Flavan-3-ol

{{Short description|Category of polyphenol compound}} {{distinguish|Flavonol}} {{use American English|date=September 2022}} thumb|right|250px|Chemical structure of flavan-3-ol

'''Flavan-3-ols''' (sometimes referred to as '''flavanols''') are a subgroup of flavonoids. They are derivatives of flavans that possess a 2-phenyl-3,4-dihydro-2''H''-chromen-3-ol skeleton. Flavan-3-ols are structurally diverse and include a range of compounds, such as catechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, proanthocyanidins, theaflavins, thearubigins. They play a part in plant defense and are present in the majority of plants.<ref>{{cite journal | vauthors = Ullah C, Unsicker SB, Fellenberg C, Constabel CP, Schmidt A, Gershenzon J, Hammerbacher A | title = Flavan-3-ols Are an Effective Chemical Defense against Rust Infection | journal = Plant Physiology | volume = 175 | issue = 4 | pages = 1560–1578 | date = December 2017 | pmid = 29070515 | pmc = 5717727 | doi = 10.1104/pp.17.00842 }}</ref>

== Chemical structure ==

The single-molecule (monomer) catechin, or isomer epicatechin (see diagram), adds four hydroxyls to flavan-3-ol, making building blocks for concatenated polymers (proanthocyanidins) and higher order polymers (anthocyanidins).<ref name="ReferenceA">{{cite book |title=OPC in Practice |vauthors=Schwitters B, Masquelier J |date=1995 |edition=3rd |oclc=45289285}}</ref>

Flavan-3-ols possess two chiral carbons, meaning four diastereoisomers occur for each of them. They are distinguished from the yellow, ketone-containing flavonoids such as quercitin and rutin, which are called flavonols. Early use of the term ''bioflavonoid'' was imprecisely applied to include the ''flavanols'', which are distinguished by the absence of ketones. Catechin monomers, dimers, and trimers (oligomers) are colorless. Higher order polymers, anthocyanidins, exhibit deepening reds and become tannins.<ref name="ReferenceA" />

Catechin and epicatechin are epimers, with (–)-epicatechin and (+)-catechin being the most common optical isomers found in nature. Catechin was first isolated from the plant extract catechu, from which it derives its name. Heating catechin past its point of decomposition releases pyrocatechol (also called catechol), which explains the common origin of the names of these compounds.

Epigallocatechin and gallocatechin contain an additional phenolic hydroxyl group when compared to epicatechin and catechin, respectively, similar to the difference in pyrogallol compared to pyrocatechol.

Catechin gallates are gallic acid esters of the catechins; an example is epigallocatechin gallate, which is commonly the most abundant catechin in tea. Proanthocyanidins and thearubigins are oligomeric flavan-3-ols.

In contrast to many other flavonoids, flavan-3-ols do not generally exist as glycosides in plants.<ref name=":1"/> center|thumb|600x600px|Structures of (epi)catechin, (epi)catechin gallate, (epi)gallocatechin and (epi)gallocatechin gallate.

=== Biosynthesis of (–)-epicatechin ===

The flavonoids are products from a cinnamoyl-CoA starter unit, with chain extension using three molecules of malonyl-CoA. Reactions are catalyzed by a type III PKS enzyme.{{cn|date=June 2025}} These enzymes use coenzyme A esters, and have a single active site to perform the necessary series of reactions: chain extension, condensation, and cyclization. Chain extension of 4-hydroxycinnamoyl-CoA with three molecules of malonyl-CoA gives initially a polyketide (Figure 1), which can be folded. These allow Claisen-like reactions to occur, generating aromatic rings.<ref name="Dewick2009p168">{{cite book | vauthors = Dewick PM | title = Medicinal Natural Products: A biosynthetic approach | publisher = John Wiley & Sons | date = 2009 | page = 168 | isbn = 978-0-471-49641-0 }}</ref><ref name="Winkel-Shirley2001p485-493">{{cite journal | vauthors = Winkel-Shirley B | title = Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology | journal = Plant Physiology | volume = 126 | issue = 2 | pages = 485–493 | date = June 2001 | pmid = 11402179 | pmc = 1540115 | doi = 10.1104/pp.126.2.485 }}</ref> Fluorescence-lifetime imaging microscopy can be used to detect flavanols in plant cells.<ref>{{cite journal | vauthors = Mueller-Harvey I, Feucht W, Polster J, Trnková L, Burgos P, Parker AW, Botchway SW | title = Two-photon excitation with pico-second fluorescence lifetime imaging to detect nuclear association of flavanols | journal = Analytica Chimica Acta | volume = 719 | pages = 68–75 | date = March 2012 | pmid = 22340533 | doi = 10.1016/j.aca.2011.12.068 | s2cid = 24094780 | url = https://zenodo.org/record/1038611 }}</ref>

600px|center

:Schematic overview of the flavan-3-ol (–)-epicatechin biosynthesis from tyrosine (Tyr) or phenylalanine (Phe) in plants. Enzymes are indicated in blue, abbreviated as follows: ::{{collist|{{unbulleted list |E1: phenylalanine ammonia lyase |E2: tyrosine ammonia lyase |E3: cinnamate 4-hydroxylase |E4: 4-coumaroyl:CoA-ligase |E5: chalcone synthase (naringenin-chalcone synthase) |E6: chalcone isomerase |E7: flavonoid 3′-hydroxylase |E8: flavanone 3-hydroxylase |E9: dihydroflavanol 4-reductase |E10: anthocyanidin synthase (leucoanthocyanidin dioxygenase) |E11: anthocyanidin reductase }}}}

=== Aglycones === {| class="wikitable sortable" |+ Flavan-3-ols ! Image!!Name!!Formula!!Oligomers |- | 100px|(+)-Catechin || Catechin, C, (+)-Catechin || C15H14O6 || Procyanidins |- | 100px|Epicatechin || Epicatechin, EC, (–)-Epicatechin (''cis'') || C15H14O6 || Procyanidins |- | 100px|Epigallocatechin || Epigallocatechin, EGC || C15H14O7 || Prodelphinidins |- | 100px|Epicatechin gallate || Epicatechin gallate, ECG || C22H18O10 || |- | 100px|Epigallocatechin gallate || Epigallocatechin gallate, EGCG, (–)-Epigallocatechin gallate || C22H18O11 || |- | 100px|Epiafzelechin || Epiafzelechin || C15H14O5 || |- | 100px|Fisetinidol || Fisetinidol || C15H14O5 || |- | 100px|Guibourtinidol || Guibourtinidol || C15H14O4 || Proguibourtinidins |- | 100px|Mesquitol || Mesquitol || C15H14O6 || |- | 100px|Robinetinidol || Robinetinidol || C15H14O6 || Prorobinetinidins |}

== Dietary sources == {{see also|Polyphenols in tea|Polyphenols in wine|Cocoa bean#Phytochemicals and research}} right|thumb|Reported range of flavan-3-ol content in foods commonly consumed.<ref name=":3">{{cite web|publisher=Phenol Explorer|title=Database on polyphenol content in foods, v3.6|url=http://phenol-explorer.eu/|date=2016}}</ref> Flavan-3-ols are abundant in teas derived from the tea plant ''Camellia sinensis'', in particular green tea. Apart from tea, main sources in the human diet are pome fruits and berries and their products such as juices or wine.<ref name=":3" /> Their content in food is highly variable and affected by various factors, such as cultivar, processing and preparation.<ref name=":2">{{cite journal | vauthors = Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L | title = Polyphenols: food sources and bioavailability | journal = The American Journal of Clinical Nutrition | volume = 79 | issue = 5 | pages = 727–747 | date = May 2004 | pmid = 15113710 | doi = 10.1093/ajcn/79.5.727 | doi-access = free }}</ref> While cocoa beans (the seeds of ''Theobroma cacao'') contain high amounts of flavan-3-ols, these are largely destroyed during processing and the flavanol content in cocoa products such as chocolate is usually very low.<ref name="Hammerstone_2000">{{cite journal | vauthors = Hammerstone JF, Lazarus SA, Schmitz HH | title = Procyanidin content and variation in some commonly consumed foods | journal = The Journal of Nutrition | volume = 130 | issue = 8 Suppl. | pages = 2086S–2092S | date = August 2000 | pmid = 10917927 | doi = 10.1093/jn/130.8.2086S | doi-access = free }}</ref><ref name="Payne_2010">{{cite journal | vauthors = Payne MJ, Hurst WJ, Miller KB, Rank C, Stuart DA | title = Impact of fermentation, drying, roasting, and Dutch processing on epicatechin and catechin content of cacao beans and cocoa ingredients | journal = Journal of Agricultural and Food Chemistry | volume = 58 | issue = 19 | pages = 10518–10527 | date = October 2010 | pmid = 20843086 | doi = 10.1021/jf102391q }}</ref> The bioavailability can be affected by nutrient-nutrient interactions with foods containing polyphenol oxidase.

== Bioavailability and metabolism==

The bioavailability of flavan-3-ols depends on the food matrix, type of compound and their stereochemical configuration.<ref name=":1">{{cite journal | vauthors = Del Río D, Rodríguez Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A | title = Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases | journal = Antioxidants & Redox Signaling | volume = 18 | issue = 14 | pages = 1818–1892 | date = May 2013 | pmid = 22794138 | doi = 10.1089/ars.2012.4581 | pmc = 3619154 }}</ref> While monomeric flavan-3-ols are readily taken up, oligomeric forms are not absorbed.<ref name=":1" /><ref>{{cite journal | vauthors = Rodríguez Mateos A, Weber T, Skene SS, Ottaviani JI, Crozier A, Kelm M, Schroeter H, Heiss C | display-authors = 6 | title = Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial | journal = The American Journal of Clinical Nutrition | volume = 108 | issue = 6 | pages = 1229–1237 | date = December 2018 | pmid = 30358831 | pmc = 6290365 | doi = 10.1093/ajcn/nqy229 }}</ref> Most data for human metabolism of flavan-3-ols are available for monomeric compounds, especially epiatechin. These compounds are taken up and metabolized upon uptake in the jejunum,<ref>{{cite journal | vauthors = Actis-Goretta L, Lévèques A, Rein M, Teml A, Schäfer C, Hofmann U, Li H, Schwab M, Eichelbaum M, Williamson G | display-authors = 6 | title = Intestinal absorption, metabolism, and excretion of (−)-epicatechin in healthy humans assessed by using an intestinal perfusion technique | journal = The American Journal of Clinical Nutrition | volume = 98 | issue = 4 | pages = 924–933 | date = October 2013 | pmid = 23864538 | doi = 10.3945/ajcn.113.065789 | doi-access = free }}</ref> mainly by ''O''-methylation and glucuronidation,<ref>{{cite journal | vauthors = Kuhnle G, Spencer JP, Schroeter H, Shenoy B, Debnam ES, Srai SK, Rice-Evans C, Hahn U | display-authors = 6 | title = Epicatechin and catechin are ''O''-methylated and glucuronidated in the small intestine | journal = Biochemical and Biophysical Research Communications | volume = 277 | issue = 2 | pages = 507–512 | date = October 2000 | pmid = 11032751 | doi = 10.1006/bbrc.2000.3701 }}</ref> and then further metabolized by the liver. The colonic microbiome also has a role in the metabolism of flavan-3-ols, which are catabolized to smaller compounds, such as 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones and hippuric acid.<ref>{{cite journal | vauthors = Das NP | title = Studies on flavonoid metabolism. Absorption and metabolism of (+)-catechin in man | journal = Biochemical Pharmacology | volume = 20 | issue = 12 | pages = 3435–3445 | date = December 1971 | pmid = 5132890 | doi = 10.1016/0006-2952(71)90449-7 }}</ref><ref name=":0" /> Only flavan-3-ols with an intact (epi)catechin moiety can be metabolized into 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones (image in Gallery).<ref name="Ottaviani 9859"/>

==Possible adverse effects== As catechins, in particular epigallocatechin gallate, in green tea extract can be hepatotoxic, Health Canada and EFSA have advised for caution,<ref>{{Cite web | author = Health Canada |title=Summary Safety Review – Green tea extract-containing natural health products – Assessing the potential risk of liver injury (hepatotoxicity) |url=https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/green-tea-extract-containing-natural-health-products-assessing-potential-risk-liver-injury.html |access-date=2022-05-06 |publisher=Health Canada, Government of Canada|date=12 December 2017}}</ref> recommending intake from supplements should not exceed 800 milligrams (mg) per day.<ref>{{cite journal | vauthors = Younes M, Aggett P, Aguilar F, Crebelli R, Dusemund B, Filipič M, Frutos MJ, Galtier P, Gott D, Gundert-Remy U, Lambré C, Leblanc JC, Lillegaard IT, Moldeus P, Mortensen A, Oskarsson A, Stankovic I, Waalkens-Berendsen I, Woutersen RA, Andrade RJ, Fortes C, Mosesso P, Restani P, Arcella D, Pizzo F, Smeraldi C, Wright M | display-authors = 6 | title = Scientific opinion on the safety of green tea catechins | journal = EFSA Journal | volume = 16 | issue = 4 | pages = e05239 | date = April 2018 | pmid = 32625874 | pmc = 7009618 | doi = 10.2903/j.efsa.2018.5239 }}</ref>

==Research== {{See also|Cocoa bean#Phytochemicals and research}} Research has shown that flavan-3-ols may affect vascular function, blood pressure, and blood lipids, with only minor effects demonstrated, as of 2019.<ref>{{cite journal | vauthors = Ried K, Fakler P, Stocks NP | title = Effect of cocoa on blood pressure | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 5 | article-number = CD008893 | date = April 2017 | pmid = 28439881 | pmc = 6478304 | doi = 10.1002/14651858.CD008893.pub3 | collaboration = Cochrane Hypertension Group }}</ref><ref name="raman">{{cite journal | vauthors = Raman G, Avendano EE, Chen S, Wang J, Matson J, Gayer B, Novotny JA, Cassidy A | display-authors = 3 | title = Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies | journal = The American Journal of Clinical Nutrition | volume = 110 | issue = 5 | pages = 1067–1078 | date = November 2019 | pmid = 31504087 | pmc = 6821550 | doi = 10.1093/ajcn/nqz178 }}</ref>

As of 2022, food-based evidence indicates that intake of 400–600 mg per day of flavan-3-ols – up to twice the normal dietary intake of flavanols by European adults – could have a small positive effect on cardiovascular biomarkers.<ref>{{cite journal |display-authors=3 |last1=Crowe-White |first1=Kristi M |last2=Evans |first2=Levi W |last3=Kuhnle |first3=Gunter G C |last4=Milenkovic |first4=Dragan |last5=Stote |first5=Kim |last6=Wallace |first6=Taylor |last7=Handu |first7=Deepa |last8=Senkus |first8=Katelyn E |title=Flavan-3-ols and cardiometabolic health: First ever dietary bioactive guideline |journal=Advances in Nutrition |date=3 October 2022 |volume=13 |issue=6 |pages=2070–2083 |doi=10.1093/advances/nmac105|pmid=36190328 |pmc=9776652 |doi-access=free }}</ref>

==Regulation== In 2015, the European Commission approved a health claim for cocoa flavanols, stating that an intake of 200 mg per day "may contribute to maintenance of vascular elasticity and normal blood flow".<ref name="EC-cocoa">{{cite web |title=Article 13(5): Cocoa flavanols; Search filters: Claim status - authorised; search - flavanols |url=https://ec.europa.eu/food/safety/labelling_nutrition/claims/register/public/?event=search |publisher=European Commission, EU Register |access-date=8 September 2022 |date=31 March 2015}}</ref><ref name="efsa2014">{{Cite journal|title=Scientific Opinion on the modification of the authorisation of a health claim related to cocoa flavanols and maintenance of normal endothelium-dependent vasodilation pursuant to Article 13(5) of Regulation (EC) No 1924/20061 following a request in accordance with Article 19 of Regulation (EC) No 1924/2006|journal = EFSA Journal|volume = 12|issue = 5|date=2014|doi=10.2903/j.efsa.2014.3654|doi-access=free|url= https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2014.3654}}</ref>

In 2023, the US Food and Drug Administration assessed a health claim for consuming 200 mg per day of cocoa powder flavanols, stating in a letter of enforcement discretion that "there is very limited credible scientific evidence for a qualified health claim for cocoa flavanols in high flavanol cocoa powder and a reduced risk of cardiovascular disease".<ref>{{Cite web |publisher=US Food and Drug Administration |date=3 February 2023 |title=FDA Announces Qualified Health Claim for Cocoa Flavanols in High Flavanol Cocoa Powder and Reduced Risk of Cardiovascular Disease: Constituent Update|url=https://www.fda.gov/food/hfp-constituent-updates/fda-announces-qualified-health-claim-cocoa-flavanols-high-flavanol-cocoa-powder-and-reduced-risk|access-date=29 May 2026}}</ref> Reasons for this assessment included a small number of credible studies, questionable methodology, inadequate number of subjects, short study duration, and poor replication and inconsistency of results.<ref name="letter">{{cite web |last=Kavanaugh |first=CS |title=FDA Letter of Enforcement Discretion on a Petition for a Qualified Health Claim for Cocoa Flavanols and Reduced Risk of Cardiovascular Disease (Docket No. FDA-2019-Q-0806) |url=https://www.fda.gov/media/165090/download?attachment |publisher=Office of Nutrition Food Labeling, Center for Food Safety and Applied Nutrition, US Food and Drug Administration |access-date=29 May 2026 |date=1 February 2023}}</ref>

The letter of enforcement discretion further stated that the evidence "does not support the establishment of a daily intake of 200 mg of cocoa flavanols or any other daily dietary intake recommendation levels for the general U.S. population."<ref name=letter/>

==Gallery== <gallery> File:Schematic representation of (−)-epicatechin metabolism in humans as a function of time post-oral intake.jpg|Schematic representation of the flavan-3-ol (−)-epicatechin metabolism in humans as a function of time post-oral intake. SREM: structurally related (−)-epicatechin metabolites. 5C-RFM: 5-carbon ring fission metabolites. 3/1C-RFM: 3- and 1-carbon-side chain ring fission metabolites. The structures of the most abundant (−)-epicatechin metabolites present in the systemic circulation and in urine are depicted.<ref name=":0">{{cite journal | vauthors = Ottaviani JI, Borges G, Momma TY, Spencer JP, Keen CL, Crozier A, Schroeter H|display-authors=3 | title = The metabolome of [2-14C](−)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives | language = En | journal = Scientific Reports | volume = 6 | issue = 1 | article-number = 29034 | date = July 2016 | pmid = 27363516 | pmc = 4929566 | doi = 10.1038/srep29034 | bibcode = 2016NatSR...629034O }}</ref> File:Flavan-3-ol precursors of the microbial metabolite 5-(3′-4′-dihydroxyphenyl)-γ-valerolactone.jpg|Flavan-3-ol precursors of the microbial metabolite 5-(3′/4′-dihydroxyphenyl)-γ-valerolactone (γVL). Only compounds with intact (epi)catechin moiety result in the formation of γVL by the intestinal microbiome. ECG, (−)-epicatechin-3-''O''-gallate; EGCG, Epigallocatechin gallate; EGC, Epigallocatechin.<ref name="Ottaviani 9859">{{cite journal | vauthors = Ottaviani JI, Fong R, Kimball J, Ensunsa JL, Britten A, Lucarelli D, Luben R, Grace PB, Mawson DH, Tym A, Wierzbicki A, Khaw KT, Schroeter H, Kuhnle GG | display-authors = 6 | title = Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies | language = En | journal = Scientific Reports | volume = 8 | issue = 1 | page = 9859 | date = June 2018 | pmid = 29959422 | pmc = 6026136 | doi = 10.1038/s41598-018-28333-w | bibcode = 2018NatSR...8.9859O }}</ref> </gallery>

== References == {{Reflist}}

== External links == *{{Commons category-inline}}

{{DEFAULTSORT:Flavan-3-Ol}} * Category:Nutrition Category:Phytochemicals Category:Polyphenols Category:Flavonoids