Health effects of natural phenols and polyphenols
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Polyphenols () are a large family of naturally occurring
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
s characterized by multiples of
phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...
units. They are abundant in plants and structurally diverse. Polyphenols include
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
s,
tannic acid Tannic acid is a specific form of tannin, a type of polyphenol. Its weak acidity ( pKa around 6) is due to the numerous phenol groups in the structure. The chemical formula for commercial tannic acid is often given as C76H52O46, which correspon ...
, and ellagitannin, some of which have been used historically as
dye A dye is a colored substance that chemically bonds to the substrate to which it is being applied. This distinguishes dyes from pigments which do not chemically bind to the material they color. Dye is generally applied in an aqueous solution an ...
s and for tanning garments.


Etymology

The name derives from the
Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: Mycenaean Greek (), Dark Ages (), the Archaic peri ...
word (''polus'', meaning "many, much") and the word phenol which refers to a chemical structure formed by attaching to an aromatic benzenoid ( phenyl) ring to a
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
(-OH) group as is found in alcohols (hence the ''-ol'' suffix). The term polyphenol has been in use at least since 1894.


Definition

The term polyphenol is not well-defined, but is generally agreed that they are natural products "having a polyphenol structure (i.e., several
hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...
s on
aromatic ring In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to saturat ...
s)" including four principal classes: "phenolic acids, flavonoids, stilbenes, and lignans". *Flavonoids include flavones, flavonols, flavanols, flavanones, isoflavones, proanthocyanidins, and anthocyanins. Particularly abundant flavanoids in foods are catechin (tea, fruits),
hesperetin Hesperetin is the 4'-methoxy derivative of eriodictyol, a flavanone. Hesperetin's 7-O-glycoside, hesperidin, is a naturally occurring flavanon-glycoside, the main flavonoid in lemons and sweet oranges. Hesperetin (and naringenin, the parent flavan ...
(citrus fruits), cyanidin (red fruits and berries), daidzein (
soybean The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses. Traditional unfermented food uses of soybeans include soy milk, from which tofu an ...
), proanthocyanidins (apple, grape, cocoa), and quercetin (onion, tea, apples). *Phenolic acid include caffeic acid * Lignans are polyphenols derived from
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
found in
Flax Flax, also known as common flax or linseed, is a flowering plant, ''Linum usitatissimum'', in the family Linaceae. It is cultivated as a food and fiber crop in regions of the world with temperate climates. Textiles made from flax are known in ...
seed and other cereals.


WBSSH definition

The White–Bate-Smith–Swain–Haslam (WBSSH) definition characterized structural characteristics common to plant phenolics used in
tanning Tanning may refer to: *Tanning (leather), treating animal skins to produce leather *Sun tanning, using the sun to darken pale skin **Indoor tanning, the use of artificial light in place of the sun **Sunless tanning, application of a stain or dye t ...
(i.e., the tannins). In terms of properties, the WBSSH describes the polyphenols thusly: * generally moderately
water-soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...
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 Gallic acid (also known as 3,4,5-trihydroxybenzoic acid) is a trihydroxybenzoic acid with the formula carbon, C6hydrogen, H2(hydroxide, OH)3CO2H. It is classified as a phenolic acid. It is found in gallnuts, sumac, Witch-hazel, witch hazel, tea l ...
and hexahydroxydiphenoyl esters and their derivatives


Quideau definition

According to Stéphane Quideau, the term "polyphenol" refers to compounds derived from the
shikimate Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower ''sh ...
/
phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functions.
Ellagic acid Ellagic acid is a polyphenol found in numerous fruits and vegetables. It is the dilactone of hexahydroxydiphenic acid. Name The name comes from the French term ''acide ellagique'', from the word ''galle'' spelled backwards because it can be ob ...
, 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 The raspberry ellagitannin is an ellagitannin found in raspberries. It is a polyphenol per se, containing 6 ellagic acid-type components and two additional monomeric phenolics, for a total of 14 gallic acid units (and all of their substituent phen ...
, on the other hand, with its 14
gallic acid Gallic acid (also known as 3,4,5-trihydroxybenzoic acid) is a trihydroxybenzoic acid with the formula C6 H2( OH)3CO2H. It is classified as a phenolic acid. It is found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and other plants. It i ...
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 Theaflavin-3-gallate is a theaflavin derivative. It can be found in abundance in black tea and is produced during fermentation. It has been studied as a cancer-fighting chemical when combined with cisplatin against ovarian cancer cells. Consuming ...
shown below, and the hydrolyzable tannin,
tannic acid Tannic acid is a specific form of tannin, a type of polyphenol. Its weak acidity ( pKa around 6) is due to the numerous phenol groups in the structure. The chemical formula for commercial tannic acid is often given as C76H52O46, which correspon ...
.


Chemistry

Polyphenols are
reactive Reactive may refer to: *Generally, capable of having a reaction (disambiguation) *An adjective abbreviation denoting a bowling ball coverstock made of reactive resin *Reactivity (chemistry) *Reactive mind *Reactive programming See also *Reactanc ...
species toward
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
, hence their description as
antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
s
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
.


Structural chemistry

Polyphenols are often larger molecules (
macromolecule A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...
s). 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
senesce Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence invol ...
s. 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 Condensed tannins (proanthocyanidins, polyflavonoid tannins, catechol-type tannins, pyrocatecollic type tannins, non-hydrolyzable tannins or flavolans) are polymers formed by the condensation of flavans. They do not contain sugar residues. The ...
). Proanthocyanidins are mostly polymeric units of catechin and
epicatechin Catechin is a flavan-3-ol, a type of secondary metabolite providing antioxidant roles in plants. It belongs to the subgroup of polyphenols called flavonoids. The name of the catechin chemical family derives from ''catechu'', which is the tannic ...
. Polyphenols often have functional groups beyond
hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...
s.
Ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
linkages are common, as are
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
s.


Analytical chemistry

The analysis techniques are those of
phytochemistry Phytochemistry is the study of phytochemicals, which are chemicals derived from plants. Phytochemists strive to describe the structures of the large number of secondary metabolites found in plants, the functions of these compounds in human and ...
:
extraction Extraction may refer to: Science and technology Biology and medicine * Comedo extraction, a method of acne treatment * Dental extraction, the surgical removal of a tooth from the mouth Computing and information science * Data extraction, the pro ...
, isolation,
structural elucidation A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...
, then quantification.


Extraction

Extraction Extraction may refer to: Science and technology Biology and medicine * Comedo extraction, a method of acne treatment * Dental extraction, the surgical removal of a tooth from the mouth Computing and information science * Data extraction, the pro ...
of polyphenols can be performed using a solvent like water,
hot water Water heating is a heat transfer process that uses an energy source to heat water above its initial temperature. Typical domestic uses of hot water include cooking, cleaning, bathing, and space heating. In industry, hot water and water heated t ...
, methanol, methanol/formic acid, methanol/water/acetic or formic acid.
Liquid–liquid extraction Liquid–liquid extraction (LLE), also known as solvent extraction and partitioning, is a method to separate compounds or metal complexes, based on their relative solubilities in two different immiscible liquids, usually water (polar) and an org ...
can be also performed or
countercurrent chromatography Countercurrent chromatography (CCC, also counter-current chromatography) is a form of liquid–liquid chromatography that uses a liquid stationary phase that is held in place by inertia of the molecules composing the stationary phase accelerating ...
. Solid phase extraction can also be made on C18 sorbent cartridges. Other techniques are ultrasonic extraction, heat reflux extraction, microwave-assisted extraction, critical carbon dioxide, high-pressure liquid extraction or use of ethanol in an immersion extractor. 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. 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. Concentration can be made by ultrafiltration. Purification can be achieved by
preparative chromatography In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system (a ...
.


Analysis techniques

Phosphomolybdic acid Phosphomolybdic acid is the heteropolymetalate with the formula . It is a yellow solid, although even slightly impure samples have a greenish coloration. It is also known as dodeca molybdophosphoric acid or PMA, is a yellow-green chemical compound ...
is used as a reagent for staining phenolics in thin layer chromatography. Polyphenols can be studied by
spectroscopy Spectroscopy is the field of study that measures and interprets the electromagnetic spectra that result from the interaction between electromagnetic radiation and matter as a function of the wavelength or frequency of the radiation. Matter wa ...
, especially in the ultraviolet domain, by fractionation or paper chromatography. They can also be analysed by chemical characterisation.
Instrumental chemistry Instrumental analysis is a field of analytical chemistry that investigates analytes using scientific instruments. Spectroscopy Spectroscopy measures the interaction of the molecules with electromagnetic radiation. Spectroscopy consists of many ...
analyses include
separation Separation may refer to: Films * ''Separation'' (1967 film), a British feature film written by and starring Jane Arden and directed by Jack Bond * ''La Séparation'', 1994 French film * ''A Separation'', 2011 Iranian film * ''Separation'' (20 ...
by
high performance liquid chromatography High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
(HPLC), and especially by
reversed-phase liquid chromatography Reversed-phase chromatography (also called RPC, reverse-phase chromatography, or hydrophobic chromatography) includes any chromatographic method that uses a hydrophobic stationary phase. RPC refers to liquid (rather than gas) chromatography. St ...
(RPLC), can be coupled to
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...
. Purified compounds can be identified by the means of nuclear magnetic resonance.


=Microscopy analysis

= 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 Botany, also called , plant biology or phytology, is the science of plant life and a branch of biology. A botanist, plant scientist or phytologist is a scientist who specialises in this field. The term "botany" comes from the Ancient Greek wo ...
, to enhance the fluorescence signal.


Quantification

Polyphenolic content in vitro can be quantified by volumetric titration. An oxidizing agent,
permanganate A permanganate () is a chemical compound containing the manganate(VII) ion, , the conjugate base of permanganic acid. Because the manganese atom is in the +7 oxidation state, the permanganate(VII) ion is a strong oxidizing agent. The ion is a tra ...
, is used to oxidize known concentrations of a standard tannin solution, producing a
standard curve In analytical chemistry, a calibration curve, also known as a standard curve, is a general method for determining the concentration of a substance in an unknown sample by comparing the unknown to a set of standard samples of known concentration. ...
. The tannin content of the unknown is then expressed as equivalents of the appropriate hydrolyzable or condensed tannin. Some methods for quantification of total polyphenol content in vitro are based on
colorimetric Colorimetry is "the science and technology used to quantify and describe physically the human color perception". It is similar to spectrophotometry, but is distinguished by its interest in reducing spectra to the physical correlates of color ...
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. Results are typically expressed as gallic acid equivalents. Polyphenols are seldom evaluated by
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
technologies. Other tests measure the antioxidant capacity of a fraction. Some make use of the
ABTS In biochemistry, ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) is a chemical compound used to observe the reaction kinetics of specific enzymes. A common use for it is in the enzyme-linked immunosorbent assay (ELISA) to detect the ...
radical
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
which is reactive towards most antioxidants including phenolics,
thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
s and
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
. 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 The Trolox equivalent antioxidant capacity (TEAC) assay measures the antioxidant capacity of a given substance, as compared to the standard, Trolox. Most commonly, antioxidant capacity is measured using the ABTS Decolorization Assay. Other antioxi ...
(TEAC) assay. The reactivity of the various antioxidants tested are compared to that of
Trolox Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) is a water-soluble analog of vitamin E sold by Hoffman-LaRoche. It is an antioxidant like vitamin E and it is used in biological or biochemical applications to reduce oxidative stre ...
, which is a
vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...
analog. Other antioxidant capacity assays which use Trolox as a standard include the
diphenylpicrylhydrazyl DPPH is a common abbreviation for the organic chemical compound 2,2-diphenyl-1-picrylhydrazyl. It is a dark-colored crystalline powder composed of stable free radical molecules. DPPH has two major applications, both in laboratory research: one is ...
(DPPH),
oxygen radical absorbance capacity Oxygen radical absorbance capacity (ORAC) was a method of measuring antioxidant capacities in biological samples ''in vitro''. Because no physiological proof ''in vivo'' existed in support of the free-radical theory or that ORAC provided informatio ...
(ORAC),
ferric reducing ability of plasma Ferric reducing ability of plasma (FRAP, also ''Ferric ion reducing antioxidant power'') is an antioxidant capacity assay that uses Trolox as a standard. The FRAP assay was first performed by Iris Benzie and J. J. Strain of the Human Nutrition Resea ...
(FRAP) assays or inhibition of copper-catalyzed ''in vitro'' human
low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
oxidation. New methods including the use of biosensors can help monitor the content of polyphenols in food. Quantitation results produced by the mean of
diode array detector A chromatography detector is a device used in gas chromatography (GC) or liquid chromatography (LC) to detect components of the mixture being eluted off the chromatography column. There are two general types of detectors: destructive and non-destruc ...
–coupled HPLC are generally given as relative rather than
absolute value In mathematics, the absolute value or modulus of a real number x, is the non-negative value without regard to its sign. Namely, , x, =x if is a positive number, and , x, =-x if x is negative (in which case negating x makes -x positive), an ...
s as there is a lack of commercially available
standards Standard may refer to: Symbols * Colours, standards and guidons, kinds of military signs * Standard (emblem), a type of a large symbol or emblem used for identification Norms, conventions or requirements * Standard (metrology), an object th ...
for all polyphenolic molecules.


Industrial applications

Some polyphenols are traditionally used as
dye A dye is a colored substance that chemically bonds to the substrate to which it is being applied. This distinguishes dyes from pigments which do not chemically bind to the material they color. Dye is generally applied in an aqueous solution an ...
s. For instance, in the
Indian subcontinent The Indian subcontinent is a list of the physiographic regions of the world, physiographical region in United Nations geoscheme for Asia#Southern Asia, Southern Asia. It is situated on the Indian Plate, projecting southwards into the Indian O ...
, the pomegranate peel, high in tannins and other polyphenols, or its juice, is employed in the dyeing of non-synthetic fabrics. Polyphenols, especially tannins, were used traditionally for tanning leather and today also as precursors in green chemistry notably to produce plastics or resins by polymerisation with or without the use of
formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
or
adhesive Adhesive, also known as glue, cement, mucilage, or paste, is any non-metallic substance applied to one or both surfaces of two separate items that binds them together and resists their separation. The use of adhesives offers certain advant ...
s for particleboards. The aims are generally to make use of plant residues from grape, olive (called
pomace Pomace ( ), or marc (; from French ''marc'' ), is the solid remains of grapes, olives, or other fruit after pressing for juice or oil. It contains the skins, pulp, seeds, and stems of the fruit. Grape pomace has traditionally been used to prod ...
s) or
pecan The pecan (''Carya illinoinensis'') is a species of hickory native to the southern United States and northern Mexico in the region of the Mississippi River. The tree is cultivated for its seed in the southern United States, primarily in Georgia, ...
shells left after processing. Pyrogallol and pyrocatechin are among the oldest photographic developers.


Biochemistry

Polyphenols are thought to play diverse roles in the ecology of plants. These functions include: * Release and suppression of growth hormones such as
auxin Auxins (plural of auxin ) are a class of plant hormones (or plant-growth regulators) with some morphogen-like characteristics. Auxins play a cardinal role in coordination of many growth and behavioral processes in plant life cycles and are essenti ...
. * UV screens to protect against ionizing radiation and to provide coloration (
plant pigment Biological pigments, also known simply as pigments or biochromes, are substances produced by living organisms that have a color resulting from selective color absorption. Biological pigments include plant pigments and flower pigments. Many biol ...
s). * Deterrence of herbivores (sensory properties). * Prevention of microbial infections ( phytoalexins). * Signaling molecules in ripening and other growth processes.


Occurrence in nature

The most abundant polyphenols are the
condensed tannin Condensed tannins (proanthocyanidins, polyflavonoid tannins, catechol-type tannins, pyrocatecollic type tannins, non-hydrolyzable tannins or flavolans) are polymers formed by the condensation of flavans. They do not contain sugar residues. They ...
s, 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 phenol In biochemistry, naturally occurring phenols are natural products containing at least one phenol functional group. Phenolic compounds are produced by plants and microorganisms. Organisms sometimes synthesize phenolic compounds in response to eco ...
s and polyphenols, calculated with reference to the dry green leaf mass. High levels of polyphenols in some woods can explain their natural
preservation Preservation may refer to: Heritage and conservation * Preservation (library and archival science), activities aimed at prolonging the life of a record while making as few changes as possible * ''Preservation'' (magazine), published by the Nat ...
against rot.
Flax Flax, also known as common flax or linseed, is a flowering plant, ''Linum usitatissimum'', in the family Linaceae. It is cultivated as a food and fiber crop in regions of the world with temperate climates. Textiles made from flax are known in ...
and ''
Myriophyllum spicatum ''Myriophyllum spicatum'' (Eurasian watermilfoil or spiked water-milfoil) is native to Europe, Asia, and north Africa, but has a wide geographic and climatic distribution among some 57 countries, extending from northern Canada to South Africa. It ...
'' (a submerged aquatic plant) secrete polyphenols that are involved in
allelopathic Allelopathy is a biological phenomenon by which an organism produces one or more biochemicals that influence the germination, growth, survival, and reproduction of other organisms. These biochemicals are known as allelochemicals and can have ben ...
interactions. Polyphenols are also found in animals. In
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s, such as insects, and
crustacean Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean group ...
s polyphenols play a role in epicuticle hardening ( sclerotization). The hardening of the cuticle is due to the presence of a
polyphenol oxidase Polyphenol oxidase (PPO; also polyphenol oxidase i, chloroplastic), an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule. PPO may accept monophenols and/or ''o''-diphenols as substrates. The ...
. In crustaceans, there is a second oxidase activity leading to cuticle pigmentation. There is apparently no polyphenol tanning occurring in arachnids cuticle.


Biosynthesis and metabolism

Polyphenols incorporate smaller parts and building blocks from simpler
natural phenol In biochemistry, naturally occurring phenols are natural products containing at least one phenol functional group. Phenolic compounds are produced by plants and microorganisms. Organisms sometimes synthesize phenolic compounds in response to eco ...
s, which originate from the
phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
pathway for the phenolic acids or the shikimic acid pathway for
gallotannin A gallotannin is any of a class of molecules belonging to the hydrolysable tannins. Gallotannins are polymers formed when gallic acid, a polyphenol monomer, esterifies and binds with the hydroxyl group of a polyol carbohydrate such as glucose. Meta ...
s and analogs. Flavonoids and caffeic acid derivatives are biosynthesized from
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
and
malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...
. 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 In enzymology, a dihydrokaempferol 4-reductase () is an enzyme that catalyzes the chemical reaction :cis-3,4-leucopelargonidin + NADP+ \rightleftharpoons (+)-dihydrokaempferol + NADPH + H+ Thus, the two substrates of this enzyme are cis-3,4-l ...
and
leucoanthocyanidin reductase In enzymology, a leucoanthocyanidin reductase () (LAR, aka leucocyanidin reductase or LCR) is an enzyme that catalyzes the chemical reaction :(2R,3S)-catechin + NADP+ + H2O \rightleftharpoons 2,3-trans-3,4-cis-leucocyanidin + NADPH + H+ The 3 ...
(LAR) are crucial enzymes with subsequent addition of catechin and epicatechin moieties for larger, non-hydrolyzable tannins. The glycosylated form develops from
glucosyltransferase Glucosyltransferases are a type of glycosyltransferase that enable the transfer of glucose. Examples include: * glycogen synthase * glycogen phosphorylase Glycogen phosphorylase is one of the phosphorylase enzymes (). Glycogen phosphorylase cat ...
activity and increases the
solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubil ...
of polyphenols.
Polyphenol oxidase Polyphenol oxidase (PPO; also polyphenol oxidase i, chloroplastic), an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule. PPO may accept monophenols and/or ''o''-diphenols as substrates. The ...
(PPO) is an enzyme that catalyses the oxidation of o-diphenols to produce
o-quinone 1,2-Benzoquinone, also called ''ortho''-benzoquinone, is an organic compound with formula . It is one of the two isomers of quinone, the other being 1,4-Benzoquinone, 1,4-benzoquinone. It is a red volatile solid that is soluble in water and eth ...
s. It is the rapid polymerisation of o-quinones to produce black, brown or red polyphenolic pigments that causes
fruit browning Browning is the process of food turning brown due to the chemical reactions that take place within. The process of browning is one of the chemical reactions that take place in food chemistry and represents an interesting research topic regarding ...
. In insects, PPO is involved in cuticle hardening.


Occurrence in food

Polyphenols comprise up to 0.2–0.3% fresh weight for many fruits. Consuming common servings of wine, chocolate,
legume A legume () is a plant in the family Fabaceae (or Leguminosae), or the fruit or seed of such a plant. When used as a dry grain, the seed is also called a pulse. Legumes are grown agriculturally, primarily for human consumption, for livestock f ...
s or tea may also contribute to about one gram of intake per day. 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.
Some polyphenols are considered antinutrients – compounds that interfere with the absorption of
essential nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s – especially iron and other metal ions, which may bind to digestive enzymes and other proteins, particularly in ruminants. In a comparison of cooking methods, phenolic and
carotenoid Carotenoids (), also called tetraterpenoids, are yellow, orange, and red organic compound, organic pigments that are produced by plants and algae, as well as several bacteria, and Fungus, fungi. Carotenoids give the characteristic color to pumpki ...
levels in vegetables were retained better by
steaming Steaming is a method of cooking using steam. This is often done with a food steamer, a kitchen appliance made specifically to cook food with steam, but food can also be steamed in a wok. In the American southwest, steam pits used for cooking ha ...
compared to
frying Frying is the cooking of food in oil or another fat. Similar to sautéing, pan-fried foods are generally turned over once or twice during cooking to make sure that the food is well-made, using tongs or a spatula, while sautéed foods are cooked ...
. Polyphenols in wine, beer and various nonalcoholic juice beverages can be removed using
finings Finings are substances that are usually added at or near the completion of the processing of brewing wine, beer, and various nonalcoholic juice beverages. They are used to remove organic compounds, either to improve clarity or adjust flavor or ar ...
, substances that are usually added at or near the completion of the processing of brewing.


Astringency

With respect to food and beverages, the cause of
astringency An astringent (sometimes called adstringent) is a chemical that shrinks or constricts body tissues. The word derives from the Latin ''adstringere'', which means "to bind fast". Calamine lotion, witch hazel, and yerba mansa, a Californian plant ...
is not fully understood, but it is measured chemically as the ability of a substance to precipitate proteins. A review published in 2005 found that astringency increases and bitterness decreases with the mean degree of
polymerization In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
. 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. Flavonoid configurations can also cause significant differences in sensory properties, e.g.
epicatechin Catechin is a flavan-3-ol, a type of secondary metabolite providing antioxidant roles in plants. It belongs to the subgroup of polyphenols called flavonoids. The name of the catechin chemical family derives from ''catechu'', which is the tannic ...
is more bitter and astringent than its chiral
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...
catechin. In contrast, hydroxycinnamic acids do not have astringent qualities, but are bitter.


Research

Polyphenols are a large, diverse group of compounds, making it difficult to determine their biological effects. They are not considered
nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s, as they are not used for growth, survival or reproduction, nor do they provide dietary energy. Therefore, they do not have recommended daily intake levels, as exist for
Vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
s,
minerals In geology and mineralogy, a mineral or mineral species is, broadly speaking, a solid chemical compound with a fairly well-defined chemical composition and a specific crystal structure that occurs naturally in pure form.John P. Rafferty, ed. (2 ...
, and
fiber Fiber or fibre (from la, fibra, links=no) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorporate ...
in the
European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...
, United Kingdom, and United States. In the US, the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
issued guidance to manufacturers that polyphenols cannot be mentioned on
food label The packaging and labeling of food is subject to regulation in most regions/jurisdictions, both to prevent false advertising and to promote food safety. Regulations by type Multi-faceted * Codex Alimentarius (international voluntary stand ...
s as antioxidant nutrients unless
physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
evidence exists to verify such a qualification and a Dietary Reference Intake value has been established, characteristics which have not been determined for polyphenols. In the
European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...
, two
health claim A health claim on a food label and in food marketing is a claim by a manufacturer of food products that their food will reduce the risk of developing a disease or condition. For example, it is claimed by the manufacturers of oat cereals that oat ...
s were authorized between 2012 and 2015: 1) flavanols in
cocoa solid Dry cocoa solids are the components of cocoa beans remaining after cocoa butter, the fatty component of the bean, is extracted from chocolate liquor, roasted cocoa beans that have been ground into a liquid state. Cocoa butter is 46% to 57% of the ...
s at doses exceeding 200 mg per day may contribute to maintenance of vascular elasticity and normal blood flow; 2) olive oil polyphenols (5 mg of
hydroxytyrosol Hydroxytyrosol is an organic compound with the formula . Classified as a phenylethanoid, i.e. a relative of phenethyl alcohol, Its derivatives are found in a variety of natural sources, notably olive oils and wines. The compound is colorless solid ...
and its derivatives (e.g. oleuropein complex and
tyrosol Tyrosol is an organic compound with the formula . Classified as a phenylethanoid, i.e. a derivative of phenethyl alcohol, It is found in a variety of natural sources. The compound is colorless solid. The principal source in the human diet is ol ...
) may "contribute to the protection of blood lipids from oxidative damage", if consumed daily. As of 2022,
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s 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. Polyphenols were once considered as antioxidants, but this concept is obsolete. 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 In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
. Some polyphenols are considered to be
bioactive compound A bioactive compound is a compound that has an effect on a living organism, tissue or cell, usually demonstrated by basic research in vitro or in vivo in the laboratory. While dietary nutrients are essential to life, bioactive compounds have not ...
s for which development of dietary recommendations was under consideration in 2017.


Cardiovascular diseases

In the 1930s, polyphenols were considered as a factor in
capillary permeability Vascular permeability, often in the form of capillary permeability or microvascular permeability, characterizes the capacity of a blood vessel wall to allow for the flow of small molecules (drugs, nutrients, water, ions) or even whole cells (lymph ...
(then called ''vitamin P''), 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.


Cancer

, there is little evidence that dietary flavonoids lower the risk of cancer.


Cognitive function

Polyphenols are under preliminary research for possible cognitive effects in healthy adults.


Phytoestrogens

Isoflavone Isoflavones are substituted derivatives of isoflavone, a type of naturally occurring isoflavonoids, many of which act as phytoestrogens in mammals. Isoflavones are produced almost exclusively by the members of the bean family, Fabaceae (Leguminosae ...
s, which are structurally related to
17β-Estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
, are classified as
phytoestrogen A phytoestrogen is a plant-derived xenoestrogen (see estrogen) not generated within the endocrine system, but consumed by eating plants or manufactured foods. Also called a "dietary estrogen", it is a diverse group of naturally occurring nonstero ...
s. There is little scientific evidence that consuming isoflavones has an effect on health or disease. A risk assessment by the European Food Safety Authority found no cause for concern when isoflavones are consumed in a normal diet.


Phlebotonic

Phlebotonics of heterogeneous composition, consisting partly of citrus peel
extract An extract is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol, oil or water. Extracts may be sold as tinctures, absolutes or in powder form. The aromatic principles of many spices, nuts, h ...
s (
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
s, such as
hesperidin Hesperidin is a flavanone glycoside found in citrus fruits. Its aglycone form is called hesperetin. Its name is derived from the word "hesperidium", for fruit produced by citrus trees. Hesperidin was first isolated in 1828 by French chemist M. ...
) and synthetic compounds, are used to treat
chronic venous insufficiency Chronic venous insufficiency (CVI) is a medical condition in which blood pools in the veins, straining the walls of the vein. The most common cause of CVI is superficial venous reflux which is a treatable condition. As functional venous valves are ...
and
hemorrhoid Hemorrhoids (or haemorrhoids), also known as piles, are vascular structures in the anal canal. In their normal state, they are cushions that help with stool control. They become a disease when swollen or inflamed; the unqualified term ''hemo ...
s. Some are non-prescription
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
s, such as Diosmin, while one other – Vasculera (
Diosmiplex Diosmin (diosmetin 7-O-rutinoside), a flavone glycoside of diosmetin, is manufactured from citrus fruit peels as a phlebotonic non-prescription dietary supplement used to aid treatment of hemorrhoids or chronic venous diseases, mainly of the ...
) – is a prescription
medical food Medical foods are foods that are specially formulated and intended for the dietary management of a disease that has distinctive nutritional needs that cannot be met by normal diet alone. In the United States they were defined in the Food and Drug A ...
intended for treating venous disorders. Their mechanism of action is undefined, and clinical evidence of benefit for using phlebotonics to treat venous diseases is limited.


Gut microbiome

Polyphenols are extensively metabolized by the
gut microbiota Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut m ...
and are investigated as a potential metabolic factor in function of the
gut microbiota Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut m ...
.


Toxicity and adverse effects

Adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
s of polyphenol intake range from mild (e.g.,
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
symptoms) to severe (e.g., hemolytic anemia or hepatotoxicity). In 1988, hemolytic anemia following polyphenol consumption was documented, resulting in the withdrawal of a catechin-containing drug. Metabolism of polyphenols can result in flavonoid-drug interactions, such as in
grapefruit–drug interactions Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits. The ...
, which involves inhibition of the liver
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
,
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
, likely by grapefruit
furanocoumarin The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...
s, a class of polyphenol. The European Food Safety Authority established upper limits for some polyphenol-containing supplements and additives, such as green tea extract or curcumin. For most polyphenols found in the diet, an adverse affect beyond nutrient-drug interactions is unlikely.


See also

* List of phytochemicals in food *
Phytochemistry Phytochemistry is the study of phytochemicals, which are chemicals derived from plants. Phytochemists strive to describe the structures of the large number of secondary metabolites found in plants, the functions of these compounds in human and ...
*
Polyphenolic protein Bioadhesives are natural polymeric materials that act as adhesives. The term is sometimes used more loosely to describe a glue formed synthetically from biological monomers such as sugars, or to mean a synthetic material designed to adhere to biolo ...
s * Secondary metabolites


References


External links


Phenol-Explorer, electronic database of polyphenol content in foods
* Dictionary of natural phenols and polyphenols molecular formulas {{Authority control Phytochemicals