Chemistry:Flavan-3-ol

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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-2H-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.[1]

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).[2]

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.[2]

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.[3]

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.[citation needed] 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.[4][5] Fluorescence-lifetime imaging microscopy can be used to detect flavanols in plant cells.[6]

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:
  • 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

Flavan-3-ols
Image Name Formula Oligomers
(+)-Catechin Catechin, C, (+)-Catechin C15H14O6 Procyanidins
Epicatechin Epicatechin, EC, (–)-Epicatechin (cis) C15H14O6 Procyanidins
Epigallocatechin Epigallocatechin, EGC C15H14O7 Prodelphinidins
Epicatechin gallate Epicatechin gallate, ECG C22H18O10
Epigallocatechin gallate Epigallocatechin gallate, EGCG,
(–)-Epigallocatechin gallate		 C22H18O11
Epiafzelechin Epiafzelechin C15H14O5
Fisetinidol Fisetinidol C15H14O5
Guibourtinidol Guibourtinidol C15H14O4 Proguibourtinidins
Mesquitol Mesquitol C15H14O6
Robinetinidol Robinetinidol C15H14O6 Prorobinetinidins

Dietary sources

Reported range of flavan-3-ol content in foods commonly consumed.[7]

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.[7] Their content in food is highly variable and affected by various factors, such as cultivar, processing and preparation.[8] 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.[9][10] 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.[3] While monomeric flavan-3-ols are readily taken up, oligomeric forms are not absorbed.[3][11] 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,[12] mainly by O-methylation and glucuronidation,[13] 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.[14][15] Only flavan-3-ols with an intact (epi)catechin moiety can be metabolized into 5-(3′/4′-dihydroxyphenyl)-γ-valerolactones (image in Gallery).[16]

Possible adverse effects

As catechins, in particular epigallocatechin gallate, in green tea extract can be hepatotoxic, Health Canada and EFSA have advised for caution,[17] recommending intake from supplements should not exceed 800 milligrams (mg) per day.[18]

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.[19][20]

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.[21]

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".[22][23]

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".[24] 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.[25]

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."[25]

  • 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.[15]
    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.[15]
  • 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.[16]
    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.[16]

References

  1. ↑ "Flavan-3-ols Are an Effective Chemical Defense against Rust Infection". Plant Physiology 175 (4): 1560–1578. December 2017. doi:10.1104/pp.17.00842. PMID 29070515. 
  2. ↑ 2.0 2.1 OPC in Practice (3rd ed.). 1995. OCLC 45289285. 
  3. ↑ 3.0 3.1 3.2 "Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases". Antioxidants & Redox Signaling 18 (14): 1818–1892. May 2013. doi:10.1089/ars.2012.4581. PMID 22794138. 
  4. ↑ Medicinal Natural Products: A biosynthetic approach. John Wiley & Sons. 2009. p. 168. ISBN 978-0-471-49641-0. 
  5. ↑ "Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology". Plant Physiology 126 (2): 485–493. June 2001. doi:10.1104/pp.126.2.485. PMID 11402179. 
  6. ↑ "Two-photon excitation with pico-second fluorescence lifetime imaging to detect nuclear association of flavanols". Analytica Chimica Acta 719: 68–75. March 2012. doi:10.1016/j.aca.2011.12.068. PMID 22340533. https://zenodo.org/record/1038611. 
  7. ↑ 7.0 7.1 "Database on polyphenol content in foods, v3.6". Phenol Explorer. 2016. http://phenol-explorer.eu/. 
  8. ↑ "Polyphenols: food sources and bioavailability". The American Journal of Clinical Nutrition 79 (5): 727–747. May 2004. doi:10.1093/ajcn/79.5.727. PMID 15113710. 
  9. ↑ "Procyanidin content and variation in some commonly consumed foods". The Journal of Nutrition 130 (8 Suppl.): 2086S–2092S. August 2000. doi:10.1093/jn/130.8.2086S. PMID 10917927. 
  10. ↑ "Impact of fermentation, drying, roasting, and Dutch processing on epicatechin and catechin content of cacao beans and cocoa ingredients". Journal of Agricultural and Food Chemistry 58 (19): 10518–10527. October 2010. doi:10.1021/jf102391q. PMID 20843086. 
  11. ↑ "Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial". The American Journal of Clinical Nutrition 108 (6): 1229–1237. December 2018. doi:10.1093/ajcn/nqy229. PMID 30358831. 
  12. ↑ "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. October 2013. doi:10.3945/ajcn.113.065789. PMID 23864538. 
  13. ↑ "Epicatechin and catechin are O-methylated and glucuronidated in the small intestine". Biochemical and Biophysical Research Communications 277 (2): 507–512. October 2000. doi:10.1006/bbrc.2000.3701. PMID 11032751. 
  14. ↑ "Studies on flavonoid metabolism. Absorption and metabolism of (+)-catechin in man". Biochemical Pharmacology 20 (12): 3435–3445. December 1971. doi:10.1016/0006-2952(71)90449-7. PMID 5132890. 
  15. ↑ 15.0 15.1 "The metabolome of [2-14C(−)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives"] (in En). Scientific Reports 6 (1). July 2016. doi:10.1038/srep29034. PMID 27363516. Bibcode: 2016NatSR...629034O. 
  16. ↑ 16.0 16.1 "Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies" (in En). Scientific Reports 8 (1): 9859. June 2018. doi:10.1038/s41598-018-28333-w. PMID 29959422. Bibcode: 2018NatSR...8.9859O. 
  17. ↑ Health Canada (12 December 2017). "Summary Safety Review – Green tea extract-containing natural health products – Assessing the potential risk of liver injury (hepatotoxicity)". Health Canada, Government of Canada. 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. 
  18. ↑ "Scientific opinion on the safety of green tea catechins". EFSA Journal 16 (4): e05239. April 2018. doi:10.2903/j.efsa.2018.5239. PMID 32625874. 
  19. ↑ "Effect of cocoa on blood pressure". The Cochrane Database of Systematic Reviews 4 (5). April 2017. doi:10.1002/14651858.CD008893.pub3. PMID 28439881. 
  20. ↑ "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. November 2019. doi:10.1093/ajcn/nqz178. PMID 31504087. 
  21. ↑ Crowe-White, Kristi M; Evans, Levi W; Kuhnle, Gunter G C et al. (3 October 2022). "Flavan-3-ols and cardiometabolic health: First ever dietary bioactive guideline". Advances in Nutrition 13 (6): 2070–2083. doi:10.1093/advances/nmac105. PMID 36190328. 
  22. ↑ "Article 13(5): Cocoa flavanols; Search filters: Claim status - authorised; search - flavanols". European Commission, EU Register. 31 March 2015. https://ec.europa.eu/food/safety/labelling_nutrition/claims/register/public/?event=search. 
  23. ↑ "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. https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2014.3654. 
  24. ↑ "FDA Announces Qualified Health Claim for Cocoa Flavanols in High Flavanol Cocoa Powder and Reduced Risk of Cardiovascular Disease: Constituent Update". US Food and Drug Administration. 3 February 2023. https://www.fda.gov/food/hfp-constituent-updates/fda-announces-qualified-health-claim-cocoa-flavanols-high-flavanol-cocoa-powder-and-reduced-risk. 
  25. ↑ 25.0 25.1 Kavanaugh, CS (1 February 2023). "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)". Office of Nutrition Food Labeling, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. https://www.fda.gov/media/165090/download?attachment. 

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