polyphenol

View on Grokipedia
from Grokipedia
Polyphenols are a structurally diverse class of naturally occurring secondary metabolites synthesized exclusively by , characterized by the presence of multiple phenol units—specifically, aromatic rings with at least two hydroxyl groups attached. These compounds play essential roles in , including defense against , pathogens, and . Over 8,000 distinct polyphenols have been identified, making them one of the most abundant groups of bioactive substances in the diet. Polyphenols are broadly classified based on their chemical structure, primarily into two main categories: flavonoids (the largest subgroup, including flavonols, flavones, flavanols, flavanones, , and anthocyanins) and non-flavonoids (encompassing phenolic acids, stilbenes, lignans, and ). This classification reflects variations in the number of phenol rings and the linking structural elements, such as heterocyclic rings in flavonoids or simpler chains in phenolic acids. Their occurs via the phenylpropanoid pathway in plants, leading to a wide array of derivatives with differing solubility and stability. In , polyphenols are primarily obtained from plant-based foods and beverages, with rich sources including fruits (e.g., berries, apples, grapes), (e.g., onions, ), whole grains, nuts, , , , and cocoa. Dietary intake varies widely but averages 800–1,000 mg per day in typical Western diets, though higher in Mediterranean-style eating patterns. is generally low (often <5%) due to poor absorption in the gut, rapid metabolism, and microbial transformation by gut microbiota, which can produce bioactive metabolites. The health benefits of polyphenols stem largely from their potent antioxidant and anti-inflammatory properties, which help neutralize free radicals, modulate cellular signaling pathways, and reduce oxidative stress. Epidemiological and clinical studies link regular polyphenol consumption to reduced risk of chronic diseases, including cardiovascular disorders (via improved endothelial function and lowered blood pressure), type 2 diabetes (through enhanced insulin sensitivity), certain cancers (by inhibiting tumor growth), and neurodegenerative conditions (such as Alzheimer's, via neuroprotection). However, excessive intake from supplements may pose risks, such as interference with iron absorption or potential pro-oxidant effects at high doses.

Terminology

Etymology

The term "polyphenol" originates from the Ancient Greek word polús (πολύς), meaning "many" or "much," combined with "phenol," referring to a chemical structure featuring a hydroxyl group attached to an aromatic hydrocarbon ring. This nomenclature reflects the compounds' characteristic multiple phenolic units, distinguishing them from simple phenols. The term first appeared in scientific literature in 1894, in the context of chemical studies on phenolic compounds. It emerged more prominently in early 20th-century plant chemistry, where researchers like Maximilian Nierenstein investigated complex phenolic substances such as tannins and catechins in plants, laying foundational work on their structures and properties without yet using the specific term "polyphenol" in its modern botanical sense. The modern application of the term "polyphenol" to describe a broad class of plant-derived polyphenolic materials previously known collectively as "vegetable tannins," emphasizing their role in leather tanning and plant defense, was proposed in 1957 by industrial chemist Theodore White. This marked a shift from narrower terms like "tannins" (referring to astringent proteins-precipitating phenolics) and "catechins" (specific flavonoid monomers) toward a more inclusive category encompassing polymers with multiple phenolic rings. White's definition focused on experimental observations of their physico-chemical behavior, such as solubility and reactivity. In 1962, E. C. Bate-Smith and Tony Swain refined the term in their seminal chapter on flavonoid compounds, defining polyphenols as "water-soluble phenolic compounds having molecular weights from 500 to 3000, possessing the typical phenolic nucleus and other ring systems." This White–Bate-Smith–Swain–Haslam (WBSSH) framework, later expanded by Edwin Haslam in 1966 to include a molecular weight range up to 4000 Da and 12–16 phenolic hydroxy groups per 1000 Da, solidified the term's usage in scientific literature, particularly for flavonoid polymers with tanning properties. The 1960s–1970s saw further evolution with advances in chromatographic techniques, enabling separation and identification of diverse polyphenols beyond tannins, broadening the term to include non-tannin phenolics in fruits and beverages. Concurrently, the French term "polyphénols" gained traction in wine chemistry, influenced by studies on grape and oak-derived compounds contributing to color and astringency.

Definition

Polyphenols are secondary metabolites produced primarily by plants, defined as organic compounds featuring multiple phenol units—aromatic rings bearing one or more hydroxyl groups—and involved in defense mechanisms against environmental stresses such as ultraviolet radiation and pathogens. This core definition excludes primary metabolites like lignins, which serve structural roles in plant cell walls rather than secondary biosynthetic functions. Definitional ambiguities arise from varying interpretations of structural criteria and scope, including the inclusion of tannins (polyphenolic polymers with astringent properties) and lignans (dimers of phenylpropane units), while excluding synthetic analogs that mimic natural structures but lack biological origin. These debates impact standardization in research, with some classifications emphasizing biosynthetic pathways over mere structural multiplicity. The Quideau definition (2011) addresses these issues by focusing on phenolic oxidation products derived from shikimate-derived precursors, prioritizing reactivity and natural assembly: the term "polyphenol" applies exclusively to plant-origin compounds with at least two distinct phenolic rings linked by C–C, O–C, or glycosidic bonds (excluding ester linkages), encompassing up to six rings and including oligomeric/polymeric forms such as proanthocyanidins, ellagitannins, and gallotannins. In contrast, the historical WBSSH framework (White 1957, Bate-Smith and Swain 1962, Haslam 1966) characterizes polyphenols as water-soluble, non-glycemic compounds with molecular weights of 500–4000 Da, multiple phenolic rings, and the ability to precipitate proteins, distinguishing them from broader, less precise uses in nutritional contexts and excluding carbohydrate-linked phenolics. Reviews from the 2020s, including those synthesizing these perspectives, advocate for unified criteria to facilitate reproducible research, resolving ambiguities around boundary cases like high-molecular-weight tannins while maintaining emphasis on plant-derived, hydroxyl-rich aromatics.

Chemistry

Molecular Structure

Polyphenols are a class of organic compounds characterized by the presence of multiple structural units, consisting of one or more aromatic rings (typically benzene or heterocyclic rings) with attached hydroxyl (-OH) groups, often in ortho or para positions relative to each other. These structures can form through polymerization via carbon-carbon (C-C) or ether (C-O) linkages, enabling a range of monomeric to polymeric forms. Key structural motifs in polyphenols include the phenolic hydroxyl groups, which facilitate hydrogen bonding and contribute to their reactivity and solubility, as well as extended conjugated π-electron systems within the aromatic rings that impart characteristic UV-visible absorption spectra around 280 nm. A representative building block is catechol (1,2-dihydroxybenzene), featuring two adjacent hydroxyl groups on a benzene ring, which serves as a core motif in many polyphenol subclasses such as flavonoids and tannins. The structural diversity of polyphenols spans from simple monomers, such as phenolic acids (e.g., caffeic acid with molecular weight around 180 Da), to complex oligomers and polymers like proanthocyanidins, which can consist of up to 50 flavan-3-ol units linked by C-C bonds, resulting in molecular weights exceeding 10,000 Da. This diversity arises from variations in ring substitution, linkage types, and degrees of polymerization, with some structures incorporating chiral centers—such as in the C-ring of flavonoids—leading to stereoisomers that influence biological activity. Physically, polyphenols exhibit polarity due to their multiple hydroxyl groups, enhancing solubility in polar solvents like water and ethanol while reducing solubility in non-polar solvents; this property is crucial for their extraction and bioavailability. Their molecular weight typically ranges from 100 Da for basic monomers to 10,000 Da or more for high-molecular-weight polymers, affecting their diffusion and interaction with biological macromolecules.

Classification

Polyphenols are classified primarily based on their chemical structures, particularly the arrangement of phenolic rings and the carbon skeleton connecting them, as well as substitution patterns such as hydroxylation and glycosylation. This structural taxonomy originates from biosynthetic pathways but emphasizes molecular architecture for categorization, with updates reflected in databases like Phenol-Explorer, which organizes compounds into hierarchical classes and subclasses as of the 2020s. Over 8,000 polyphenol structures have been identified to date, predominantly from plant sources, though microbial and synthetic analogs exist in limited contexts. The largest class is flavonoids, accounting for approximately 60% of all known polyphenols, characterized by a core C6-C3-C6 carbon skeleton consisting of two phenyl rings (A and B) linked by a heterocyclic pyran ring (C). Subgroups include flavonols (e.g., quercetin, found in onions and apples), flavones (e.g., apigenin, in parsley and chamomile), and others like anthocyanins and isoflavonoids, differentiated by oxidation levels and substitutions on the rings. Phenolic acids form another major group, divided into hydroxybenzoic acids (e.g., gallic acid) and hydroxycinnamic acids (e.g., caffeic and ferulic acids), featuring a single phenolic ring with carboxylic acid side chains. Stilbenes, with a simpler C6-C2-C6 skeleton, include resveratrol (prominent in grapes and red wine), while lignans possess a C6-C3-C3-C6 framework derived from two phenylpropane units, such as secoisolariciresinol in flaxseeds. Tannins represent complex polyphenols, subclassified into condensed tannins (proanthocyanidins, polymers of flavonoids) and hydrolyzable tannins (gallotannins and ellagitannins, esters of phenolic acids with sugars). Additional groups encompass coumarins (benzopyrones like umbelliferone) and xanthones (tricyclic structures such as mangostin), often grouped under "other polyphenols" in databases. While the focus remains on plant-derived polyphenols due to their prevalence in nature and dietary relevance, non-plant sources include microbial metabolites like those produced by gut bacteria from dietary precursors, and synthetic polyphenols engineered for industrial applications, though these are not central to natural classification schemes.

Reactivity

Polyphenols exhibit reactivity primarily through their phenolic hydroxyl (-OH) groups, which enable them to act as antioxidants by scavenging free radicals via hydrogen atom transfer (HAT). In this mechanism, a phenolic compound (ArOH) donates a hydrogen atom to a reactive oxygen species (ROS) such as an alkoxyl radical (RO•), forming a relatively stable phenoxyl radical (ArO•) and the corresponding alcohol (ROH), as represented by the equation: \ceArOH+RO∙−>ArO∙+ROH\ce{ArOH + RO^\bullet -> ArO^\bullet + ROH} This process is facilitated by the stabilization of the resulting ArO•, particularly in polyphenols with multiple phenolic rings. Additionally, polyphenols contribute to antioxidant activity through metal , where their ortho-dihydroxy () or adjacent hydroxyl groups bind transition metals like iron (Fe²⁺/Fe³⁺) or , preventing Fenton reactions that generate highly reactive hydroxyl radicals (•OH). This alters the of the metals, inhibiting their catalytic role in oxidative damage. Oxidation of polyphenols can lead to , often initiated by auto-oxidation under alkaline conditions, where molecular oxygen oxidizes the phenolic rings to form reactive o-quinones. These quinones are electrophilic intermediates that can further react with nucleophiles, such as thiols or amines, resulting in cross-linking and formation. Enzymatic oxidation, mediated by (PPO), accelerates this process in the presence of oxygen, converting monophenols or o-diphenols to quinones and causing enzymatic in tissues. PPO, a copper-containing , catalyzes the of and their subsequent oxidation, leading to melanin-like polymers. The stability of polyphenols is influenced by environmental factors, including , , and oxygen exposure, which can promote degradation via oxidation or . In alkaline (>7), auto-oxidation rates increase dramatically, leading to formation and loss of bioactivity, whereas acidic conditions enhance stability. Exposure to , particularly UV, and oxygen sensitizes polyphenols to and peroxidation, respectively, reducing their in solutions or foods. , the attachment of sugar moieties to phenolic hydroxyls, improves stability by sterically hindering oxidation sites and enhancing , thereby protecting against enzymatic and non-enzymatic degradation. Reactivity varies among structural classes; for instance, catechols (ortho-dihydroxybenzenes) are more prone to oxidation and radical scavenging than resorcinols (meta-dihydroxybenzenes) due to lower oxidation potentials and greater electron-donating ability of the adjacent -OH groups. Polyphenols also interact with biomolecules, binding to proteins through hydrogen bonding and hydrophobic interactions, which precipitate salivary proline-rich proteins and contribute to astringency in foods and beverages. This binding forms complexes that alter protein conformation and sensory perception. Furthermore, polyphenols inhibit by scavenging peroxyl radicals (LOO•) in cell membranes and chelating pro-oxidant metals, thereby preventing chain reactions that damage unsaturated fatty acids and maintaining membrane integrity.

Analytical Methods

Extraction

Polyphenols are typically isolated from materials such as fruits, , and using a variety of extraction techniques designed to maximize yield while preserving their structural . Conventional extraction remains the most widely used method, employing polar s like or , often in 50-80% aqueous solutions, at temperatures of 50-80°C to enhance and . Maceration involves soaking the matrix in for extended periods, typically 24-50 hours, allowing passive but requiring larger volumes and longer times compared to dynamic methods. In contrast, Soxhlet extraction uses a continuous process, hot through the sample for 4-8 hours, which improves and reduces use, though it may degrade heat-sensitive compounds. Yields from these techniques generally range from 10-50% of the dry matrix weight, varying with the source and polarity; for example, 80% maceration of peels achieves up to 18.5% yield. Advanced methods have gained prominence for their efficiency and reduced environmental impact. Ultrasound-assisted extraction (UAE) applies ultrasonic waves at 20-40 kHz to generate bubbles that disrupt cell walls, accelerating solvent penetration and typically completing in 15-60 minutes with yields 20-50% higher than conventional approaches. (MAE) uses electromagnetic waves at 300-900 W to rapidly heat the solvent-sample mixture, often in 1-10 minutes, enhancing and achieving comparable or superior polyphenol recovery, such as 30% more phenolics from apple than maceration. Supercritical CO2 extraction targets less polar polyphenols using CO2 above its critical point (31°C, 73.8 bar), often with as a co-solvent, and is ideal for heat-labile compounds but less effective for highly polar ones without modifiers. solvents like ionic liquids, such as 1-butyl-3-methylimidazolium-based variants, offer tunable polarity and low volatility, enabling higher selectivity and yields in or combinations compared to traditional organic solvents. Optimization strategies address polyphenol variability and stability. Acidic adjustment (e.g., to 3-5) during extraction stabilizes sensitive structures like catechins by minimizing oxidation and , improving recovery by up to 25% in extracts. Enzyme pretreatment with cellulases, pectinases, or tannases hydrolyzes cell walls and releases bound polyphenols, boosting yields by 15-40% in materials like grape pomace, though it requires controlled conditions to avoid over-degradation. Challenges arise with thermolabile polyphenols, such as glycosides, which degrade above 60°C, necessitating lower-temperature methods like UAE or enzyme-assisted approaches to retain bioactivity. Post-extraction processing ensures purity and concentration. Crude extracts are first filtered through Whatman paper or to remove particulate matter, followed by solvent removal via rotary under reduced (40-60°C) to yield a concentrated residue, often 10-20 times the original volume reduction without significant polyphenol loss.

Detection Techniques

Detection of polyphenols typically follows extraction procedures to isolate these compounds from complex matrices such as tissues or food samples. Spectroscopic methods provide foundational tools for initial identification based on characteristic absorption or resonance patterns. Ultraviolet-visible (UV-Vis) spectroscopy exploits the conjugated aromatic systems in polyphenols, which exhibit strong absorption bands generally between 250 and 370 nm, enabling rapid screening of phenolic compounds. Fourier-transform infrared (FTIR) spectroscopy identifies functional groups through vibrational modes, such as the broad O-H stretching band at 3200–3600 cm⁻¹ indicative of phenolic hydroxyl groups. Nuclear magnetic resonance (NMR) spectroscopy, particularly ¹H and ¹³C NMR, elucidates structural features like aromatic ring protons and carbon environments, offering detailed confirmation of polyphenol identity in purified samples. Chromatographic techniques separate polyphenols for subsequent identification, often using reversed-phase columns. High-performance liquid chromatography (HPLC) with C18 stationary phases and gradient elution systems (e.g., water-acetonitrile with ) resolves diverse phenolic classes based on polarity and hydrophobicity. Gas chromatography-mass spectrometry (GC-) suits volatile or derivatized polyphenols, providing retention time and mass spectral data for compound matching. Hyphenated methods like liquid chromatography-tandem mass spectrometry (LC-/MS) enhance specificity through fragmentation patterns, where precursor ions are selected and collided to yield diagnostic product ions for structural elucidation. Emerging instrumental approaches improve sensitivity and throughput for polyphenol characterization. High-resolution mass spectrometry (HRMS), such as Orbitrap systems, determines exact masses (typically <5 ppm error) to confirm molecular formulas and aid in untargeted profiling of complex mixtures. Electrochemical sensors, often based on modified electrodes (e.g., carbon nanomaterials), detect polyphenols via oxidation-reduction currents, enabling rapid, portable screening in real-time applications like food quality assessment. Standard practices ensure method reliability, with gallic acid commonly used as a reference for calibrating spectroscopic detections of phenolics. Validation adheres to AOAC International guidelines, emphasizing parameters like limit of detection, linearity, and specificity for accurate polyphenol identification.

Quantification

Quantification of polyphenols typically involves a range of analytical assays that measure total content or antioxidant capacity, as well as chromatographic techniques for individual compounds. The Folin-Ciocalteu (FC) assay is a widely used colorimetric method for estimating total phenolic content (TPC), where the reagent reacts with phenolic compounds in alkaline medium to form a blue molybdenum-tungsten complex, measured spectrophotometrically at 765 nm. Gallic acid is commonly employed as the standard for expressing results in gallic acid equivalents (GAE). However, the assay's non-specificity leads to overestimation due to interference from reducing agents such as ascorbic acid, sugars, and proteins. For assessing antioxidant capacity linked to polyphenols, the DPPH and ABTS assays are frequently applied; the DPPH method evaluates the ability of polyphenols to scavenge 2,2-diphenyl-1-picrylhydrazyl radicals, resulting in decolorization quantified by IC50 values (the concentration inhibiting 50% of the radical), while ABTS measures scavenging of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals with similar IC50 metrics. These assays are particularly suitable for lipophilic polyphenols like and . High-performance liquid chromatography (HPLC) enables precise quantification of individual polyphenols through separation and detection, typically using diode array or detectors, with s constructed from standards to determine concentrations, alongside limits of detection () and quantification (LOQ) for method sensitivity. The total phenolic content is calculated using the linear equation from the : TPC=absorbance−interceptslope×dilution factor\text{TPC} = \frac{\text{absorbance} - \text{intercept}}{\text{slope}} \times \text{dilution factor} expressed in units of mg GAE/g sample. Recent advances include near-infrared (NIR) spectroscopy for non-destructive quantification of polyphenols in foods, where chemometric models such as partial least squares regression achieve high predictive accuracy with coefficients of determination (R²) exceeding 0.9 in 2020s applications for items like olive oil and tea.

Natural Occurrence

In Plants

Polyphenols are ubiquitous secondary metabolites in the plant kingdom, present in virtually all vascular , where they serve essential physiological and ecological functions. They are particularly abundant in protective tissues such as bark, leaves, and fruits, often comprising a significant portion of the dry weight in these organs. For instance, in tea leaves (), polyphenols constitute 25–35% of the dry weight, primarily as catechins that contribute to the plant's resilience. These compounds originate from phenylpropanoid biosynthetic pathways and accumulate variably across plant species and tissues to support adaptation and survival. In plants, polyphenols play critical ecological roles, primarily in defense mechanisms against biotic and abiotic stresses. They deter herbivores and pathogens by acting as toxins or feeding inhibitors, with and binding to proteins to reduce digestibility in potential predators. also function as UV protectants, absorbing harmful radiation and preventing DNA damage in exposed tissues like leaves. Additionally, certain phenolic acids mediate by inhibiting the growth of neighboring plants through root exudates that disrupt or nutrient uptake. Polyphenols further facilitate symbiotic interactions, such as signaling in legume-rhizobia or arbuscular mycorrhizal associations, where they regulate microbial colonization in . The distribution and concentration of polyphenols exhibit species-specific variation, influenced by genetic factors and environmental cues. Grapes (Vitis vinifera), for example, are notably rich in , a stilbene polyphenol concentrated in skins and seeds, which enhances fungal resistance in this species. Environmental stresses, such as , can significantly elevate polyphenol levels as a protective response; studies show increases of 2–3-fold in total polyphenols and under progressive water deficit, aiding in osmotic adjustment and defense. This upregulation underscores polyphenols' role in stress acclimation across diverse plant taxa.

In Foods and Beverages

Polyphenols are abundant in various foods and beverages derived from sources, serving as key contributors to their nutritional profiles. Berries represent one of the richest dietary sources, with total polyphenol contents ranging from approximately 250 to 1,200 mg per 100 g fresh weight, primarily in the form of anthocyanins. For instance, elderberries contain about 1,191 mg/100 g, blueberries around 525 mg/100 g, and blackcurrants up to 560 mg/100 g, making them standout examples among fruits. In beverages, provides significant catechins, with a typical cup of delivering 100–200 mg of (EGCG) alone, and total catechins often exceeding 200 mg per 240 mL serving. similarly contributes chlorogenic acids, with light roast varieties offering up to 188 mg per cup, while total phenolic content in brewed averages around 200–500 mg per serving. stands out for its diverse polyphenols, with total contents ranging from 1,800 to 4,000 mg/L, including trace amounts of (typically 0.1–10 mg/L, higher in varieties like ). These values are documented in comprehensive databases such as the USDA Database for the Content of Selected Foods (Release 3.3, 2018), integrated into the Food and Database for Dietary Studies (FNDDS) for NHANES cycles up to 2021–2023 as of 2024. Food processing significantly alters polyphenol levels and bioaccessibility. and oxidation alter polyphenol profiles in products like , where enzymatic oxidation converts catechins to theaflavins and thearubigins, potentially improving of these metabolites compared to unprocessed forms, though total content decreases relative to . Enzymatic activities during processing transform complex structures into more absorbable compounds in some cases. In contrast, thermal processing such as cooking reduces heat-sensitive polyphenols by 30–50%, with losses observed in anthocyanins from berries and phenolic acids in due to degradation and leaching into cooking water; for example, can diminish in potatoes by similar margins. These changes are influenced by factors like temperature, duration, and medium volume, with minimal processing (e.g., ) preserving more compounds than prolonged high-heat methods. Average daily polyphenol intake in Western diets is estimated at around 1 g per person, varying by 300–1,200 mg based on consumption patterns, with , , and fruits as primary contributors. This figure aligns with epidemiological data from European and North American cohorts, where from beverages account for over 50% of total intake. The USDA Flavonoid Database provides analytical values for hundreds of foods, supporting precise intake estimations in dietary surveys like What We Eat in America (NHANES). Beyond nutrition, polyphenols influence sensory attributes in foods and beverages, imparting color through anthocyanins (e.g., red hues in berries and wine) and contributing to bitterness and astringency via catechins and proanthocyanidins. In tea and wine, these compounds elicit a puckering astringency and bitter aftertaste, which enhance perceived quality but can vary with concentration and processing; for instance, higher polyphenol levels in dark-roast coffee amplify bitterness from chlorogenic acids.

Biosynthesis and Metabolism

Biosynthesis Pathways

Polyphenols in are synthesized primarily through the integration of the and the phenylpropanoid pathway, with contributions from the acetate-malonate pathway for certain branches. The initiates with the condensation of phosphoenolpyruvate (derived from ) and erythrose-4-phosphate (from the ) to form 3-deoxy-D-arabino-heptulosonate 7-phosphate (), catalyzed by ; this seven-step process, involving enzymes such as 3-dehydroquinate and shikimate , culminates in chorismate formation. Chorismate is then channeled into the arogenate pathway to produce , the key precursor for most phenolic compounds. From , the phenylpropanoid pathway begins with the deamination by (PAL) to yield trans-cinnamic acid, which is subsequently hydroxylated by cinnamate 4-hydroxylase (C4H) to . This core pathway branches into various polyphenol classes; for instance, p-coumaroyl-CoA is condensed with three molecules of by chalcone synthase (CHS), the first committed enzyme of the flavonoid branch, to form , which isomerizes to and further diversifies into , anthocyanins, and proanthocyanidins via enzymes like flavanone 3-hydroxylase and dihydroflavonol 4-reductase. Other branches lead to lignins, coumarins, and stilbenes, such as produced by stilbene synthase in response to stress. The biosynthesis of polyphenols is tightly regulated at transcriptional, post-transcriptional, and enzymatic levels to respond to developmental cues and environmental stresses. MYB transcription factors, particularly R2R3-MYB proteins like AtMYB12 in , activate promoters of key genes such as PAL, CHS, and chalcone isomerase, thereby coordinating flux through the pathway for accumulation. Elicitors like (JA) induce polyphenol production by activating JA-responsive signaling cascades that upregulate MYB factors and downstream enzymes, enhancing defense against pathogens and herbivores. has demonstrated the potential for pathway manipulation; for example, /Cas9-mediated knockout of the Vitis davidii CHS2 gene redirects metabolic flux from to stilbenoids, resulting in elevated levels in cell cultures. Evolutionarily, polyphenol biosynthesis traces back to ancient origins, with PAL-like genes present in as early as two copies per , indicating a primitive capacity for phenylpropanoid in non-vascular organisms. Gene duplications and expansions during the transition to land and diversification in angiosperms led to increased PAL family members—up to dozens in —enabling specialized polyphenol production for structural reinforcement, UV protection, and biotic interactions in complex terrestrial environments.

Metabolism in Organisms

Polyphenols are primarily absorbed in the , where low molecular weight compounds (<500 Da), such as aglycones, undergo passive diffusion across the intestinal epithelium.14380-4/fulltext) Higher molecular weight or glycosylated forms, like glucosides, require deconjugation by or intestinal enzymes (e.g., lactase-phlorizin ) to release absorbable aglycones before uptake. Only about 5-10% of ingested polyphenols are absorbed in the , with the remainder reaching the colon for further microbial transformation. Following absorption, polyphenols undergo phase I and II metabolism primarily in the intestinal mucosa and liver. Phase I reactions involve (CYP450) enzymes, such as and , which perform oxidation to introduce or modify hydroxyl groups, enhancing reactivity for subsequent conjugation. Phase II metabolism, more dominant for polyphenols, includes , sulfation, and , mediated by UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and catechol-O-methyltransferases (COMTs), respectively, to increase water solubility. For example, is rapidly conjugated in the liver to form quercetin-3-glucuronide via UGT1A1: Quercetin+UDPGA→UGT1A1Quercetin-3-glucuronide+UDP\text{Quercetin} + \text{UDPGA} \xrightarrow{\text{UGT1A1}} \text{Quercetin-3-glucuronide} + \text{UDP}
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