Flavan-3-ol

Flavan-3-ols (sometimes referred to as flavanols) are derivatives of flavans that possess a 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton. These compounds include catechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, proanthocyanidins, theaflavins, thearubigins.

Not to be confused with Flavonol.
Chemical structure of flavan-3-ol
Epicatechin (EC)
Epigallocatechin (EGC)

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).[1]

Flavanols possess two chiral carbons, meaning four diastereoisomers occur for each of them.

Catechins 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 absence of ketone(s). Catechin monomers, dimers, and trimers (oligomers) are colorless. Higher order polymers, anthocyanidins, exhibit deepening reds and become tannins.[1]

Sources of catechins
Main articles: Polyphenols in tea and Polyphenols in wine
See also: Cocoa bean § Health_benefits

The catechins are abundant in teas derived from the tea plant Camellia sinensis, as well as in some cocoas and chocolates[2] (made from the seeds of Theobroma cacao). Catechins are also present in the human diet in fruits, vegetables and wine,[3] and are found in many other plant species.[4][5]

Catechin and the gallates

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.

Metabolism of flavan-3-ols

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. These enzyme do not use ACPSs, but instead employ coenzyme A esters and have a single active site to perform the necessary series of reactions, e.g. 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.[6][7]

Figure 1

Figure 1:Schematic overview of the flavan-3-ol (-)-epicatechin biosynthesis in plants: Enzymes are indicated in blue, abbreviated as follows: 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. HSCoA, Coenzyme A. L-Tyr, L-tyrosine, L-Phe, L-phenylalanine.

Metabolism in humans
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.[8]
Flavan-3-ol precursors of the microbial metabolite 5-(3′/4′-dihydroxyphenyl)-γ-valerolactone (gVL). 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[9]

Most data for human metabolism of flavan-3-ols are available for monomeric compounds, especially Catechin. These compounds are taken up and metabolised upon uptake in the jejunum,[10] mainly by O-methylation and glucuronidation,[11] and then further metabolised by the liver. The colonic microbiome has also an important role in the metabolism of flavan-3-ols and they are catabolised to smaller compounds such as 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones and hippuric acid.[12][8] Only flavan-3-ols with an intact (epi)catechin moiety can be metabolised 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones.[9]

Research and health claims
Main articles: Tea and health, Wine and health, and Cocoa bean § Phytochemicals and research

Potential health effects of long-term consumption of flavan-3-ols under study include decreased levels of blood lipids[13] and a minor effect on blood pressure (2 mmHg) when flavan-3-ols were consumed (about 55 mg of epicatechin per day) over 9 weeks.[14] A 2019 review provided moderate-quality evidence that long-term dietary intake of flavan-3-ols may reduce the risk of cardiovascular diseases,[13] a topic remaining under preliminary research as of 2022.[15]

Until 2013, neither the Food and Drug Administration nor the European Food Safety Authority had approved any health claim for catechins or approved any as pharmaceutical drugs.[16][17][18] Moreover, several companies have been cautioned by the FDA over misleading health claims.[19][20]

In 2014, the European Food Safety Authority approved the following health claim for cocoa products containing 200 mg of flavanols and meeting the qualification in dietary supplement products: "cocoa flavanols help maintain the elasticity of blood vessels, which contributes to normal blood flow".[21]

Aglycones
Flavan-3-ols
ImageNameFormulaOligomers
Catechin, C, (+)-CatechinC15H14O6Procyanidins
Epicatechin, EC, (-)-Epicatechin (cis)C15H14O6Procyanidins
Epigallocatechin, EGCC15H14O7Prodelphinidins
Epicatechin gallate, ECGC22H18O10
Epigallocatechin gallate, EGCG,
(-)-Epigallocatechin gallate		C22H18O11
EpiafzelechinC15H14O5
FisetinidolC15H14O5
GuibourtinidolC15H14O4Proguibourtinidins
MesquitolC15H14O6
RobinetinidolC15H14O6Prorobinetinidins

Analysis

Fluorescence-lifetime imaging microscopy (FLIM) can be used to detect flavanols in plant cells[22]

Other uses

Recent study tested catechins employed to coat nanoparticles of iron oxides in the blood. These particles allow visualization of vessels – and especially cancer tumors in mice – in an MRI exam. The nanoparticles would clump together without the catechin coating.[23]

References
  1. Schwitters B, Masquelier J (1995). OPC in Practice (3rd ed.). OCLC 45289285.
  2. Hammerstone JF, Lazarus SA, Schmitz HH (August 2000). "Procyanidin content and variation in some commonly consumed foods". The Journal of Nutrition. 130 (8S Suppl): 2086S–2092S. doi:10.1093/jn/130.8.2086S. PMID 10917927.
  3. Ruidavets J, Teissedre P, Ferrières J, Carando S, Bougard G, Cabanis J (November 2000). "Catechin in the Mediterranean diet: vegetable, fruit or wine?". Atherosclerosis. 153 (1): 107–117. doi:10.1016/S0021-9150(00)00377-4. PMID 11058705.
  4. BBC News | Health | Chocolate 'has health benefits'
  5. Mabrym H, Harborne JB, Mabry TJ (1975). The Flavonoids. London: Chapman and Hall. ISBN 978-0-412-11960-6.
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  8. Ottaviani JI, Borges G, Momma TY, Spencer JP, Keen CL, Crozier A, Schroeter H (July 2016). "The metabolome of [2-(14)C](-)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives". Scientific Reports. 6 (1): 29034. doi:10.1038/srep29034. PMC 4929566. PMID 27363516.
  9. Ottaviani JI, Fong R, Kimball J, Ensunsa JL, Britten A, Lucarelli D, et al. (June 2018). "Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies". Scientific Reports. 8 (1): 9859. doi:10.1038/s41598-018-28333-w. PMC 6026136. PMID 29959422.
  10. Actis-Goretta L, Lévèques A, Rein M, Teml A, Schäfer C, Hofmann U, et al. (October 2013). "Intestinal absorption, metabolism, and excretion of (-)-epicatechin in healthy humans assessed by using an intestinal perfusion technique". The American Journal of Clinical Nutrition. 98 (4): 924–933. doi:10.3945/ajcn.113.065789. PMID 23864538.
  11. Kuhnle G, Spencer JP, Schroeter H, Shenoy B, Debnam ES, Srai SK, et al. (October 2000). "Epicatechin and catechin are O-methylated and glucuronidated in the small intestine". Biochemical and Biophysical Research Communications. 277 (2): 507–512. doi:10.1006/bbrc.2000.3701. PMID 11032751.
  12. Das NP (December 1971). "Studies on flavonoid metabolism. Absorption and metabolism of (+)-catechin in man". Biochemical Pharmacology. 20 (12): 3435–3445. doi:10.1016/0006-2952(71)90449-7. PMID 5132890.
  13. Raman G, Avendano EE, Chen S, Wang J, Matson J, Gayer B, et al. (November 2019). "Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies". The American Journal of Clinical Nutrition. 110 (5): 1067–1078. doi:10.1093/ajcn/nqz178. PMC 6821550. PMID 31504087.
  14. Ried, Karin; Fakler, Peter; Stocks, Nigel P (2017-04-25). Cochrane Hypertension Group (ed.). "Effect of cocoa on blood pressure". Cochrane Database of Systematic Reviews. 2017 (5). doi:10.1002/14651858.CD008893.pub3. PMC 6478304. PMID 28439881.
  15. Sesso, Howard D; Manson, JoAnn E; Aragaki, Aaron K; Rist, Pamela M; et al. (2022-03-16). "Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial". American Journal of Clinical Nutrition: nqac055. doi:10.1093/ajcn/nqac055. ISSN 0002-9165. PMID 35294962.
  16. "FDA approved drug products". US Food and Drug Administration. Retrieved 1 November 2014.
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  19. "Inspections, Compliance, Enforcement, and Criminal Investigations (Flavonoid Sciences)". US Food and Drug Administration. Retrieved 1 November 2014.
  20. "Inspections, Compliance, Enforcement, and Criminal Investigations (Unilever, Inc.)". US Food and Drug Administration. Retrieved 31 October 2014.
  21. "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". EFSA Journal. 12 (5). 2014. doi:10.2903/j.efsa.2014.3654.
  22. Mueller-Harvey I, Feucht W, Polster J, Trnková L, Burgos P, Parker AW, Botchway SW (March 2012). "Two-photon excitation with pico-second fluorescence lifetime imaging to detect nuclear association of flavanols". Analytica Chimica Acta. 719: 68–75. doi:10.1016/j.aca.2011.12.068. PMID 22340533.
  23. Xiao L, Mertens M, Wortmann L, Kremer S, Valldor M, Lammers T, et al. (April 2015). "Enhanced in vitro and in vivo cellular imaging with green tea coated water-soluble iron oxide nanocrystals". ACS Applied Materials & Interfaces. 7 (12): 6530–6540. doi:10.1021/am508404t. PMID 25729881.
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