IngredientsFlavonols are a structurally defined subclass of flavonoids, themselves members of the broader polyphenol superfamily of plant secondary metabolites. They belong to a large group of compounds called flavonoids, which are diverse in their chemical structure and characteristics. All flavonoids share a common chemical backbone: a 15-carbon skeleton consisting of two benzene rings (labeled A and B) connected by a three-carbon heterocyclic C ring. Within the flavonoid class, flavonols have a hydroxyl group in position 3 of the C ring, which may also be glycosylated. This single structural feature — the 3-hydroxyl substitution on the C ring — constitutes the defining chemical characteristic of the flavonol subclass and is directly responsible for much of its biological activity. The hydroxyl group in the third position of the regular flavone structure is the key structural feature responsible for the antioxidant and biological action of flavonols.
Flavonols are hydroxylated at position C-3 of ring C by flavonol synthase. In natural sources, they may occur in free forms (aglycones), as glycosylated or acylated derivatives, and as oligomeric and polymeric structures. The incredible diversity of over 6,000 known flavonoids comes from variations in this basic structure. Flavonols themselves account for a significant proportion of this diversity, given the wide range of hydroxylation, methylation, and glycosylation patterns found across species.
Quercetin, myricetin, kaempferol, and fisetin are the major dietary flavonols. Other notable members include isorhamnetin, galangin, rutin (quercetin-3-rutinoside), and hyperoside. Each differs from the others in the number and positions of hydroxyl groups on the B ring:
These compounds are characterized by the presence of a C6-C3-C6 skeleton forming the A-C-B ring system, with one, two and three hydroxyl groups present in the B ring of kaempferol, quercetin and myricetin, respectively. The number and site of hydroxyl groups in flavonols obviously affect their anti-inflammatory activity.
Flavonols are one of the most common flavonoid subgroups in fruits and vegetables. Fruits, vegetables, and beverages such as tea and red wine are major sources of flavonols in the human diet. More specifically, flavonols are polyphenols that are especially abundant in broccoli, apples, grapes, tomatoes, onion, kale, tea, red wine, olive, and citrus fruits.
The flavonol quercetin is found as glycosides in many vegetables and fruits, as well as in seeds, nuts, flowers, bark, and leaves. Rich sources include apples, asparagus, berries, Brassica vegetables (e.g., broccoli), capers, grapes, onions, shallots, tea, and tomatoes. Quercetin is also found in large amounts in ginkgo, St. John's wort, and elder. Myricetin is present in various fruits, vegetables, tea, berries, and red wine. Myricetin is found in the Myricaceae, Anacardiaceae, Polygonaceae, Pinaceae and Primulaceae families.
In plants, flavonoid compounds are normally found in flowers, fruits, leaves, and seeds, which are responsible for their color, fragrance, and flavor characteristics. They are responsible for the vibrant colors and aromas of flowers that attract pollinating insects and also protect plants from various stresses like UV radiation, drought, and frost. Flavonoids play protective roles against abiotic (ultraviolet radiation, cold, salt, drought, and heavy metals) and biotic (herbivores, bacteria, fungi) stresses.
Food sources, dietary intakes, and bioavailability of flavonols are strongly influenced by variations in plant type and growth, season, light, degree of ripeness, food preparation, and processing. Dietary consumption of quercetin is estimated to be between 25 and 50 mg per day, accounting for approximately 70% of the total dietary flavonol and flavone intake. The background dietary intake of quercetin across the general U.S. population has been estimated more precisely: the background consumption of quercetin from naturally occurring sources is 5.9 mg per person per day at the mean and 14.7 mg per person per day at the 90th percentile, with a maximum intake value of 258 mg per person per day.
Grape seed, cranberry, and green tea supplements — which are all rich sources of proanthocyanidins as well as flavonols like quercetin, hyperoside, and rutin — can be found in over twelve thousand registered botanical products. Flavonols are commercially available as isolated aglycones (e.g., pure quercetin powder or capsules), as glycosylated forms (e.g., rutin, isoquercetin/isoquercitrin), and as part of standardized botanical extracts (e.g., ginkgo biloba extract, onion skin extract, elder flower extract). The global polyphenols market, as ingredients in dietary supplements, was estimated to be $2.14 billion in 2023. Novel delivery systems under research investigation include nanoformulations, liposomal encapsulation, and complexation with phospholipids, designed to address the relatively low oral bioavailability of flavonol aglycones.
Since ancient times, the presence of flavonoids in plants has been identified, but their chemical structure was not known until the end of the nineteenth century. Natural plants and plant-derived formulations have been used by mankind from the ancient period of time, and for the past few years, many investigations have elaborated the therapeutic potential of various secondary chemicals present in plants.
Traditional medicinal recipes are the sources of flavonoids and other polyphenols aside from medicinal plants. Humans have long used traditional medicines, using them since ancient times, especially in Asian countries. In traditional Chinese medicine, flavonoid-containing herbs have been used for a variety of medicinal purposes, including treatment or prevention of cardiovascular disease, cancer, and inflammation. This ancient practice reflects a deep-rooted understanding of using flavonoid-rich botanicals alongside other natural compounds to create synergistic healing effects.
Plants containing high concentrations of flavonols have been central to multiple traditional medicine traditions. Pomegranate (Punica granatum L.) is a polyphenol-rich edible food and medicinal plant of ancient origin, containing flavonols, anthocyanins, and tannins. Onions, a primary quercetin source, have been used medicinally in ancient Egyptian, Greek, and Roman traditions for inflammatory conditions, infections, and gastrointestinal complaints. Ginkgo biloba, rich in flavonols including quercetin and kaempferol glycosides, has been used in traditional Chinese medicine for over a thousand years to address cognitive decline and circulatory disorders. Evidence exists for the beneficial and neuromodulatory effects of flavonoid-rich ginkgo biloba extracts, particularly in connection with age-related dementias and Alzheimer's disease. Elder (Sambucus nigra), another traditional European medicinal plant rich in flavonols, was used in European folk medicine for respiratory conditions, fever, and as a general tonic.
Researchers worldwide are very interested in discovering the potential of flavonoids and other polyphenols, used in traditional medicines and taken from medicinal plants, in relation to medical and pharmaceutical applications. It is important to note that historical use of flavonol-rich plants does not constitute evidence for the therapeutic activity of isolated flavonols; in traditional contexts these compounds were consumed as part of complex botanical matrices alongside dozens of other phytochemicals.
Quercetin is a potent scavenger of free radicals, providing protection from free radical damage and oxidation-associated diseases. Three structural groups are important for biological activity, including anti-oxidative and radical-scavenging activity of flavonoids: (1) the o-dihydroxyl group in ring B; (2) the double bond at 2,3 attached to 4-oxy group in ring C; and (3) hydroxyl groups at positions C3 and C5. The bioavailability, metabolism, and biological activity of flavonoids depend upon the configuration, total number of hydroxyl groups, and substitution of functional groups about their nuclear structure.
Oxidative stress has been attributed to inflammation, atherosclerosis, ischemic damage, cancer, and neurodegenerative disorders like Parkinson's and Alzheimer's. Flavonols may act as antioxidants, preventing DNA damage by scavenging reactive oxygen radicals, reinforcing DNA repair, disrupting chemical damages by induction of phase II enzymes, and modifying signal transduction pathways.
Mechanistic advances related to antioxidant, anti-inflammatory, antimicrobial, anti-obesity, neuroprotective, cardioprotective, and anticancer activities are highlighted, focusing on the modulation of critical cellular pathways such as PI3K/Akt/mTOR, NF-κB, and AMPK. Flavonols suppress the overproduction of nitric oxide. Fisetin showed the best activity with an inhibition rate of 52% at 20 μM. Moreover, these flavonols reduced the levels of ROS, TNF-α, and IL-6. These findings derive from cell culture (in vitro) models and cannot be directly applied to human physiology without clinical confirmation.
Previous research has produced strong and consistent evidence that flavonoids may improve endothelial function and maintain and enhance nitric oxide (NO) status. There is evidence that these substances can impact lipid and glucose metabolism, platelet function and thrombosis, inflammation, oxidative damage, blood pressure, and inflammation. The potential of flavonols to promote vasodilation and regulation of apoptotic processes in the endothelium are other beneficial effects on the cardiovascular system.
By specifically targeting important molecules and signaling pathways in a range of tumor cells, flavonoids can cause apoptosis and prevent cell growth and metastasis. Flavonoids interact with several signal transduction pathways in the process of carcinogenesis, thereby reducing proliferation, angiogenesis and metastasis and increasing apoptosis. With respect to kaempferol specifically, some studies concluded that quercetin is a promising antioxidant agent while kaempferol could be effective against human gastric cancer. In addition, kaempferol prevents apoptosis of pancreatic beta-cells via boosting the function and survival rate of the beta-cells, leading to increased insulin secretion. These mechanisms have been established predominantly in cell-based and animal models; translation to human cancer outcomes requires clinical evidence (see Section 6).
Flavonoids exert a multiplicity of neuroprotective actions within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. These effects appear to be underpinned by two common processes. First, they interact with critical protein and lipid kinase signalling cascades in the brain leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and synaptic plasticity. Second, they induce beneficial effects on the vascular system leading to changes in cerebrovascular blood flow capable of causing angiogenesis, neurogenesis and changes in neuronal morphology.
The bioavailability of dietary flavonoids is highly variable between individuals. Flavonoids are extensively metabolized by phase I and phase II metabolism (which occur predominantly in the gastrointestinal tract and liver) and colonic microbial metabolism. A number of factors, including age, sex, and genotype, may affect these metabolic processes.
After ingestion, flavonoids undergo extensive metabolization with absorption occurring in both the small and large intestines, with a substantial fraction of intake reaching the colon, where the flavonoids are exposed to colonic microbiota. The resident microbiome operates as a metabolic reactor, thereby playing a key role in catabolizing unabsorbed flavonoids into smaller molecules such as phenolic and aromatic acids, which may become bioavailable.
Upon ingestion, 90% of flavonoids consumed require further enzymatic metabolism by the gut microbiome to enhance their bioavailability and absorption. Except for a small portion of the flavonoid glycosides in the daily diet, which are hydrolyzed into aglycones by enzymes in the digestive tract, most of them are transformed into aglycones by the gut microbiota in the colon and combined with the body's own function. They are further metabolized into various metabolites and small-molecule phenolic acids that can be absorbed by the intestinal cells. Consequently, this biotransformation process of flavonoids mediated by gut microbiota can effectively improve the bioavailability of flavonoid glycosides.
Metabolism of di- and trisaccharides is much slower compared to that of flavonol monosaccharides. The position of the hydroxyl groups may also influence their degradation, as recent studies indicate that flavonoids without hydroxyl groups at the C5, C7, and C4′ positions are degraded slower. There is extensive heterogeneity in the response to increased intake, which is likely mediated via wide interindividual variability in flavonoid absorption and metabolism. Studies have reported a poor bioavailability of flavonoid compounds in humans, which presents a major challenge for determining their optimal dosage, recommended intake, and, consequently, their therapeutic value.
Preclinical data have established flavonols as chemicals with metabolic regulatory actions that may contribute to preventing or delaying the onset of cardiovascular diseases, but human evidence is still limited. The anti-inflammatory effects of flavonols, their impact on the cardiovascular system in both cardiovascular-risk and cardiovascular-disease populations have been the subject of current randomized controlled human trials.
Blood pressure: Quercetin may lower blood pressure slightly, as was demonstrated in a randomized trial of 43 individuals treated with quercetin 365 mg twice daily for 28 days. Both systolic and diastolic blood pressure were modestly lower at 28 days in the quercetin-treated patients (7 mmHg and 5 mmHg, respectively), although this effect was not observed in other studies.
Blood lipids: Apart from a significant reduction in triglycerides at doses above 500 mg/day, quercetin supplementation had no positive effect on plasma lipids according to a meta-analysis by Sahebkar, which included 221 subjects from five randomized controlled trials. Similarly, a recent meta-analysis of 18 randomized controlled studies with a total of 896 participants reported that quercetin administration for 8 weeks or longer had no significant effect on total cholesterol and LDL-c levels. However, levels of HDL-c and TG were favorably changed.
Meta-analysis evidence on cardiometabolic biomarkers: Results of one meta-analysis showed significant reductions in total cholesterol, LDL cholesterol, and triacylglycerol. The results suggest that intake of flavonols, particularly quercetin, has a beneficial effect on blood lipids, glucose, and blood pressure, contributing to lower global risk of cardiovascular disease. In the future, large-scale studies with direct clinical endpoints should be conducted to further corroborate these findings and establish a causal link between a diet rich in flavonols and cardiovascular health.
Overall assessment: Despite promising experimental findings, randomized controlled trials and meta-analyses have yielded inconsistent results on the influence of these substances on human cardiovascular parameters. No randomized controlled trial to date has studied effects on CVD morbidity or mortality. Significant heterogeneity confirms differential effects between flavonoid subclasses and foods. Evidence for flavonols' cardiovascular benefits in humans should therefore be characterized as preliminary and inconsistent, with no established clinical endpoints yet demonstrated.
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. Endothelial function can be described as arterial vasomotor responses mediated by the release of vasodilatory and vasoconstricting chemicals from the endothelium. An imbalance in these endothelium-derived relaxing and contracting factors results in endothelial dysfunction, most commonly characterised by the impaired release of the vasodilator, nitric oxide (NO), predisposing the vasculature to vasoconstriction. The evidence from randomized trials in this area is supportive but heterogeneous across different flavonoid types and populations.
Additional investigations have evidenced that increased intake of flavonols, flavones, and isoflavones is correlated with a reduced incidence of breast, ovarian, and endometrial cancers. These associations are derived from epidemiological (observational) studies and cannot establish causality. There is substantial scientific evidence that high consumption of flavonols is associated with reduced risk of cancer and coronary diseases, free radical damage alleviation, and tumor growth prevention.
At the molecular level, preclinical work on fisetin has shown that fisetin affects over 140 genes, increasing the level of 61 and decreasing the level of 81 genes. A considerable increase in SESN2 protein expression was observed in cells treated with fisetin, and SESN2 mediates apoptosis induced by fisetin. Additionally, fisetin decreases the levels of p-mTOR and Mcl-1 protein expression, suggesting that apoptosis induced by fisetin might be associated with the SESN2/mTOR/Mcl-1 signaling axis. These are in vitro findings. No polyphenol has been identified as a primary treatment for any disease, but many flavonoids appear to provide potentially important adjuvant and preventative treatments. The human clinical evidence for flavonols as anticancer agents remains absent; no flavonol has been approved as a cancer therapy.
A meta-analysis of observational studies suggested that consumption of dietary flavonoids, particularly anthocyanins, flavonols, flavones, and flavan-3-ols, had positive effects on human cognitive function. More observational studies, especially large prospective cohort studies, are needed to provide further evidence about the associations of dietary flavonoids and subclasses consumption with cognitive function.
Through these mechanisms, the consumption of flavonoid-rich foods throughout life holds the potential to limit neurodegeneration and to prevent or reverse age-dependent losses in cognitive performance. The use of flavonoid-rich plant or food extracts in humans and animal dietary supplementation studies have shown improvements in cognition function, possibly by protecting vulnerable neurons, enhancing existing neuronal function, or by stimulating neuronal regeneration.
Recent studies have shown that regular use of flavonoid-rich foodstuffs can effectively enhance cognitive capabilities in humans. Additionally, several flavonoids have been reported to restrain the progression of pathologies of Alzheimer's disease, stemming from their ability to quash the cognitive deficits in numerous normal and transgenic preclinical animal models. 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. Consequently, clinical studies are required to determine if the beneficial effects observed in animal models are replicable in human populations.
Flavonols may play a role in antagonizing diabetes, cancer, cardiovascular disease, and viral and bacterial diseases. Kaempferol prevents apoptosis of pancreatic beta-cells via boosting the function and survival rate of the beta-cells, leading to increased insulin secretion. These pancreatic beta-cell protection findings arise from laboratory models. Perhaps the strongest evidence for the benefits of flavonoids in diseases of aging relates to their effect on components of the metabolic syndrome. Flavonoids from soy, grape seed, kudzu, and other sources all lower arterial pressure in hypertensive animal models and in a limited number of tests in humans. They also decrease the plasma concentration of lipids and buffer plasma glucose. Human clinical evidence specifically for flavonols in diabetes management remains limited; most published data come from surrogate endpoints in small randomized trials.
In a randomized trial of 1,002 outpatients treated with oral quercetin 500 mg or 1,000 mg daily for 3 months to prevent upper respiratory infections, there were no significant adverse events reported. Flavonoids including flavonols have been investigated for their role in respiratory health. Multiple preclinical studies, partially supported by clinical evidence, show quercetin's possible therapeutic/prophylaxis efficacy against SARS-CoV as well as comorbidities like chronic obstructive pulmonary disease (COPD), diabetes mellitus, obesity, coagulopathy, and hypertension. As of the time of that review, 14 interventional clinical trials were underway assessing the efficacy of quercetin along with other antiviral drugs/nutritional supplements as prophylaxis/treatment option against COVID‐19. The overall respiratory evidence base for flavonols remains preliminary and does not yet support firm clinical recommendations.
Flavonoids are widely present in the customary diet and may produce numerous advantageous biological processes in the body when consumed. Previous research has produced strong and consistent evidence that flavonoids may improve endothelial function and maintain and enhance nitric oxide status. There is evidence that these substances can impact lipid and glucose metabolism, platelet function and thrombosis, inflammation, oxidative damage, blood pressure, and inflammation. Population-based analyses using the National Health and Nutrition Examination Survey (NHANES) database have examined the association between dietary flavonol intake and all-cause and cause-specific mortality risk in U.S. adults, with results generally supporting higher flavonol intake being associated with lower mortality — though the observational design precludes causal inference.
Although specific evidence to support dosing recommendations is limited, most clinical studies use quercetin 500 to 1,000 mg per day in divided doses. Specific dosing details reported in source-verified studies include:
Oral supplemental doses of up to 1,000 mg per day for as long as 12 weeks showed no evidence of toxicity. More studies are required to determine the appropriate dietary concentration, dose, and type of flavonol for a particular condition to prevent any adverse side effects.
There is extensive literature on the beneficial effects of quercetin in animal models, and multiple lines of non-clinical data suggest that it should be well tolerated in human subjects. Published and unpublished information support the safety of quercetin, including absorption, distribution, metabolism, and elimination studies; acute, subchronic, and chronic toxicity studies; carcinogenicity, genotoxicity, and reproductive/developmental toxicity studies; pharmacokinetic studies; and human clinical and epidemiological studies. From all of the 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 safety of this agent, and the no observed adverse effect level for this study was approximately 2,200 mg/kg body weight per day (highest dose tested).
In the Ames test, quercetin was initially regarded as mutagenic. However, recent in vitro studies indicate that quercetin is protective against genotoxicants, and is regarded as antimutagenic. In 1999, the International Agency for Research on Cancer (IARC) concluded that quercetin is not classifiable as carcinogenic to humans.
Nephrotoxicity has been reported with high doses of intravenous (IV) quercetin. In a phase I study where quercetin was administered intravenously at doses greater than 2,000 mg, there was evidence of nephrotoxicity in several patients. This risk is specific to intravenous administration and has not been demonstrated at oral supplemental doses.
Data on long-term safety at high doses are lacking, and concerns regarding carcinogenicity remain unresolved.
A published case report describes a 79-year-old man on stable warfarin therapy for atrial fibrillation who presented with an INR of 7.5 after starting quercetin supplementation (250 mg quercetin per day). The patient previously had a stable INR between 2 and 3. Warfarin is primarily metabolized by CYP2C9, which is inhibited by quercetin. Quercetin, especially at high concentrations, increases the concentration of free unbound warfarin, potentially prompting warfarin toxicity in patients.
Quercetin modulates a number of drug-metabolizing enzymes (DMEs) and drug transporters (DTs), including cytochrome P450 (CYP) 1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5-diphospho-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), glutathione-S-transferase (GSTs), P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1).
Quercetin and its metabolites showed weak inhibitory effects on CYP2C19 and CYP3A4, while they did not affect CYP2D6 activity. Most of the compounds tested proved to be strong inhibitors of OATP1B1, OATP1B3, OATP2B1, and BCRP. Not only quercetin but some of its conjugates can also interact with CYP enzymes and drug transporters. Therefore, high intake of quercetin may interfere with the pharmacokinetics of drugs.
Evidence demonstrates that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP (breast cancer resistance protein). Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding food–drug interactions should be considered.
Quercetin is an acidic compound and shows metabolic interaction with some antivirals, antibiotics, and anti-inflammatory agents. Therefore, the physicochemical and metabolic drug interactions between quercetin and combined drugs/compounds must be better understood before developing new compositions.
The quercetin metabolites examined can significantly inhibit certain enzymes/transporters; therefore, 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.
In the U.S. and Europe, supplements of quercetin are commercially available, and beneficial effects of quercetin supplements have been reported in clinical trials. Safety is an important consideration that must be assessed through meticulous and extensive quality control testing, especially since supplements are not subject to the same stringent regulations as pharmaceuticals. Furthermore, human studies (e.g., randomized controlled trials) are required in order to provide clinical and scientific evidence regarding safe and efficacious dose ranges.
Dietary flavonoids are emerging as multifunctional bioactive compounds with significant implications for the prevention and management of chronic diseases. There has been increasing interest in the research on flavonoids from plant sources because of their versatile health benefits reported in various epidemiological studies. Nevertheless, the gap between preclinical findings and validated human clinical endpoints remains substantial. Many studies have focused on the health benefits of flavonoids and other polyphenols tested using in silico, in vitro, and in vivo models. However, few studies have been carried out using clinical trials that have trustworthy subject sizes and are in accordance with clinical practice guidelines.
There is substantial scientific evidence that high consumption of flavonols is associated with reduced risk of cancer and coronary diseases, free radical damage alleviation, tumor growth prevention, and insulin secretion improvement, among other diverse health benefits. Nevertheless, more studies are required to determine the appropriate dietary concentration, dose, and type of flavonol for a particular condition to prevent any adverse side effects.
Health conditions that Flavonols may help support.
Body systems that Flavonols may help support.
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