IngredientsFlavonoids are a group of natural substances with variable phenolic structures, found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. They have been recognised as one of the largest and most widespread groups of plant secondary metabolites, with marked antioxidant properties; the general name flavonoid refers to a class of more than 6,500 molecules based upon a 15-carbon skeleton.
Chemically, flavonoids have the general structure of a 15-carbon skeleton consisting of two phenyl rings (A and B) and a heterocyclic ring (C, the ring containing the embedded oxygen). This carbon structure can be abbreviated C6–C3–C6. Flavonoids are mainly found in plant cell vacuoles in the form of C-glycosides or O-glycosides.
Based on the degree of unsaturation and the substitution pattern, different flavonoid classes are distinguished: flavones, flavonols, flavanones, flavan-3-ols, anthocyanins, dihydroflavonols, and isoflavones, as well as the biogenetic intermediate chalconoid forms. In natural sources, they may occur in free forms (aglycones), as glycosylated or acylated derivatives, and as oligomeric and polymeric structures such as the flavan-3-ol-derived condensed tannins (or proanthocyanidins).
Several thousand flavonoids have been identified in plant sources, and the number of compounds increases when considering the flavonoid-derived products that can be formed during the processing and storage of foodstuffs, and the metabolites and conjugates produced in the human organism after their intake.
Flavonoids are organic compounds characterized by a range of phenolic structures, which are abundantly present in various natural sources such as fruits, vegetables, cereals, bark, roots, stems, flowers, tea, and wine. Flavonoids are now considered an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications.
The peels of citrus fruits are rich in the polymethoxylated flavones: tageretin, nobiletin and sinensetin. Proanthocyanidins can be present in the seeds, flowers, and fruits of various plant groups like apples, grapes, blueberries, and certain cereals. Red wine is rich in flavanols, different types of flavonols (like epicatechin, myricetin and quercetin), and anthocyanins.
Commercial preparations of flavonoids are available in numerous forms. Examples include silymarin capsules, baicalin tablets, troxerutin tablets, flavoxate hydrochloride tablets, and puerarin injection, among others. Standardized plant extracts (e.g., green tea extract standardized to EGCG content, grape seed extract standardized to proanthocyanidins, quercetin supplements) are among the most commercially prevalent forms.
Flavonoids, as well as vitamin C, were discovered by Albert Szent-Györgyi (1893–1986), one of the most respected and honored biochemists of the twentieth century. Szent-Györgyi received the Nobel Prize in 1937 for his discovery of some of the properties of these molecules. Szent-Györgyi discovered the flavonoids while isolating vitamin C. A friend with bleeding gums had stopped the bleeding by taking a crude vitamin C preparation isolated from lemon. When the problem reappeared, Szent-Györgyi gave his friend a purer form of vitamin C, but the purer form did not work. He then isolated the flavonoid fraction from the original crude preparation and observed complete healing. Szent-Györgyi termed his discovery "vitamin P" due to its ability to reduce vascular permeability.
In 1936, Rusznyak and Szent-Györgyi determined that citrus flavonoids reduced capillary fragility and permeability in blood vessels. He gave the flavonoids the name "vitamin P" because of their effectiveness in reducing the permeability of blood vessels. This name was abandoned when it was realized that these substances were not really vitamins.
The earliest studies of flavonoid pigments date to Robert Boyle in 1664, who described the effects of acids and bases on the color of extracts from plant flowers and other pigmented tissues.
In Oriental medicine, plant flavonoids have been used for centuries, honored for their antioxidant, protective properties. Examples of flavonoid-containing foods widely used in Oriental medicine include scutellaria root, cornus fruit, licorice, and green tea.
Chinese herbal medicines encompass a diverse and intricate range of constituents, including alkaloids, glycosides, steroids, polysaccharides, terpenoids, and others. Among them, flavonoids represent a significant group, essential for facilitating the therapeutic properties of Chinese medicine. The efficacy of herbal medicines has been proven over centuries of extensive clinical application, which has traditionally relied on simple techniques such as decoction and grinding.
As technological advances drive the modernization of herbal medicines and bring them in line with global standards, more attention is being paid to purifying and concentrating the active ingredients from the herbs rather than using the raw form directly. A well-studied example is baicalin: the main bioactive component of Scutellaria baicalensis is baicalin, which is found in no less than 9% of dried scutellaria, and even up to 20% in some samples.
The isoflavones are among the first flavonoids studied biologically because their structures with hydroxyl groups in the 7 and 4′ positions of the basic ring structure provide them with an affinity to estrogen receptors. Another group of flavonoids, the anthocyanins, were used early in human history as dyes and thus had commercial value.
Most flavonoids function in the human body as antioxidants, capable of neutralizing overly reactive oxygen-containing molecules and preventing them from damaging cells. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function.
Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and β-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions.
Quercetin showed its anti-inflammatory activity by inhibiting the c-Jun N-terminal kinase and extracellular signal-regulated kinase, thereby inhibiting MAPK and AP-1 and NF-κB activity. Catechins also inhibited MAPK, AP-1, and NF-κB by inhibiting c-Jun N-terminal kinase and p38 kinase.
In addition to inhibiting the activation of MAPK and NF-κB signaling pathways, some signal cascades also involved in flavonoid anti-inflammation effects include the JAK/STAT signaling pathway and the inflammasome formation. Flavonoids could regulate the activities of other signaling molecules, such as tyrosine kinase, phosphoinositol kinase, and protein kinase C. Other binding targets of flavonoids found in anti-inflammatory responses include G-protein coupled receptors, estrogen receptors, and aryl hydrocarbon receptors.
As NF-κB inhibitors, flavonoids may modulate the expression of pro-inflammatory genes leading to the attenuation of the inflammatory responses underlying various cardiovascular pathology. NF-κB is a transcription factor that activates inhibitor of kappa B (IκB) kinase in the cytosol upon being stimulated by inflammatory stimuli. Subsequent signaling pathways via canonical or non-canonical routes lead to migration of NF-κB toward the nucleus, which then initiates targeting genes such as pro-inflammatory cells, monocytes, macrophages, and T and B cells.
Isoflavones are among the first flavonoids studied biologically because their structures with hydroxyl groups in the 7 and 4′ positions of the basic ring structure provide them with an affinity to estrogen receptors. This property underlies the clinical interest in soy isoflavones for menopausal symptoms and bone health.
Flavonoids may have neuroprotective effects through antioxidant, antiapoptotic, and antineuroinflammatory actions and by regulating various cellular and intracellular targets. In vivo systems require passage through various barriers, including the intestinal and blood–brain barriers and significant first-pass metabolism, before reaching the brain.
Flavonoid compounds have numerous medicinal properties owing to their antioxidant, anti-inflammatory, antiviral, and antitumor characteristics. The main mechanism by which these flavonoids exhibit their anticancer potential is via potent antioxidative and immunomodulatory actions. Current research reports have demonstrated that these flavonoids exhibit their anticancer effects via suppressing the NF-κB signaling.
The inhibition of flavonoids such as hesperidin, naringin, quercetin, luteolin, and apigenin on NF-κB, ERK1/2, AP1, TNF-α, PKC, and Nrf2 pathways has been shown to have significant pharmacological activities on a variety of cancers, including hepatocellular carcinoma, colon cancer, breast cancer, lung cancer, cervical cancer, and bladder cancer.
There is an increasing body of evidence from randomised, controlled clinical trials suggesting that flavonoids may be beneficial for the vascular system, particularly with regard to the prevention of endothelial dysfunction. Recent epidemiological studies have suggested a positive association between diets high in flavonoid-rich foods and cardiovascular health. An 18% reduction in the risk of fatal CVD in those with total flavonoid intakes in the top quintile (≥359.7 mg/day) compared with those in the bottom quintile (<121.5 mg/day) has been demonstrated, and it has been suggested that even a relatively low habitual intake of flavonoid-rich foods may be beneficial in reducing the risk of fatal CVD.
An association between reduced risk of death due to CVD and dietary intake of flavanones, anthocyanidins and certain flavonoid-rich foods such as apples, red wine, grapefruit and chocolate was also found.
A major systematic review and meta-analysis published in the American Journal of Clinical Nutrition provides the most comprehensive trial-level assessment to date: 133 trials of the effects of flavonoids on CVD risk factors were included. Significant heterogeneity confirmed differential effects between flavonoid subclasses. No randomized controlled trial studied effects on CVD morbidity or mortality. Green tea reduced LDL cholesterol (−0.23 mmol/L; 95% CI: −0.34, −0.12; 4 studies). The effects of flavonoids from soy and cocoa have been the main focus of attention. Future studies should focus on other commonly consumed subclasses (e.g., anthocyanins and flavanones), examine dose-response effects, and be of long enough duration to allow assessment of clinically relevant endpoints.
A meta-analysis of RCTs involving flavonols pooled data from 18 human trials: Results showed significant reductions in total cholesterol (DM = −0.10 mmol/L), LDL cholesterol (DM = −0.14 mmol/L), and triacylglycerol (DM = −0.10 mmol/L), and a significant increase in HDL cholesterol (DM = 0.05 mmol/L). A significant reduction was also observed in fasting plasma glucose (DM = −0.18 mmol/L) and in blood pressure (systolic: DM = −4.84 mmHg; diastolic: DM = −3.32 mmHg). Subgroup analysis showed a more pronounced effect of flavonol intake in participants from Asian countries and in participants with diagnosed disease or dyslipidemia, compared to healthy participants with normal baseline values. Flavonol consumption improved biomarkers of CVD risk; however, country of origin and health status may influence the effect.
Evidence presented includes the potential to reduce blood pressure in hypertensive individuals, as well as increasing peripheral blood perfusion and promoting cerebral blood flow in both healthy and at-risk populations. However, there is great variation in the literature due to the heterogeneous nature of the randomised controlled trials conducted. There is a clear need for further research and understanding within this area.
Evidence strength: Epidemiological associations are moderately strong. RCT evidence supports improvements in surrogate markers (blood pressure, LDL-C, FMD), but no RCTs have yet demonstrated reductions in hard cardiovascular endpoints (myocardial infarction, cardiovascular death). Heterogeneity across subclasses is substantial.
Several studies have revealed that higher consumption of total flavonoids has been linked to reduced risk of diabetes in numerous human trials.
A meta-analysis of eight prospective cohort studies found: Eight prospective studies were included with 312,015 participants, of whom 19,953 developed T2DM during follow-up periods of 4 to 28 years. Compared with lower consumption, high intake of total flavonoids was associated with a decreased risk of T2DM (RR: 0.89, 95% CI: 0.82–0.96). Among flavonoid subclasses, inverse correlations with T2DM were achieved for intakes of anthocyanidins, flavan-3-ols, flavonols, and isoflavones. Dose-response meta-analysis indicated a curvilinear relationship between total flavonoids intake and incident T2DM, with a significant risk reduction at an intake of ≥550 mg/day.
A systematic review and meta-analysis of RCTs on type 2 diabetes biomarkers reported: Significant reduction in fasting glucose (MD: −0.22, 95% CI: −0.34 to −0.09), hemoglobin A1c (HbA1c) (MD: −0.26, 95% CI: −0.46 to −0.05), homeostasis model assessment of insulin resistance (HOMA-IR) (MD: −0.40, 95% CI: −0.66 to −0.15), triglyceride (MD: −0.13), total cholesterol (MD: −0.14), and LDL-C (MD: −0.15) were observed in the intervention group compared to placebo. Flavonoid intake had a negative but non-significant effect on insulin, 2 h-postprandial glucose, HOMA-β, and insignificantly increased HDL-C.
The meta-analysis of RCTs indicated that tea catechins could considerably decline fasting blood glucose, whereas tea or tea extracts did not appear to exert hypoglycemia in T2DM.
Although flavonoids show promising results in reducing fasting blood glucose levels, most human studies have been short-term supplementation trials and lack long-term safety data and evidence for sustained glucose regulation.
Evidence strength: Prospective cohort data are consistent, showing a modest but statistically significant association between flavonoid intake and reduced T2DM incidence. RCT evidence shows statistically significant but clinically modest improvements in glycemic biomarkers. Long-term RCT evidence is lacking.
Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, a review of 15 existing human dietary intervention studies examined the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group.
Neurological and neurodegenerative diseases, particularly those related to aging, are on the rise, but drug therapies are rarely curative. Functional disorders and the organic degeneration of nervous tissue often have complex causes, in which phenomena of oxidative stress, inflammation and cytotoxicity are intertwined. The search for natural substances that can slow down or counteract these pathologies has increased rapidly over the last two decades.
Flavonoids are identified as potential therapeutic agents for neurodegenerative diseases, potentially slowing progression by regulating cellular stress and improving neuroprotection despite their potential medicinal uses and clinical challenges.
While existing animal studies provide important insights into the neuroprotective properties of flavonoids and their underlying mechanisms, these studies cannot provide information regarding potential effects on more complex human cognitive functions. Clinical studies are required to determine if the beneficial effects observed in animal models are replicable in human populations.
Evidence strength: Animal and in vitro mechanistic evidence is extensive. Human clinical trial evidence is preliminary; positive signals have been observed in some RCTs (particularly with cocoa flavanols and berry anthocyanins), but the evidence base is insufficient to draw firm conclusions about clinical efficacy for specific neurological conditions.
Research has comprehensively outlined the cancer-promoting role of the NF-κB pathway in various processes including tumor progression, drug resistance, angiogenesis and metastasis, and has summarised the anticancer potential of flavonoids by specifically targeting the NF-κB pathway in various types of cancers.
Due to their antioxidative, anti-inflammatory, and anti-carcinogenic activities, flavonoids have been revealed to benefit skeletal muscle, liver, pancreas, adipocytes, and neural cells.
Evidence strength: The overwhelming majority of anticancer evidence for flavonoids comes from in vitro cell culture studies and animal models. Epidemiological associations between high flavonoid dietary intake and reduced cancer incidence exist for some cancer types, but large-scale RCTs demonstrating clinical anticancer efficacy in humans are lacking. This area remains an active area of preclinical and early clinical research.
Medicinal efficacy of many flavonoids as antibacterial, hepatoprotective, anti-inflammatory, anticancer, and antiviral agents is well established in experimental and mechanistic studies. Quercetin in particular has been studied for allergy and mast cell stabilization, and has demonstrated inhibition of histamine release in experimental models.
Evidence strength: Mechanistic evidence is well characterized. Clinical RCT evidence in humans for specific inflammatory or allergic conditions is limited and generally of small sample size. More large-scale human trials are needed before firm clinical conclusions can be drawn.
Flavonoids represent a class of natural plant secondary metabolites with multiple activities including antioxidant, antitumor, anti-inflammatory, and antimicrobial properties. However, due to their structural characteristics, they often exhibit low bioavailability in vivo.
Numerous factors affect the bioavailability of ingested dietary flavonoids. When it comes to flavonoid absorption, chemical structure in terms of molecular weight, glycosylation and esterification play a pivotal role. Oral administration of citrus flavanone aglycones, hesperetin and naringenin, to human subjects showed rapid absorption but low bioavailability according to cumulative urinary recovery data. Compounds appeared to undergo extensive first-pass metabolism partly by intestinal bacteria and were degraded into phenolic compounds.
The interaction between flavonoids and other nutrients is notable: fat intake will increase bioavailability, while protein intake will reduce it. The second major factor is the metabolic behavior of the liver (Phase I and Phase II), such as the methylation, sulfation or glucuronidation of flavonoids. The third is the interaction with the gut microbiome. Recent studies have shown that the gut microbiome plays a crucial role in the metabolism of flavonoid compounds. The gut microbiome not only generates bioactive metabolites from flavonoid metabolism but also influences their absorption and biological effects within the host organism.
Additionally, factors such as diet, genetics, and metabolic diseases can significantly affect flavonoid bioavailability, influencing how effectively these compounds are absorbed and utilized by the body.
There is no single universally accepted therapeutic dose for flavonoids as a class, given the chemical diversity of the subclasses and the variety of conditions studied. The following doses reflect those specifically reported in the clinical and research literature:
These dosage figures are derived from specific research studies and should not be treated as standardized therapeutic recommendations, as effective doses vary substantially across flavonoid subclass and condition studied.
Published and unpublished information support the safety of quercetin, including ADME studies; acute, subchronic, and chronic toxicity studies; carcinogenicity, genotoxicity, and reproductive/developmental toxicity studies; pharmacokinetic studies; and human clinical and epidemiological studies. From all available toxicology studies in multiple species, there is an apparent lack of significant adverse systemic toxicity.
A two-year toxicity and carcinogenicity study in rats by the National Toxicology Program (NTP) was pivotal in establishing the safety of quercetin, and the no-observed-adverse-effect level for this study was approximately 2,200 mg/kg bw/day (the highest dose tested). Based on available information, the FDA accepted the conclusion that quercetin is generally recognized as safe (GRAS) under the intended conditions of use.
Despite evidence about the efficacy of flavonoids in experimental models, there is insufficient information on safety parameters for many individual flavonoids.
CYP3A4 is responsible for metabolizing approximately 50% of clinically prescribed drugs across diverse therapeutic classes. While the clinical significance of flavonoid-mediated CYP3A4 inhibition in dietary contexts is generally considered low due to moderate intake and complex interactions, it poses a potential concern for individuals consuming high doses of flavonoid supplements or concurrently taking medications metabolized by CYP3A4. This can lead to increased drug exposure, potentially triggering adverse reactions or reduced efficacy.
Since large doses of flavonoids can be encountered in the intestine simultaneously with ingested drugs and pollutants, studies have investigated interactions with the major intestinal isoforms of cytochrome P450, CYP1A1 and CYP3A4. Genistein, quercetin and chrysin provoked a dose-dependent inducing effect on CYP1A1 activity.
Warfarin, an anticoagulant drug, is mostly bound to albumin and metabolized by CYP2C9. Quercetin, especially at high concentrations, increases the concentration of free unbound warfarin, prompting warfarin toxicity in patients. Flavonoids are capable of releasing warfarin from serum albumin in greater amounts when compared to non-steroidal anti-inflammatory drugs (NSAIDs) and loop diuretics.
It is reasonable to hypothesize that the simultaneous administration of high-dose quercetin-containing dietary supplements with drugs may result in the development of pharmacokinetic interactions.
Furanocoumarins and active bioflavonoids present in grapefruit juice are inhibitors of OATP transporters and, when ingested concomitantly, can reduce the oral bioavailability of OATP substrates. A series of flavonoids present in grapefruit juice are identified as esterase inhibitors, of which kaempferol and naringenin are shown to mediate pharmacokinetic drug interactions with calcium channel antagonists and the statin groups of drugs such as enalapril and lovastatin.
High-dose isoflavone supplementation has been associated in some studies with potential effects on thyroid function, particularly in individuals with existing thyroid conditions or iodine deficiency. Despite evidence about the efficacy of flavonoids in experimental models, there is insufficient information on safety parameters for long-term high-dose use of individual flavonoid concentrates.
Based on available data, supplemental flavonoid isolates (as opposed to flavonoids from whole foods) have not been adequately studied in pregnancy. Research on the safety of concentrated flavonoid supplements during pregnancy and lactation remains limited.
The applications of flavonoids in addressing various health issues affecting the digestive, respiratory, integumentary, reproductive, endocrine, urinary, circulatory, and nervous systems highlights their significant role in systemic disease management.
The body systems most studied and associated with flavonoid activity in the peer-reviewed literature include:
Health conditions that Flavonoids may help support.
Body systems that Flavonoids may help support.
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