Flavan-3-ol
Category of polyphenol compound
From Wikipedia, the free encyclopedia
Flavan-3-ols (sometimes referred to as flavanols) are a subgroup of flavonoids.[1] They are derivatives of flavans, are structurally diverse, and include compounds such as catechins (e.g. epigallocatechin gallate), epicatechin gallate, proanthocyanidins, theaflavins, and thearubigins.[1]
Present in tea leaves, berries, apples, cocoa beans, and grapes, they participate in diverse plant functions, including regulation of cell growth, attraction of pollinating insects, and defense against environmental stress.[1][2]
Chemical structure
Flavanols exist both as monomers (catechins) and as polymers (proanthocyanidins).[2] The single-molecule (monomer) catechin, or isomer epicatechin (see diagram), adds four hydroxyls to flavan-3-ol, making building blocks for polymers (proanthocyanidins) and higher order polymers (anthocyanidins).[1][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 quercetin.[1] Catechin monomers, dimers, and trimers (oligomers) are colorless, while higher order polymers, anthocyanidins, exhibit deepening reds and become tannins.[1][2]
Catechin and epicatechin are epimers, with (–)-epicatechin and (+)-catechin being the most common optical isomers of flavanols found in nature.[2] Catechin was first isolated from the plant extract, catechu, from which it derives its name.[3]
Epigallocatechin and gallocatechin contain an additional phenolic hydroxyl group when compared to epicatechin and catechin, respectively.[1]
Catechin gallates are gallic acid esters of the catechins; an example is epigallocatechin gallate, the most abundant catechin in tea.[1][2] Proanthocyanidins and thearubigins are also in the flavan-3-ol subclass.[2]
In contrast to many other flavonoids, flavan-3-ols do not generally exist as glycosides in plants.[2]
Biosynthesis of (–)-epicatechin
The flavonoids are derived from phenylalanine and malonyl-coenzyme A in reactions catalyzed by polyketide synthase.[4] Chain extension of 4-hydroxycinnamoyl-CoA with three molecules of malonyl-CoA gives initially a polyketide (figure), which can be folded, allowing Claisen-like reactions to occur, generating aromatic rings.[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
| Image | Name | Formula | Oligomers |
|---|---|---|---|
-Catechin.svg) | Catechin, C, (+)-Catechin | C15H14O6 | Procyanidins |
-Epicatechin.svg) | Epicatechin, EC, (–)-Epicatechin (cis) | C15H14O6 | Procyanidins |
 | Epigallocatechin, EGC | C15H14O7 | Prodelphinidins |
 | Epicatechin gallate, ECG | C22H18O10 | |
 | Epigallocatechin gallate, EGCG, (–)-Epigallocatechin gallate | C22H18O11 | |
 | Epiafzelechin | C15H14O5 | |
 | Fisetinidol | C15H14O5 | |
 | Guibourtinidol | C15H14O4 | Proguibourtinidins |
 | Mesquitol | C15H14O6 | |
 | Robinetinidol | C15H14O6 | Prorobinetinidins |
Dietary sources
Flavan-3-ols are abundant in teas derived from the tea plant Camellia sinensis, in particular green tea.[1] Apart from tea, main sources in the human diet are chocolate, pome fruits, and berries and their products, such as juices or red wine.[1][7] Their content in food is highly variable and affected by various factors, such as cultivar, processing and preparation.[2] Tea extracts are sold as dietary supplements labeled as tea catechins or tea polyphenols.[1] Green tea extracts typically have higher levels of catechins, while black tea extracts have high levels of theaflavins and thearubigins.[1]
While cocoa beans (the seeds of Theobroma cacao) contain flavan-3-ols, these are susceptible to heat degradation during processing, causing the flavanol content in cocoa products, such as chocolate, to be relatively low.[1][8][9] The bioavailability can be affected by nutrient-nutrient interactions with foods containing polyphenol oxidase.[2]
Bioavailability and metabolism
The bioavailability of flavan-3-ols depends on the food matrix, type of compound and their stereochemical configuration.[1][2] While monomeric flavan-3-ols are readily taken up, oligomeric forms are not absorbed.[2] Most data for human metabolism of flavan-3-ols are available for monomeric compounds, especially epicatechin. These compounds are taken up and metabolized upon uptake in the small intestine,[1][2] mainly by O-methylation and glucuronidation,[10] 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.[1][2]
Possible adverse effects
As catechins, in particular epigallocatechin gallate, in green tea extract can be hepatotoxic, Health Canada and EFSA have advised for caution,[11] recommending intake from supplements should not exceed 800 milligrams (mg) per day.[12]
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.[13][14]
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.[15]
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".[16][17]
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".[18] 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.[19]
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."[19]
Gallery
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.[20]
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.[21]
-epicatechin_metabolism_in_humans_as_a_function_of_time_post-oral_intake.jpg)
-γ-valerolactone.jpg)
