Last Updated: September 28, 2022

Theaflavins are a group of molecules that are found in black tea (due to an additional fermentation process from green tea) that are said to be the bioactives of black tea.

Theaflavins is most often used for.

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Sources and Structure



Theaflavins are said to be the main bioactive of black tea. While both green tea and black tea (as well as white tea) are derived from the same plant, Camellia Sinensis, black tea involves an additional fermentation stage in which the enzyme polyphenoloxidase acts on polyphenols and generates the theaflavins and thearubigins found in black tea.[1][2] Theaflavins are actually the molecules to credit for both the taste and visual aspect of Black Tea (relative to Green Tea) as they are also pigments.[3][4][5]

Catechins (a particular molecular structure class) appear to be sligthly damaged during excessive heating and fermentation required to form black tea. After this damage, they spontaneously reconfigure into theaflavins and the rich gallic acid content of Camellia Sinensis can attach themself to theaflavins (similar to how they attach themselves to catechins to for EGC, ECG, and EGCG)

It is estimated that average human Theaflavin intake is 25.3-29.3mg per day at its highest (in the UK) although with high variability, as this same survey noted that the Greece population had near no dietary intake; most dietary intake comes from fermented teas, of which Black Tea is the most popular.[6]

The total Theaflavin content has been estimated to be as high as 2-6%[7][8] although other estimates are more moderate at 0.8−2.8% of dry leaf weight depending on fermentation processes.[9][10][11] The Theaflavin content is a balance between generation (from the fermentation process as catechins are transformed into Theaflavins) and preventing excessive fermentation, and overly fermented teas have reduced Theaflavin content thought to be related to degeneration.[12]

Regardless of the total Theaflavin content, the total polyphenolics of black tea tend to be just 10% theaflavins with 30% and 50-60% being catechins and thearubigins; respectively.[1] Thearubigins are likely to mediated a variety of bioactivities associated with black tea, but are currently not well defined (thus research tends to cater to what it can define; Theaflavins).

Theaflavins have a variable content in Black Tea depending on cooking time, and do not appear to be the major source of Black Tea polyphenolics either; that being said, there appears to be enough Theaflavins in Black Tea for it to be bioactive in some instances



Theaflavins are divided into several similarly structured molecules; Theaflavin, Theaflavin-3-gallate, Theaflavin-3'-gallate, and Theaflavin-3,3'-digallate (essentially, the Theaflavin molecule with or without additional gallic acid molecules added to it). These four molecules are collectively referred to as 'Theaflavins'.[13] For the purpose of this article, Theaflavin-3,3'-Digallate is simply referred to as 'Theaflavin Digallate'.


Theaflavin per se is the basic structure and is formed from two catechins (in these pictures, the top catechin opened up its hexane ring and reattached; now appearing to be a heptane) and gallic acid molecules attach to either of or both of the 3-carbon positions on the catechins

Although not classically referred to as one of the main theflavins, Theaflavin Trigallate and Tetragallate have been detected where additional gallic acid moieties are attached to the 5-carbon and 5'-carbon positions, with trigallate attaching to the 5' position and tetragallate adding an additional gallic acid to the 5-carbon.[14]

Theaflavin is a molecule that results from heat and fermentation of products containing catechin, the most basic of the green tea catechins; as such, it is high in black tea (which is a more highly processed green tea). Theaflavin, like catechin, can be attached to gallic acid molecules at numerous locations

The common term 'Theaflavins' tends to refer to all Theaflavin-like structures, but usually the four pictured




Absorption and Serum

One study using 50mg/g of decaffeinated black tea (8.8mg/g theaflavins) in the diet for two weeks noted that the circulating levels of the digallate form of Theaflavin (Theaflavin-3,3'-digallate) were less than 1nmol/g when measuring in tissue;[22] this study noted that Theaflavin in its free form and monogallic acid form (Theaflavin-3-gallate) were detected in higher amounts.[22] Another rat study measuring the serum of animals given Theaflavins as 0.05% of their drinking water for life failed to find any detectable serum Theaflavins; the limit of detection was approximately 5ng/mL.[23]

A small human study (n=2) suggest that the serum spike of theaflavin in human serum after consumption of 700mg is approximately 1ng/mL.[24]

Limited evidence currently, but it appears that the absorption of Theaflavins from the diet into systemic circulation is quite low at around 1ng/mL; many bioactivities of Theaflavins after absorption may be due to metabolites



In a test using germ-free (lacking intestinal bacteria) and normal mice, ingestion of 200mg/kg Theaflavin-3,3'-digallate noted that only the latter had detectable levels of Theflavin, each monogallate, and gallic acid; suggesting that intestinal bacteria is required for metabolism of Theaflavin-3,3'-digallate.[13] When bacteria is present, Theaflavin Digallate (200mg/kg) can get metabolized into any of the other three Theaflavin molecules and confers free Gallic acid molecules as a result.[25]

This may explain why in a small (n=2) human study ingesting 700mg Theaflavins, only parent Theaflavin was detected in urine; the authors hypothesized that the gallic acid moeties were metabolized.[24]

Theaflavin-3,3'-Digallate can be metabolized into any other Theaflavin and Theaflavin monogallates can be metabolized into Theaflavin per se; this appears to require intestinal microflora


Pharmacological Targets

Theaflavin-3-Gallate is able to inhibit DNA methyltransferase 3a with a 1:1 stoichiometric ratio with an inhibition constant of 25μM[26] with some thearubigins (Theaflavin derivatives) showing a lesser IC50 value.[26] Theaflavin, Theaflavin-3-Gallate, and Theaflavin Digallate have further been shown to interact with histone proteins[27] and Theaflavin Digallate showed low affinity for double stranded ds26 yet high affinity quadruplex oligonucleotide 22AG (which also had affinity to EGCG yet not chlorogenic acid) and the DC50 values of Theaflavin Digallate (DC50 value being the concentration required to displace from DNA, lower concentrations indicating more affinity for DNA) of 0.26μM (duplex) and 0.20μM (quadruplex) showing low selectivity (in contrast, EGCG had high selectivity for quadruplexed).[27]

Theaflavins have the ability to bind to human DNA, much like EGCG, although the practical implications of this research is not yet known

Ephrin receptors are a class of cell surface tyrosine-kinase receptors with a variety of actions mediating cell-cell interactions.[28] Interactions between ephrin receptors and their ligands (Ephrins) tends to promote cancer cell development and angiogenesis,[29] and the interaction between receptor and ligand can be inhibited with both Theaflavin monogallates, particular towards the A2-A4 subsets with two-fold affinity for EphA4 and IC50 values between 40-80uM;[30] these molecules were competitive inhibitors, and Theaflavin itself as well as Theaflavic acids (also found in black tea) were not significantly effective.[30]

Appears to interact with Ephrin receptors, practical significance unknown

Theaflavins (those with gallic acid moieties) have been found to inhibit ATP Synthase with IC50 values in the range of 10-20uM.[31] This has been noted with EGCG (Green tea catechins)[32] but EGCG has an IC50 of 30uM and Theaflavin per se has an IC50 of 60uM.[31] The binding site of Theaflavins appears to be distinct from that of Quercetin (which is fairly close to ATP binding site) and instead bound closer to the membrane where the antibiotic efrapeptin is known to act.[33][31]

Theaflavins also appear to inhibit mitochondrial respratory complex 2 in the Electron Transport Chain (ETC) with IC50 values in the 1-4uM range and Complex 1 with weaker inhibition in the 20-50uM range.[31] Interestingly, this study noted that there was no Superoxide production (free radical production; a natural consequence of ETC inhibition) possibly due to direct antioxidative properties of Gallated Theaflavins.[31]

Gallated Theaflavins appear to inhibit ATP synthase and the ETC, but at the same time their anti-oxidant properties circumvent the production of superoxide (O-) that results form ETC inhibition

Black tea was found to inhibit SULT1A1 and SULT1A3, which was due to both the Theaflavins and Thearubigins (with trace catechins likely also active); SULT1A1 was inhibited by 90% when 1% of the medium contained Theaflavins (and activity was wholly abolished at 5%) while SULT1A3 only had 10% activity inhibited at 1% of the medium (while 10% of the medium as Theaflavins abolished SULT1A3 activity).[34]



It has been noted that tea catechins in general exhibit strong binding to lipid bilayers including those found in cytoplasmic membranes[35][36] which appears to extend to Theaflavins.[37] This study noted that all Theaflavins showed binding affinity to the lipid bilayer via their hydroxyl groups, with Theaflavin Digallate showing more binding affinity than Theaflavin or either Monogallate (the latter two being similar).[37]

Theaflavins, like other tea polyphenolics, can bind to the cell membrane





Theaflavins have been found to induce phosphorylation of FOXO1a in a concentration dependent manner (authors noted in a similar manner to IGF-1) and appeared to act in a PtdIns 3-kinase-sensitive manner; inhibiting mTOR or p90RSK by Rapamycin and PD98059 failed to abolish the effects of Theaflavins.[38] The IC50 was in the range of 23-27uM, and required at least one gallic acid molecule (Theaflavin per se inactive).[38]

Theaflavins were also noted to suppress PEPCK-CAT with an IC50 of approximately 20mcg/mL, and was additive with insulin until reaching the maximal insulin-related repression.[38]

Theaflavin appears to have some IGF-1 like mechanisms thought to underlie life extension, although these occur at a fairly high concentration (not yet seen in serum after oral ingestion)



In fruit flies (model for longevity research due to short lifespans and high possible sample sizes) administration of Theaflavins was associated with an increase in lifespan from 51 days on average to 56 days (9.8%) and appeared to be mediated through an increase in Superoxide Dismutase 1 (SOD1), an antioxidant enzyme.[39] Similar effects are noted with green tea catechins.[40]

One study in fruit flies has confirmed longevity promoting effects of Black Tea, which appear to be related to SOD1 induction (an antioxidant enzyme known as 'Superoxide Dismutase')





Theaflavins have been noted to, in vitro, inhibit formation of Aβ40 and Aβ42 fibrils in the classical formation and instead was associated with spherical formations; it appears that Theaflavins bind to hydrophobic regions of Aβ monomers and alter aggregate formation away from fibrils into spheres,[41] a seemingly protective effect previously noted with EGCG and green tea catechins that reduces toxicity of Aβ aggregates[42] and other protein misfoldings.[43] These protein modification effects, similar to EGCG, are independent of antioxidant potentials of Theaflavins.[41]

Has mechanisms in place to alter the shape of protein aggregates (observed in the pathology of Alzheimer's and Parkinson's) into more spherical and less toxic shapes; no in vivo evidence currently, but appear to be independent of anti-oxidant properties



10-20mg/kg of Theaflavins (intraperitoneal injection) given prior to an MCAO injury in rats was associated with improved cognitive function (normalizing about half of the injury-induced deficit) associated with anti-oxidative properties which negatively influenced NF-kB activation and iNOS induction.[44] These results (same methodology) have been replicated elsewhere, with emphasis placed on reduced phosphorylation of STAT1 to credit for the observed protection;[45] STAT1 is upstream of iNOS and COX2 induction[46][47] which mediated downstream inflammatory reactions, and STAT1 itself appeared to be subject to prooxidative changes in cerebral ischemia.[48]

Injections of Theaflavin are neuroprotection prior to neural injury, no studies conduted on oral ingestion at this moment in time nor comparisons to reference drugs



In a mouse model of MPTP-induced neurodegeneration (model of Parkinson's Disease) given 10mg/kg Theaflavins (20mg/kg being equally effective, and 10mg/kg more effective than 5mg/kg) one hour prior to MPTP administration noted an attenuation in the amount of behavioural deficits and reduction in oxidative biomarkers (TBARS, SOD, GPx, Catalase).[49] A preservation of dopamine and MAO-B levels were also noted, but did not reach levels seen in control.[49] A follow-up to this study noted that the protective effects of 10mg/kg Theaflavins also extended to a reduction in apoptosis of dopaminergic neurons and less neuroinflammation[50] and these results are replicated elsewhere by the same research group.[51]

Oral intake of low doses of Theaflavins (10mg/kg in rats; 1.6mg/kg in humans as a likely estimate) has been noted to protect from Parkinson's toxin possibly via antioxidative effects; the protective effect is not absolute, but it appears to be in a dose relevant to Black Tea consumption


Cardiovascular Health



A study using 0.4mg/mL Theaflavins in vitro to assess lipase inhibition noted that while Theaflavin per se was wholly ineffective the Theaflavin-3-O-Gallate inhibited 29.6+/-7.5% of Lipase while the Digallate form inhibited 48.9+/-2.8% of activity[18] and this inhibition has been noted elsewhere with black tea per se possessing an IC50 of 0.9-1.3ug/mL in inhibiting pancreatic lipase when extracted between 100-140°C and the isolated theaflavins inhibited pancreatic lipase with IC50 values of 0.679ug/mL (Theaflavin), 0.320-0.368 (monogallated), and 0.316 (Theaflavin Digallate) all of which underperformed relative to Orlistat (0.042ug/mL) and EGCG (0.081ug/mL);[52] one other study notes slightly more potent inhibition with Black Tea extract (IC50 0.254mg/mL) and confirmed that gallic acid bound Theaflavins were more effective than Theaflavin per se,[53] and Theaflavins are not the only lipase inhibitors found in black tea.[18]

Black tea polyphenols have been noted to increase the amount of lipids detected in the feces of rats, suggesting that this lipase inhibition is biologically relevant.[54]

Black tea has mechanisms to inhibit lipid (fatty acid) absorption form the diet following oral administration, which could result in less bioactivities of those fatty acids in the body if they are not absorbed


Cardiac Tissue

Theaflavin at 10-40umol/L in cardiac tissue prior to Ischemia/Reperfusion (I/R Injury) noted that while Theaflavins failed to influence cardiac tissue at rest it was associated with a concentration-dependent protective effect on cardiac function after I/R injury was resolved (with a Theaflavin pretreatment); these protective effects were abolished by incubation with a potassium channel blocker (Glibenclamide or 5-HD) and mPTP opener (Atractyloside).[55] Both KATP[56] and mPTP closure[57] are known to be cardioprotective mechanisms during Ischemia, and Theaflavins appear to work via these mechanisms.[55]

May have protective effects in response to cardiac ischemia, but requires a fairly high concentration

Cardioprotection in isolated cardiomyocyte (from an H2O2 insult) has been noted to occur as a result of anti-oxidative purposes, and the induction of JNK and p38 (MAPKs) by Theaflavins were noted to be unrelated to protective effects.[58]

A modest positive (between 100-150% of control in vitro) inotropic effect has been noted with Theaflavins between 10-1,000ng/mL with most efficacy at 100ng/mL, a concentration range possibly relevant to black tea ingestion.[59] This did not correlate with the antioxidant potential of Theaflavins, and Theaflavin Digallate was found to induce PKCε in isolated rat tissue possibly secondary to pro-oxidative effects (abolished with pretreatment of N-Acetylcysteine).[59]

There may be a small hormetic protection of the heart associated with low concentrations of Theaflavins, possible in the range of oral supplementation



Absorption of cholesterol may be reduced following oral administration of black tea catechins, as increased fecal cholesterol has been noted[54] alongside less lymphatic recovery following 50mg/kg black tea polyphenols in rats.[60] This reduced absorption is thought to underlie cholesterol reducing effects in rat models via inhibiting cholesterol incorporation into micelles (required intermediate for absorption).[61][62]

In persons with mild to moderate hypercholesterolemia given 375mg of a Theaflavin enriched green tea extract (75mg Theaflavins, 150mg green tea catechins, 150mg other polyphenols) for 12 weeks, it was noted that total cholesterol was reduced 11.3+/-0.9% and LDL-C by 16.4%+/-1.1% while HDL-C increased 2.3%+/-2.1% and triglycerides increased by 2.6%+/-3.5%.[63] A similar trial was replicated with 77.5mg Theaflavins in isolation in mildly hyperhcolesterolemic women (with or without additional catechins) noted that while a decrease in cholesterol was noted that it was not different than placebo.[64]

Theaflavins have mechanisms to reduce cholesterol and tea extracts may, but evidence to support Theaflavins per se (rather than Black Tea Extract) is minimal with at least one study suggesting no effect on cholesterol



Feeding of black tea (1.5%) is able to reduce serum triglycerides slightly after 30 weeks relative to green tea and relative to baseline, although 4% was not effective; oolong and Pu-erh teas were both effective to larger degrees.[65]



Theaflavins appear to reduce homocystine-induced endothelial damage at concentrations between 10 and 20mcg/mL, although not full protection (control still exhibited less endothelial damage) which was thought to be due to antioxidative effects; both reduced DNA damage as well as the homocysteine-induced reduction of nitric oxide were comparable attenuated with Theaflavins.[66] The oxidative protection appears to be general rather than specific for homocysteine.[67]

Some general protective effects on the endothelium via the anti-oxidant potential of Theaflavins; not remarkably potent nor unique to this group of molecules

It has been noted that green tea and black tea seem to be equally potent at inducing nitric oxide and the inducible enzyme eNOS in isolated aortic cells, as the lack of catechins in black tea is met by somewhat equal efficacy from the theaflavins (and thearubigins);[68] this comparability in vitro has been replicated elsewhere.[69]

The comparable efficacy has been noted in vivo, where persons drinking tea consisting of 5g tea leaves daily for 4 weeks leading up to a Flow-Mediated Vasodilation (FMD) test noted that while both groups had an improvement in blood flow relative to water (control) that they were not different from one another.[69] Max FMD improved in control by 16.3% when measured before testing to 2 hours after, yet improved by 88% and 82% in green and black tea groups respectively.[69]

Theaflavin-3'-Gallate as well as Theaflavin Digallate have the ability inhibit plasminogen activator inhibitor type 1 (PAI-1) due to the gallic acid molecule on the 3' position, as Theaflavin and Theaflavin-3-O-Gallate were ineffective.[70] PAI-1 is an inhibitor of fibrolysis, and Theaflavin-3'-Gallate inhibits this protein with an IC50 of around 18mM;[71] beyond preventing blood clot degradation, PAI-1 inhibition is also implicated in Alzheimer's and Obesity.[71]


Interactions with Glucose Metabolism



It has been noted that many polyphenolic compounds structural related to catechins exert a degree of carbohydrate absorption inhibition[72] and that Theaflavin-3-Gallate most potently (competitively) inhibited the enzyme maltase (catalyzes Maltose) with an IC50 of 10uM; the other three Theaflavins were also effective at 58uM (Digallate), 136uM (3‘O-gallate), and 500uM (Theaflavin).[73] Theaflavin-3-Gallate was more potent than any green tea catechin tested with ECG and EGCG being similarly effective as Theaflavin-3-3‘-Digallate, all compounds less potent than Arcabose (430nM).[73] This inhibition on Maltase has been noted elsewhere.[74]

The potency of Theaflavins on sucrase is subpar (ranging from 159uM from digallate to Theaflavin being ineffective) although equally subpar as the green tea catechins.[73]

Tea from Camellia Sinensis,[75] as well as black tea particularly (where a higher level of inhibition was noted with black tea relative to green tea, implicating Theaflavins),[76] have been noted to inhibit α-amylase. A later study using fully fermented black tea noted the tea itself had an IC50 value 0.42-0.67mg/mL while the IC50 values of isolated theaflavins were 67μM (Theaflavin), 5.5μM (Theaflavin 'monogallate') and 2.9μM (Theaflavin digallate) on Salivary α-amylase.[77] Another study using 0.4mg/mL Theaflavin digallate as positive control noted 81.6+/-2.8% inhibition of Amylase.[18]

It has been hypothesized that the protective effect of Arcarbose on diabetes risk (via inhibiting carbohydrate absorption) may be applied to tea polyphenols including Theaflavins pending more intervention research.[72]

Black tea theaflavins have been shown in numerous instances to inhibit alpha-amylase, an enzyme that inhibits the breakdown of starch and prepares it for absorption; its inhibition would result in less carbohydrates absorbed, and this may result in weight loss or reduced glucose spikes following meals (and less risk for diabetes). There are currently no human studies, but numerous in vitro studies suggesting it is effective and in a concentration range that is relevant following oral intake of tea or supplements


Interactions with Fat Mass



Feeding of 1.5% black tea to rats, relative to other forms of tea from Camellia Sinensis, caused greater weight loss effects over 30 weeks which were not observed (ie. both groups similar) when the dose increased to 4%;[65] both underperformed relative to Oolong and Pu-erh teas.[65]

Possible weight loss effects, not highly explored


Skeletal Muscle and Performance



Theaflavins, in a skeletal muscle myoneural junction, appear to induce concentration-dependent improvments in muscle cell contraction (17-76% at concentrations of 12-96mg/mL) via calcium-dependent as well as nitric oxide dependent mechansims.[78] Calcium[79] as well as nitric oxide[80] are both positive mediators of muscle contraction, and the authors hypothesized that Theaflavins augmented muscle contraction via these mechanisms.[78]

Has mechanisms to increase muscle contractile strength, although the concentration used is much higher than that observed in serum following black tea ingestion; may not be biologically relevant



In men consuming a Black Tea Extract (1,760mg of 40% Theaflavins daily for 9 days) who were subject to a Wingate test (a 10 second all-out cycling repeated 8 times with short breaks) prior to and after supplementation, it was found that those supplementing Black Tea extract appeared to have greater peak power output during the trial after 9 days (2.3%) with no influence on mean power.[81] This study noted reduced cortisol, Delayed onset muscle soreness (DOMS), and antioxidative biomarkers with no significant influence on IL-6.[81]

One study noting an increase in power associated with Black Tea consumption, although this study assessed power via a Wingate test and also noted reductions in Delayed Onset Muscle Soreness (DOMS) which could have influenced the testing


Skeletal Mass and Bone Metabolism



Rat osteoclastic precursor cells incubated with either 10 or 100uM of Theaflavin Digallate suppressed differentiation in a concentration-dependent manner and to a greater degree than EGCG (the major of the four green tea catechins), these results paired with suppression of MMP2 and MMP9 secretion suggest anti-osteoporotic effects.[82]

Possible anti-osteoporotic effects, although at fairly high (possibly not biologically relevant) concentrations


Inflammation and Immunology



In stimulated macrophages (RAW 264.7), 0.1ug/mL of Theaflavins was able to slightly suppress TNF-α secretion.[83]

A study in bone marrow derived macrophages, no cytotoxicity is noted up to 100mcg/mL while 50mcg/mL is noted to suppress subsequent LPS-induction of IL-6, MCP-1, and ICAM-1 mRNA; all of which were due to NF-kB activation which was downstream of MAPKs (specifically, MCP-1 was downstream of JNK and both IL-6 and ICAM-1 were downstream of p38).[84] The MAPKs consist of p38, JNK, and ERK, with Theaflavins appearing to inhibit p38 and JNK.[84] ICAM-1, as well as VCAM, have been found to also be inhibited in intestinal epithelial cells via similar mechanisms.[85]

Possesses some anti-inflammatory properties, but there isn't any evidence to support any potent anti-inflammatory effects of Theaflavins. The anti-inflammatory effects appear to be minor or moderate in effect size


Innate Immunity

The Retinoic acid-inducible gene I (RIG-1) receptor of innate immunity[86] is inhibited by Theaflavin-3,3'-Digallate with an IC50 of approximately 1uM, while EGCG inhibits this receptor with an IC50 of approximately 1-2uM; both were inactive on TLR3, 4, and 9 receptors.[87] RIG-1 receptors are important for innate immunity, and their hyperactivity is thought to be linked to autoimmune disorders[87][88] such as Epstein Barr virus which is known to activate RIG-1.[89]

One study suggests Theaflavins might be useful in autoimmune diseases (by inhibting a receptor implicated in being overactive in some cases of autoimmunity) and the concentration is not too high to be infeasible; however, there is a lack of evidence in living models to support these claims


T Cells

Prostaglandin E2 (PGE2) is known to inhibit CD4+ T cell activation[90] and cause T-cell apoptosis[91][92] via acting on its receptor[93] which is thought to partly be responsible to immunosuppression in cancer patients since many tumors secrete PGE2[94][95] and CD4+ T-cells are known to be chemoprotective.[96][97] Beyond the reduction in CD4+ T-cells, there is also a change in cytokine secretion status towards more of a Th2-like status rather than Th1.[98] In this scenario reducing PGE2, preventing PGE2 from acting on its receptor, or preventing the sequelae of receptor activation from occurring are all seen as therapeutic.

Theaflavins at a concentration of 25µg/mL in tumor cells appears to reduce the amount that the tumor cell kills T-cells,[99] as it seems that the PGE2 is able to prevent phosphorylation of a protein known as STAT5A and theflavins preserve phosphorylation, which subsequently preserves IL2Rγc signalling (the receptor for IL-2) and T-cell structure.[99]

CD4+ T-cells are protective against cancer by causing tumor cell death, but increased PGE2 concentrations impair the ability of the body to activate CD4+ T-cells and also cause death of T-cells via preventing the signalling of IL-2 (a beneficial cytokine for T-cells). Theaflavins appear to preserve signalling of IL-2 in T-cells, and thus attenuate the negative effects of PGE2



In oxazolone induced type IV allergic reaction (skin hypersensitivity) in male mice, either percutaneous administration (solution) of 0.2mg or oral ingestion of 50mg/kg Theaflavins were able to significantly reduce the subsequent Oxazolone-induced allergic response.[100] Application of 0.2mg Theaflavins was not significantly different than 0.1mg Hydrocortisone as active control, and oral administration of 50mg/kg Theaflavin Digallate (but not monogallated) was not significantly different than 50mg/kg Hydrocortisone (trended to be weaker) and thought to be mediated by anti-inflammatory effects due to less circulating IFN-γ and TNF-α.[100]

Topically, Theaflavins appear to be potent anti-allergic molecules and large doses orally (possibly via metabolites) share these anti-allergic properties



In regards to the Influenza Virus ('The Flu'), Theaflavins appear to have Neuroaminase inhibitory potential (mechanism of action of oseltamivir and zanamivir) with Theaflavin Digallate having an IC50 of 10.67+/-0.31μM on the H3N2 strain (less potent than the active control Oseltamivir carboxylate at 8.88+?-2.17nM).[101] Theaflavins were also noted to inhibit viral replication in cells in a concentration dependent manner with 10μM nearly abolishing replication.[101]

Preliminary evidence to suggest that Theaflavins work against the flu and prevent viral replication

A 90% Theaflavin mixture was noted to inhibit infection of cells by HIV with IC50 values between 210nM (X4 virus) and 1.2μM (R5 virus) and inhibited infection by primary HIV-1 isolates of clades A, B and group G (X4R5 or R5) with IC50 values of 0.29-0.67μM.[102] Inhibitory effects were noted against three NL4-3 variants (which are TI249 resistant[103]) with IC50 values between 300-410nM.[102] An inhibitory effect was noted against HIV replication (via interference with HIV-1 RT activity) but at a much higher IC50 value of 48.67μM.[102]

The mechanism is thought to be via interacting with the pg41 pocket region and preventing fusion core formation, a mechanism also attribted to green tea catechins;[104] this blocking of membrane fusion was noted elsewhere[102] and both Theaflavin Digallate and another black tea polyphenol (Theasinensin A) were found to be more effective than EGCG from green tea.[105]

Theaflavins appear to be stable at a pH of 3-6[102] and can remain in vaginal and cervical cells up to 6 hours after direct application without exerting any noticeable toxicity;[106] due to these effects, Theaflavins are thought to have some promise in preventing HIV transmission as a direct vaginal cream.[106]

Appears to have fairly potent in vitro effects on preventing HIV infection, with some (but less potent) inhibitory effects on viral replication. Has been shown in vitro to be similarly potent on many strains of HIV, and is a promising intervention for non-oral uses of Theaflavins (ie. Vaginal gels or condom lining)



At least one study has noted that Theaflavins could inhibit multiplication of Leishmania major in infected monocytic cells.[107]



One study has noted that Theaflavins should inhibit the growth of various Candidia (Yeast) species of bacteria with a Minimum Inhibitory Concentration (MIC) of 6.25 mg/mL on Candidia Albicans and with efficacy on four other strains, possibly mediated via damage to the cell wall.[108]


Interactions with Oxidation



Antioxidative effects have been noted against superoxide radical with IC50 values ranging between 14.50-21.70µmol/L (more effective than the active control of EGCG at 45.80µmol/L), can sequester singlet oxygen radicals with IC50 values between 0.55-0.86µmol/L (EGCG at 0.87µmol/L) and both hydroxyl peroxides and radicals (IC50 of 0.39-0.49µmol/L and 25.07-37.96µmol/L; more potent and equally potent as EGCG, respectively)[109] and sequestering of Methylglycoxal has been noted.[110] This potency has been replicated elsewhere, where it was noted that Theaflavins with Gallic Acid moieties were more effective than EGCG yet Theaflavin per se was less potent.[111]

In regards to copper-mediated LDL oxidation (an oxidative process that turns LDL into oxidized LDL; used in research to assess the ability of molecules to reduce risk of atherosclerosis) it appears 5-40ug/mL of Theaflavins have equal antioxidative potential as green tea catechins; the authors suggested that this was evidence that black tea consumption over green tea should not reduce health benefits associated with oxidation.[112]

In regards to DNA mutations mediated by oxidation, only gallated Theaflavins appear to be able to prevent hydroxyl-mediated DNA damage (with both EGCG and basic Theaflavin being ineffective).[109]

Theaflavins have antioxidative potential, and when compared to Green tea catechins (EGCG in particular) Theaflavins appear to be more effective anti-oxidants

Like most anti-oxidants and phenolics,[113] Theaflavins may also confer pro-oxidative effects depending on context. This has been noted in vitro with oral cancer cells where Theaflavins have produced Hydrogen Peroxide[114][115] and Oxygen free radicals.[115]

In some cancer cell lines, activation of JNK (a cellular protein that appears to be a target of Theaflavins) appears to be downstream and dependent on oxidation,[116] which is a similar mechanism to that of EGCG.[117] It has been thought that Hydrogen Peroxide production from polyphenolics underlies the chemotherapeutic potential thereof.[118]

In studies that note pro-oxidative effects from Theaflavins in cancer cells, there appears to be a slight preference for cytotoxicity in cancer cells relative to normal cells; toxicity occurs to CAL27 carcinoma and HSC-2 cancer cells at a concentration lower than that observed with GN46 and HF-1 normal cells[115] while there appears to be a larger therapeutic threshol for CAL27 cells relative to healthy oral cancer cells.[114][115]

Theaflavins hold pro-oxidative potential, which is thought to underlie their chemotherapeutic effects on cancer cells


Interactions with Organ Systems



Theaflavins are investigated for oral purposes for numerous reasons, including their affinity to mix with saliva rapidly[3] and the low absorption from the intestines does not matter when direct oral application (via black tea) is undertaken.

In human gingival fibroblasts (which are known to secrete CXCL10 in response to Oncostatin M[119] and the subsequent activation of Th1 immune cells thought to play a significant role in Gingivitis pathology[120]) Theaflavin Digallate is able to inhibit JNK (but not p38 or ERK; the other two MAPKs) and inhibited Akt without influencing STAT3, thought to be through suppressing the expression of the Oncostatin M receptor.[121] Suppression of IL-6 production has also been noted (IL-6 and Oncostatin M belong to the same superfamily) through suppressing the receptor of the agonist used, TNF superfamily 14.[122]

It appears that these effects of Theaflavins on reducing receptor expression extend to green tea catechins.[119][122]

Possesses anti-gingivitus properties



In Indomethacin-induced stomach ulceration followed by consumption of 10-50mg/kg Black Tea or 0.5-5mg/kg Theaflavins for three days, a dose-dependent reduction in Myeloperoxidase (MPO) was noted (Theaflavins more effective than Black Tea) although both Black Tea (40mg/kg) and Theaflavin (1mg/kg) was as effective as Omeprazole (3mg/kg) in reducing stomach ulceration as assessed by histological examination; the damage score was reduced by 81.3%, 78.1% and 79.7% relative to ulcer control.[123] These effects have been replicated elsewhere with 40mg/kg Black tea and 1mg/kg Theaflavins, with Theaflavins at 1mg/kg being as effective as 3mg/kg Omeprazole as active control.[124] These effects appear to be mediated by mixed anti-oxidative[124] and anti-inflammatory[123] mechanisms.

Remarkably potent anti-ulcer effects after NSAID-induced ulceration in mice



In liver cells (HepG2), 50μM Theaflavins are able to induce AMPK activity in an LKB1-dependent manner and was dependent on ROS production; incubation with N-Acetylcysteine abolished the effects observed.[125] An increase of AMPK activity in the liver tissue has been confirmed in vivo when rats are fed a diet containing 50mg/kg Theaflavins daily.[125]

In response to hepatic Ischemic/Reperfusion injury (via occluding the portal vein), injections of 30mg/kg Theaflavins 24 and 48 hours prior to I/R injury was able to suppress the oxidative and inflammatory response to I/R injury and, secondary to these, suppressed the number of apoptotic cells.[83]



Oral consumption of 50-200mg/kg Theaflavins for five weeks alongside cadmium ingestion (to assess cadmium-induced testicular toxicity) was able to dose-dependently attenuate the testicular size reduction and DNA damage induced by cadmium, although no dose outright normalized parameters relative to control.[126]

Theaflavin (gallated) has been found to inhibit testicular CYP17 activity with an IC50 of 11.5-15µM, which was more effective than EGCG from green tea catechins (24.5µM) and Ketoconazole (35µM), with Theaflavin (ungallated) having an IC50 of 25µM.[127]



In pathogen-free rats subject to cigarette smoke at a high rate (10 cigarette equivalent per hour for 6 hours a day for 60 days) and then given 100-400mg Theaflavins (although 200mg was maximally effective; 800mg/kg) noted that Theaflavins were associated with suppression of MUC5AC mRNA and dose-dependently less mucus secretion from lung tissue in response to cigarette smoke.[128] This may be related to suppression of the epidermal growth factor receptor (EGFR) which appears to positively influence mucus production.[129]


Interactions with Cancer Metabolism


Mechanisms (General)

AP-1 appears to be inhibited by Theaflavins at a concentration of 1-20uM secondary to c-Jun inhibition[130] and JNK.[131]

Theaflavin (Digallate) has been noted to suppress the expression of the receptor for epidermal growth factor (EGFR) and reduces autophosphorylation of the receptor[132] which is inhibited with incubation of the proteasome inhibitor MG132 (a peptide aldehyde used in research[133]); these mechanisms appear to underlie some anti-proliferative effects of Theaflavins.[134]



Epithelial-to-mesenchymal transition (EMT) is a process where cancerous cells lose adherin proteins and gain metastatic potential and the ability to spread (this phenomena is not isolated to oral cancers[135]) which is associated with increased Vimentin[136] and later stages associated with increased levels of Metalloproteinases (MMPs) that break down the extracellular matrix (ECM) and facilitate tumor metastasis.[137]

Black tea extract (2.63% Theaflavin Digallate, catechins, and 10.46% gallic acid) in SCC-4 oral cancer cells inhibited cell migration and invasiveness in a concentration-dependent manner and prevented SCC-4 adhesion to the ECM, which precedes EMT.[138] Black tea was found to concentration-dependently reduce both Vimentin and MMP2 expression (as well as FAK and p-Src) and upregulate E-Cadherin in concentrations below 40ug/mL, and 20ug/mL effectively abolished the PMA-induced induction of u-PA and MMP9.[138]

Possible anti-proliferative and anti-metastatic potential of Black Tea

Theaflavin has been noted to bind directly to the 20S proteasome of tumor cells, which may underlie bioactivities.[139]



Theaflavins appear to be capable of inducing H2O2 production in oral cancer cells, with the increased prooxidation occurring at a lower concentration in cancer cells relative to normal oral cells (showing selectivity for inducing cytotoxicity in cancer cells).[114][115][140]



Theaflavins are investigated for their interaction with Breast Cancer as to explain possible difference between green tea and black tea consumption as it pertains to Breast Cancer risk, due to the popularity of the two teas; this is despite epidemiological evidence not yet showing a conclusive protective effect associated with Black Tea.[141][142]

In breast cancer cells (T47D and MDA-MB-231) at 25mcg/mL, Theaflavins were able to induce apoptosis to around 40% and are mechanistically independent of p53 (p53 siRNA failed to abolish the effects of Theaflavins).[143] Cells were accumulated in sub-G0/G1 phase, and apoptosis appeared to be caspase 8 and 9 dependent and mediated by the Fas death receptor, which was upregulated due to JNK activation.[143] Signalling via the death receptor Fas, which would be enhanced via receptor upregulation, can induce apoptosis in the manner observed with Theaflavins.[144] Apoptosis at this concentration range has been replicated elsewhere in MDA-MB-231.[23]

Interestingly, in both functional p53 cells[145] and mutated p53 cells[143] Theaflavins induce expression of p53 despite apoptosis not being dependent on p53.[143] Induction of p53 appears to be more related to the anti-proliferative effects of Theaflavins on breast cancer cells, where both p53 induction as well as reactive oxygen species (ROS) appear to contribute to reduced cell migration.[146]

Possesses mechanisms in vitro to induce apoptosis of the two main research breast cancer cells, MCF-7 (estrogen responsive) and MDA-MB-231 (estrogen nonresonsive; highly proliferative)

In C3(1)SV40 mice (assurance of developing breast tumors in their lives[147]) consuming Theaflavins (0.05% of their drinking water; 0.01% failed to exert benefit) for their lifetime was associated with a slight prolongation of life and reduction of tumor pathology when measured at organic death or when measured at a set time point of life (two separate experiments). Tumor size in the latter case was reduced to 61% of control, and outperformed green tea catechin intervention (74.6% of control).[23] Other studies note that green tea is more effective than black tea, however.[148]

A reduction in tumor induction has been noted with Black tea (1.5% of the diet) with or without milk when given to rats prior to inducing a tumor with the DMBA toxin,[149] which has been replicated elsewhere (similar dosage).[150]anthracene in rats fed control or high fat diets|published=1998 Jul|authors=Rogers AE, Hafer LJ, Iskander YS, Yang S|journal=Carcinogenesis]

Limited evidence, but there is in vivo evidence to support anti-breast cancer actions of Theaflavins at relatively low doses. For the most part, Theaflavins and catechins (Black and Green tea, respectively) are fairly interchangeable in regards to potency



Theaflavins are able to suppress MMP2 secretion and mRNA content in human melanoma A375 cells and suppress the adhesive potential of these cells to the Extracellular matrix, both thought to play a role in attenuating invasiveness of melanoma tumors.[151]

Activation of JNK and p38 (MAPKs) has been noted in A375 cells to be dependent on reactive oxygen species (ROS), and was effectively abolished by N-Acetylcysteine.[116]



One study using a medullary thyroid carcinoma (MTC) cell line noted that theaflavins were able to induce apoptosis via hindering the PI3K/Akt/Bad pathway and preserving a p38MAPK dependent capsase-3 release pathway.[152]



While normal lymphocytes did not show altered cell viability with Theaflavins up to 80ug/mL, U937 and K562 leukemic cells had proliferation hindered with IC50 values of 44.6ug/mL and 50.2ugmL, respectively; apoptosis was characterized by cellular arrest at G0/G1 phase associated with inhibition of Akt (and secondary to that, nuclear accumulation and overall induction of FOX01) thought to be downstream of Hsp90 depletion.[153]



Theaflavins appear to have an inhibitory effect on the proliferation of SPC-A-1 lung cancer adenocarcinoma cells with an IC50 value of 4.78μmol/L associated with cell cycle accumulation in G0/G1 phase; there appeared to be synergism with Vitamin C in this regard.[154]

In a mouse model of lung carcinoma (benzopyrene induced), daily injections of 0.02mg Theaflavins for 36 weeks was associated with reductions in the relative proliferative index and improvements in apoptosis rates with comparable efficacy to 0.01mg EGCG.[155]pyrene-induced lung carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1|published=2009 May|authors=Manna S, Mukherjee S, Roy A, Das S, Panda CK|journal=J Nutr Biochem] These effects were associated with increased p53 expression in excised cells, whereas p21 and p27 appeared to be suppressed.[155]pyrene-induced lung carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1|published=2009 May|authors=Manna S, Mukherjee S, Roy A, Das S, Panda CK|journal=J Nutr Biochem]



Theaflavins have been noted to induce a concentration and time dependent apoptosis in HeLa cervical cancer cells associated with caspase release and a loss of mitochondrial membrane potential, attributed to inhibition of the Akt/NF-kB signalling pathways.[156]

Anti-proliferative effects have been noted with an IC50 of 110+/-2.1μg/mL (48 hours) and cell cycle arrest at G2/M;[157] it was noted in this study that polymerization of tubulin (into microtubules) was inhibited by Theaflavins with an IC50 of 78+/-2.43μg/mL.[157] Microtubulin is a cytoskeleton of the cell which aids in signalling and structural aspects[158][159] and is a chemotherapeutic target, with Vinblastine being known to disrupt tubulin polymerization[160] and tubulin polymerization inhibition halting the cell cycle at G2/M.[161]



In HTB-37 and HT-29 colon cancer cells, Theaflavin Digallate can cause apoptosis associated with an induction of p53 and Bax and appears to be mediated by mitochondria-induced apoptosis (as indicated by clustering and vacuole formation and rhodamine 123 accumulation, indicative of mitochondria hyperpolarization).[162]

This study also noted that inflammation-induced COX2 was significantly attenuated with Theaflavins,[162] which has been noted elsewhere to occur mostly with Theaflavin Monogallate (both 3 and 3' in Caco-2 and WI38VA cells),[163] which appears to be related to the Regulator of G protein signaling 10 (RGS10);[164] Theaflavins were found to selectively induce RGS10 at lower concentrations (10uM) and became able to induce both RGS10 and the related RGS14 (no influence on RGS4) at 50-100uM. This was found to also occur with EGCG.[164]

The suppressive effect of Theaflavins on colon cancer cells appears to be greater than that of diallyl sulfide from garlic and lycopene (from tomatoes).[165]



In PC-3 human prostate cells incubated with Theaflavins, there was a concentration and time dependent induction of apoptosis up to 100mcg/mL (some detectable effects at 10mcg/mL) associated with increased cell count in the G2/M phase of the cell cycle (from 19% in untreated to 40.4% at 80mcg/mL).[166] The IC50 was deemed to be 60mcg/mL, and was associated with a two-fold increase in P21wap1/cip1 expression.[166]

LNCaP prostate cancer cells appear to be subject to Theaflavin-3-Gallate induced cytotoxicity at an IC50 37.4mcg/mL[127] which may be related to an induction of p53 and suppression of NF-kB signalling.[167]


Interactions with Aesthetics



Theaflavin Digallate appears to reduce tyrosinase activity, with this study noting the effect was not significantly different from (but trending to be weaker) than sulforaphane[168] and mediated through suppression of Tyrosinase mRNA and protein content.[169]


Nutrient-Nutrient Interactions


Green Tea Catechins

Green tea catechins are a group of catechin structures widely distributed in nature but found in high amounts in the plant Camellia Sinensis; they are still present in black tea where Theaflavins are a large component.

When testing the antibacterial effects of Theaflavin and the catechin known as (-)-epicatechin, it appears that they are synergistically antibacterial;[170] potentially useful for oral pathogens.


Vitamin C

Vitamin C and Theaflavins appear to have synergism in inhibiting the proliferation of SPC-A-1 lung cancer adenocarcinoma cells, with Vitamin C also exerting synergism with EGCG (main green tea catechin).[154]



Loquat (Japanese Plum; Eriobotrya japonica) is more commonly known for the fruit, but the leaves from the plant also confer some benefit. Processing of green tea leaves alongside Loquat leaves during fermentation into black tea can increase the content of Theaflavins found in the black tea product.[171]


Milk (Tea preparation)

In vitro, Theaflavins (and catechins) appear to form complexes with milk proteins[172][173] which has been noted to reduce the in vitro antioxidative potential of the aforementioned polyphenolics.

The addition to milk to black tea fails to reduce the amount of circulating phenolics in serum of volunteers when measured 80 minutes after consumption.[174] Other studies have replicated this lack of alteration in plasma antioxidant capacity with the addition of milk[175] which also appears to extend to green tea catechins.[176] At least one study has noted reduced anti-oxidant potential with milk consumption, however.[177]

Protein complexes readily form with tea polyphenolics including Theaflavins. Although there is mixed evidence as to the consequences of consuming tea with milk, most studies suggest that it does not appear to inhibit the subsequent antioxidant rise in serum when they are coingested

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