flavan-3-ol#Other uses

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).{{cite book |title=OPC in Practice |vauthors=Schwitters B, Masquelier J |date=1995 |edition=3rd |oclc=45289285}}

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 ketonse. Catechin monomers, dimers, and trimers (oligomers) are colorless. Higher order polymers, anthocyanidins, exhibit deepening reds and become tannins.

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.

File:Catechin molecule file.png

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. These enzymes do not use ACPSs, but instead employ 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.{{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 }}{{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 }} Fluorescence-lifetime imaging microscopy (FLIM) can be used to detect flavanols in plant cells.{{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 }}

File:Epicatechin Biosynthesis-2.png

:Figure 1: 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 (PAL)

|E2: tyrosine ammonia lyase (TAL)

|E3: cinnamate 4-hydroxylase

|E4: 4-coumaroyl:CoA-ligase

|E5: chalcone synthase (naringenin-chalcone synthase)

|E6: chalcone isomerase

|E7: flavonoid 3′-hydroxylase

|E8: flavonone 3-hydroxylase

|E9: dihydroflavanol 4-reductase

|E10: anthocyanidin synthase (leucoanthocyanidin dioxygenase)

|E11: anthocyanidin reductase

}}}}

{{see also|Polyphenols in tea|Polyphenols in wine|Cocoa bean#Phytochemicals and research}}

File:Variability of flavan-3-ol content in foods.png

Flavan-3-ols are abundant in teas derived from the tea plant Camellia sinensis, as well as in some cocoas (made from the seeds of Theobroma cacao), although the content is affected considerably by processing, especially in chocolate.{{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 }}{{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 }} Flavan-3-ols are also present in the human diet in fruits, in particular pome fruits, berries, vegetables, and wine.{{cite book | vauthors = Mabrym H, Harborne JB, Mabry TJ |title=The Flavonoids |publisher=Chapman and Hall |location=London |year=1975 |isbn=978-0-412-11960-6 }} Their content in food is variable and affected by various factors, such as cultivar, processing, and preparation.{{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 }}

The bioavailability of flavan-3-ols depends on the food matrix, type of compound and their stereochemical configuration.{{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 }} While monomeric flavan-3-ols are readily taken up, oligomeric forms are not absorbed.{{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 }} 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,{{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 }} mainly by O-methylation and glucuronidation,{{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 }} and then further metabolized by the liver. The colonic microbiome has also an important role in the metabolism of flavan-3-ols and they are catabolized to smaller compounds such as 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones and hippuric acid.{{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 }} Only flavan-3-ols with an intact (epi)catechin moiety can be metabolized into 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones (image in Gallery).

As catechins in green tea extract can be hepatotoxic, Health Canada and EFSA have advised for caution,{{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}} recommending intake should not exceed 800 mg per day.{{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 }}

{{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.{{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 | pages = CD008893 | date = April 2017 | pmid = 28439881 | pmc = 6478304 | doi = 10.1002/14651858.CD008893.pub3 | collaboration = Cochrane Hypertension Group }}{{cite journal | vauthors = Raman G, Avendano EE, Chen S, Wang J, Matson J, Gayer B, Novotny JA, Cassidy A | display-authors = 6 | 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 }} In 2015, the European Commission approved a health claim for cocoa solids containing 200 mg of flavanols, stating that such intake "may contribute to maintenance of vascular elasticity and normal blood flow".{{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}}{{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}} As of 2022, food-based evidence indicates that intake of 400–600 mg per day of flavan-3-ols could have a small positive effect on cardiovascular biomarkers.{{cite journal |name-list-style=vanc |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 | url=https://academic.oup.com/advances/article/13/6/2070/6747118|doi-access=free }}

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.{{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 | pages = 29034 | date = July 2016 | pmid = 27363516 | pmc = 4929566 | doi = 10.1038/srep29034 | bibcode = 2016NatSR...629034O }}

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.{{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 | pages = 9859 | date = June 2018 | pmid = 29959422 | pmc = 6026136 | doi = 10.1038/s41598-018-28333-w | bibcode = 2018NatSR...8.9859O }}

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