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Quercetin

Quercetin is a naturally occurring flavonol, a subclass of the flavonoid family of plant polyphenols, with the chemical formula C₁₅H₁₀O₇ and systematic name 3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one, featuring a core structure of two aromatic rings connected by a heterocyclic pyrone ring bearing five hydroxyl groups.^[1] This compound acts as a secondary metabolite in plants, contributing to pigmentation, UV protection, and defense against pathogens, and is abundant in various dietary sources including onions (up to 300 mg/kg), apples, berries, broccoli, capers, green tea, red wine, and seeds like coriander and walnuts.^[1]^[2] As a potent antioxidant, quercetin neutralizes reactive oxygen species such as hydroxyl radicals (OH⁻) and hydrogen peroxide (H₂O₂), inhibits lipid peroxidation, and mitigates oxidative stress, thereby protecting cells from damage associated with aging and chronic conditions.^[2] Its anti-inflammatory properties involve suppressing pro-inflammatory cytokines like TNF-α and IL-1β, inhibiting enzymes such as cyclooxygenase-1 (COX-1) and lipoxygenase-12 (LOX-12), and modulating pathways including NF-κB and PI3K/Akt, which may alleviate symptoms in allergies, asthma, and inflammatory diseases.^[2]^[1] Research highlights additional health benefits, including cardiovascular protection through blood pressure reduction and cholesterol lowering, anticancer effects via induction of apoptosis and inhibition of tumor cell proliferation in models of breast and lung cancer, antidiabetic potential by improving insulin sensitivity, and neuroprotective roles against cerebral ischemia.^[1] However, quercetin's bioavailability in humans is limited, typically ranging from 1% to 17% due to poor water solubility and rapid metabolism, prompting investigations into nanoencapsulation techniques like liposomes and cyclodextrin complexes to enhance absorption and therapeutic efficacy.^[2]^[1] Daily dietary intake generally falls between 5 and 100 mg, though supplements can provide higher doses, underscoring its role as a promising nutraceutical despite ongoing needs for clinical validation.^[2]

Chemical Properties

Molecular Structure

Quercetin has the molecular formula C₁₅H₁₀O₇ and a molecular weight of 302.24 g/mol.^[3] It features a flavone core structure, specifically as 3,3',4',5,7-pentahydroxyflavone, with five phenolic hydroxyl groups attached at the 3-position on the C ring, the 5- and 7-positions on the A ring, and the 3'- and 4'-positions on the B ring.^[3]^[4] Quercetin is classified as a flavonol, a subclass of flavonoids characterized by a 3-hydroxyflavone backbone.^[4] Flavonoids generally consist of a 15-carbon skeleton organized into three rings: the A ring (a fused benzene ring), the C ring (a heterocyclic pyrone ring), and the B ring (a phenyl substituent attached at the 2-position of the C ring); in flavonols like quercetin, the hydroxyl group at the 3-position on the C ring distinguishes this subclass.^[5]^[4] The multiple hydroxyl groups enable intramolecular tautomerism, particularly involving proton transfer from these groups to adjacent carbon atoms, which is facilitated at transition states by cooperative hydrogen bonding.^[6] Additionally, these hydroxyl groups contribute to resonance stabilization across the conjugated π-system of the rings, enhancing the planarity and electron delocalization of the molecule.^[7]^[8]

Physical and Chemical Characteristics

Quercetin is typically observed as a yellow crystalline powder or needles.^[3] It exhibits poor solubility in water, with reported values of approximately 2 mg/L at 25 °C (ranging from 1–13 mg/L depending on pH and whether in anhydrous or dihydrate form), but shows good solubility in organic solvents including ethanol (approximately 2 mg/mL), dimethyl sulfoxide (DMSO; approximately 30 mg/mL), acetone, pyridine, and acetic acid, as well as in aqueous alkaline solutions where it produces a yellow coloration.^[3]^[9]^[10] The compound has a melting point of 316–318 °C, during which it decomposes, releasing acrid smoke and irritating fumes.^[3] Quercetin demonstrates sensitivity to light, air (leading to oxidation), and heat, contributing to its instability under these conditions. Its acidic behavior arises from the hydroxyl groups, with pKa values of 7.17, 8.26, 10.13, 12.30, and 13.11, facilitating deprotonation primarily in the range of 7–10.^[3] In terms of spectroscopic properties, quercetin displays UV-Vis absorption maxima at 256 nm, 301 nm (shoulder), and 373 nm in alcoholic solutions. Additionally, it exhibits intrinsic fluorescence, with an excitation maximum near 370 nm and an emission maximum around 530 nm, a property that is particularly pronounced in cellular milieus.^[3]

Natural Occurrence

In Plants and Foods

Quercetin is a flavonoid abundantly present in various plant sources, serving as a key secondary metabolite in many species. It occurs frequently in fruits such as apples and berries (including blueberries and blackberries), where it contributes to pigmentation and antioxidant defenses. In vegetables, notable sources include onions (particularly red varieties), kale, and capers, with capers exhibiting some of the highest concentrations. Additionally, quercetin is found in grains like buckwheat and in beverages such as tea and red wine, where it leaches into infusions or fermentations from plant materials.^[11] Among these, capers stand out with the highest reported quercetin levels, reaching up to 233.84 mg per 100 g in raw form, while lovage leaves contain approximately 170 mg per 100 g and red onions range from 20 to 50 mg per 100 g. Other high-content examples include kale (20–30 mg per 100 g) and blueberries (7.67 mg per 100 g). These concentrations vary based on factors like plant variety, growing conditions, and preparation methods, but such foods represent primary dietary contributors to quercetin exposure.^[11] In plants, quercetin predominantly exists as glycosides, such as quercetin-3-O-glucoside and quercetin-3-O-rutinoside (rutin), which enhance its solubility and stability within plant tissues. These conjugated forms are the main storage mode, with the free aglycone typically comprising only a minor fraction. During human digestion, intestinal enzymes like lactase-phlorizin hydrolase hydrolyze these glycosides, releasing the bioactive quercetin aglycone for absorption.^[12]^[13] The quercetin content in plant foods can be modulated by agricultural practices. For instance, a long-term study of tomatoes demonstrated that organic farming methods resulted in 79% higher quercetin levels (115.5 mg per g dry matter) compared to conventional approaches, attributed to increased plant stress responses in organic systems.^[14]

Dietary Intake Levels

The typical daily dietary intake of quercetin in Western populations ranges from 5 to 40 mg, with medians often reported around 10 mg, primarily derived from flavonoid-rich foods. In the United States, average intakes are lower, approximately 3.5 to 9.75 mg per day among adults, reflecting moderate consumption of fruits and vegetables.^[15]^[16] Higher intakes, up to 100 mg per day, occur in diets emphasizing flavonoid-dense foods, such as those abundant in plant-based produce.^[17] Major sources of quercetin intake include fruits and vegetables, which contribute roughly 60% collectively, with vegetables accounting for about 50% and fruits around 10% of total flavonoid intake, of which quercetin comprises 70%. The remainder comes predominantly from beverages like tea and red wine, with onions, apples, and green tea serving as key contributors in various studies.^[18]^[19] For instance, in European cohorts, tea and onions are prominent, enhancing overall exposure beyond fruit and vegetable bases.^[20] Intake levels vary by dietary patterns and region; Mediterranean diets, such as in Spain, yield higher averages of 18.5 mg per day due to greater emphasis on fruits, vegetables, and olive oil-associated foods, compared to lower U.S. levels. European intakes generally exceed those in the U.S., with total flavonols reaching 51-52 mg per day in the UK, partly attributable to higher tea consumption. In contrast, some Asian populations report medians of 15-18 mg per day, influenced by green tea and seasonal vegetable intake.^[16]^[15]^[20]

Biosynthesis and Derivatives

Biosynthetic Pathway

Quercetin is biosynthesized in plants primarily through the integration of the shikimate pathway and the phenylpropanoid pathway, starting from the amino acid phenylalanine. The shikimate pathway, localized in plastids, converts phosphoenolpyruvate and erythrose-4-phosphate into chorismate, which is then transformed into phenylalanine. This precursor enters the phenylpropanoid pathway in the cytosol, where phenylalanine ammonia-lyase (PAL) deaminates phenylalanine to form trans-cinnamic acid. Subsequent hydroxylation by cinnamate 4-hydroxylase (C4H) yields p-coumaric acid, which is activated to p-coumaroyl-CoA by 4-coumarate:CoA ligase (4CL).^[21]^[21] The flavonoid branch diverges from p-coumaroyl-CoA, which condenses with three molecules of malonyl-CoA (derived from the acetate pathway) via chalcone synthase (CHS) to produce naringenin chalcone. Chalcone isomerase (CHI) then cyclizes this to the flavanone naringenin. Hydroxylation at the 3-position by flavanone 3-hydroxylase (F3H) generates dihydrokaempferol, followed by 3'-hydroxylation via flavanone 3'-hydroxylase (F3'H) to dihydroquercetin. Finally, flavonol synthase (FLS) oxidizes dihydroquercetin to quercetin, the core aglycone structure. The overall pathway can be summarized as: phenylalanine → cinnamic acid → p-coumaric acid → p-coumaroyl-CoA → chalcone → naringenin → dihydrokaempferol → dihydroquercetin → quercetin.^[21]^[21] Biosynthesis of quercetin is tightly regulated by environmental cues to enhance plant defense and adaptation. Ultraviolet (UV) light, particularly UV-B, induces the pathway by activating transcription factors like those in the MBW complex (MYB-bHLH-WD40), upregulating genes such as CHS and FLS to increase quercetin accumulation as a UV protectant. Wounding triggers rapid PAL and CHS expression through jasmonate signaling, boosting quercetin production for wound healing and antimicrobial activity. Similarly, microbial attack elicits the pathway via elicitor-induced signaling, elevating quercetin levels to inhibit pathogen growth and scavenge reactive oxygen species. These quercetin molecules often undergo glycosylation to form stable derivatives like quercetin-3-O-rutinoside.^[22]^[23]^[24] Quercetin, a flavonol aglycone, commonly exists in plants as glycosylated derivatives, where sugar moieties are attached to its structure, enhancing its properties. The major glycosides include quercetin-3-O-rutinoside, known as rutin, which features a disaccharide rutinose (a combination of glucose and rhamnose) at the 3-position; quercetin-3-O-glucoside, referred to as isoquercitrin, with a single glucose unit; and quercitrin, or quercetin-3-O-rhamnoside, attached to a rhamnose sugar.^[25]^[26]^[27] These glycosides form through enzymatic glycosylation, primarily catalyzed by UDP-glycosyltransferases (UGTs) that transfer sugar groups from nucleotide sugar donors to the hydroxyl groups of quercetin. For instance, UDP-glucose provides the glucose for isoquercitrin, UDP-rhamnose adds rhamnose for quercitrin, and sequential action involving UDP-rhamnose and UDP-glucose yields the rutinose in rutin.^[28]^[29] Rutin can undergo enzymatic degradation in plants via rutinosidase, which hydrolyzes the glycosidic bond to release quercetin and the component sugars, facilitating turnover or mobilization during stress responses.^[30] Glycosylation confers greater stability and water solubility to quercetin compared to its aglycone form, reducing susceptibility to oxidation and improving bioavailability within plant tissues. These compounds also play key roles in plant defense against biotic and abiotic stresses, such as UV radiation and pathogens, and contribute to pigmentation in flowers and fruits by absorbing visible light.^[31]^[32]^[33]

Chemical Synthesis

Natural Extraction Methods

Quercetin has long been extracted from natural sources for traditional applications in dyes and medicines, predating modern industrial processes. In historical contexts, plant materials rich in quercetin glycosides, such as the seeds of Fava d'anta (Dimorphandra mollis) from the Brazilian Cerrado biome, were utilized by indigenous communities for medicinal uses, including treatments for inflammation and circulatory issues, due to the abundant rutin content which can be hydrolyzed to quercetin. Similarly, onion skins (Allium cepa) have been employed in Europe and Arab regions since ancient times to produce yellow and orange textile dyes, leveraging quercetin's natural pigmentation under alkaline conditions. These early methods relied on simple aqueous or alkaline extractions, laying the foundation for contemporary isolation techniques focused on commercial production.^[34]^[35]^[36] The primary modern method for natural extraction of quercetin involves solvent-based techniques, particularly using ethanol or methanol to dissolve the compound from plant matrices like onion peels and Sophora japonica flowers. For onion peels, a common approach entails maceration in 50-80% ethanol at room temperature or mildly elevated temperatures (40-60°C) for several hours, followed by filtration; this yields approximately 2-20 mg of quercetin per gram of dry peel, representing 0.2-2% of the starting material depending on solvent ratio and extraction time. In the case of Sophora japonica flower buds, ethanol extraction under reflux conditions (e.g., 70-90% ethanol at 70-80°C for 1-2 hours) is widely adopted, achieving yields of 1-5% quercetin equivalents after accounting for glycoside hydrolysis, with the plant's high flavonoid content (up to 20% rutin) facilitating efficient recovery. These solvent methods are favored for their simplicity and scalability in commercial settings, though they require subsequent steps to remove solvent residues.^[37]^[38]^[39] Advanced green extraction techniques, such as supercritical CO2 extraction, offer higher purity and environmental benefits by avoiding toxic organic solvents, though yields are generally lower than other methods. This process uses carbon dioxide in a supercritical state (typically 40-60°C and 20-30 MPa) with ethanol as a co-solvent (5-10%) to selectively extract quercetin from sources like onion skins or Sophora japonica, with extraction times of 30-120 minutes yielding approximately 0.02 mg/g from onion material. Subcritical water extraction provides higher yields, up to 16 mg/g from onion skin under optimized conditions (e.g., 165°C, 15 min). Maceration, a foundational solvent soaking method, is often integrated as a preliminary step in these processes, where ground plant material is immersed in ethanol for 24-72 hours to maximize diffusion before advanced refinement. Yields from such natural extractions generally range from 1-5% of the dry plant weight across sources, influenced by factors like particle size, solvent-to-material ratio (1:10-1:20), and pH adjustment to enhance solubility.^[40]^[41]^[42] Purification of crude quercetin extracts is essential for commercial-grade isolates and typically employs chromatographic techniques to separate the target compound from impurities like sugars and other flavonoids. Column chromatography on silica gel, using ethyl acetate-methanol gradients, is a standard method that achieves purities exceeding 95%, as demonstrated in extractions from onion and Sophora sources. Alternatively, preparative high-performance liquid chromatography (HPLC) with reversed-phase columns provides even higher resolution for large-scale purification, often resulting in yields of 80-90% recovery from the crude extract. These steps ensure the final product meets pharmaceutical and supplement standards, building on quercetin's prevalence in plants such as onions and Sophora japonica.^[43]^[44]^[45]

Synthetic Production Routes

The Kostanecki acylation, first reported in 1904, enables the synthesis of quercetin through a multi-step process beginning with the acylation of phloroglucinol using 3,4-dimethoxybenzoyl chloride derivatives. This is followed by Claisen-Schmidt condensation with appropriate aldehydes, cyclization to form the chromone ring, and subsequent demethylation and oxidation steps to introduce the 3-hydroxyl group and achieve the flavonol structure.^[46] The method, while pioneering, typically yields modest overall efficiency due to the complexity of protecting groups and selective hydroxylations required.^[47] The Allan-Robinson reaction, developed in 1926, offers an alternative multi-step route starting from resorcinol derivatives and coumarin intermediates. It proceeds via the condensation of o-hydroxyaryl ketones, such as 2-hydroxy-4-methoxyacetophenone, with aromatic anhydrides like 3,4-methylenedioxybenzoyl anhydride in the presence of a base, leading to pyrone ring formation and subsequent modifications including demethylation and dehydrogenation to produce quercetin.^[48] This approach has been widely adopted for flavonol synthesis, providing a versatile framework for structural analogs despite multi-stage purifications that limit scalability. Contemporary synthetic strategies emphasize enzymatic and microbial routes for sustainable de novo production, bypassing traditional chemical limitations. In engineered Saccharomyces cerevisiae, co-expression of flavonoid 3'-monooxygenase and flavonol synthase pathways from naringenin precursors has yielded up to 20.4 mg/L quercetin from glucose, with optimizations in enzyme sourcing and pathway flux enhancing titer by over 50-fold compared to early efforts.^[49] Similarly, metabolic engineering in Yarrowia lipolytica incorporating a F3H-FLS fusion enzyme and FMOCPR under optimized promoters has achieved 278.9 mg/L in shake-flask fermentations, demonstrating 20-30% molar conversion efficiencies from fed substrates like phenylalanine.^[50] These biotech methods draw briefly from natural biosynthetic precursors such as chalcones but enable fully synthetic production in controlled bioreactors. On an industrial scale, synthetic quercetin via microbial routes has been pursued since the 1990s as a precursor for food colorants and supplements, with recent advancements in strain engineering supporting gram-scale outputs for commercial nutraceuticals.

Pharmacology

Pharmacokinetics

Quercetin exhibits low oral bioavailability, primarily due to its poor water solubility and extensive presystemic metabolism. The aglycone form of quercetin has a bioavailability of less than 1%, while its glycoside forms demonstrate higher absorption rates of 20-50% in humans.^[51] Absorption predominantly occurs in the small intestine via passive diffusion for the aglycone and sodium-dependent glucose transporters (SGLT1 and GLUT2) for glycosides, with minimal uptake in the stomach or colon.^[52]^[51] Bioavailability is enhanced when quercetin is consumed with dietary fats or in quercetin-rich meals, as lipids facilitate micellization and improve dissolution in the gastrointestinal tract.^[52]^[53] Following absorption, quercetin reaches peak plasma concentrations (C_max) of approximately 0.7-6.2 µM within 0.5-2 hours post-ingestion.^[53] It binds extensively to plasma proteins, particularly albumin (70-80%), which aids in its circulation.^[51] Distribution favors accumulation in tissues such as the liver and kidneys, with uptake facilitated by organic anion-transporting polypeptides (OATPs).^[52]^[51] Elimination of quercetin occurs primarily through renal excretion, with a plasma half-life ranging from 11-28 hours after oral administration.^[51] Factors influencing pharmacokinetics include gut microbiota composition, which affects glycoside hydrolysis and uptake; and advanced formulations such as phytosomes, which can increase bioavailability up to several-fold by improving solubility and stability.^[53]^[51]^[52]

Metabolism and Interactions

Quercetin undergoes extensive phase I and phase II metabolism, primarily in the enterocytes of the small intestine and hepatocytes of the liver. Phase I reactions involve oxidation and reduction, while phase II conjugation processes—O-methylation, glucuronidation, and sulfation—occur rapidly upon absorption, converting the aglycone into more water-soluble forms for distribution and elimination.^[54]^[25] Major metabolites include isorhamnetin, formed via O-methylation at the 3'-position, and quercetin-3-glucuronide, a primary glucuronidation product that predominates in plasma.^[55]^[56] Prior to these transformations, the gut microbiota contributes significantly to quercetin's bioavailability by hydrolyzing glycosylated forms, such as rutin (quercetin-3-rutinoside), through bacterial enzymes including α-rhamnosidase and β-glucosidase. This deglycosylation in the colon releases the free quercetin aglycone, which may then be absorbed in the colon, although much of the parent compound remains unabsorbed and is metabolized further by colonic bacteria.^[57]^[58] Quercetin exhibits moderate inhibitory effects on key cytochrome P450 enzymes involved in drug metabolism, including CYP3A4 (Ki = 4.12 μM), CYP2C9 (IC50 = 23.09 μM), and CYP2C19 (Ki = 1.74 μM), potentially altering the pharmacokinetics of co-administered medications.^[59]^[60] These interactions are particularly relevant for substrates like statins (metabolized by CYP3A4), where inhibition may elevate plasma concentrations and increase risk of adverse effects, and warfarin (a CYP2C9 substrate), where quercetin and its metabolites can both inhibit enzymatic clearance and displace the drug from serum albumin binding sites, enhancing anticoagulant activity.^[60]^[61] The absorbed quercetin and its metabolites are primarily eliminated through renal and biliary routes, with the majority appearing as phase II conjugates—such as glucuronides and sulfates—in urine within 24 hours post-ingestion.^[62]^[56] Biliary excretion into feces accounts for a smaller portion, often representing unabsorbed or recirculated material via enterohepatic cycling.^[63]

Safety and Regulation

Food and Supplement Safety

In the United States, the Food and Drug Administration (FDA) has affirmed quercetin as generally recognized as safe (GRAS) for use as a direct food ingredient at levels up to 500 mg per serving, based on scientific procedures outlined in GRAS Notice No. 341 submitted by Quercegen Pharmaceuticals LLC in 2010. This status applies specifically to food applications, such as addition to beverages and other products, but does not impose a strict upper limit for dietary supplements, which are regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994 with ongoing safety monitoring through adverse event reporting. In the European Union, the European Food Safety Authority (EFSA) has not established a specific tolerable upper intake level for quercetin, but evaluations of related compounds and toxicity data support safety at supplemental intakes up to 1 g per day for adults, particularly when used as an antioxidant in foods.^[64] High-purity quercetin extracts (e.g., ≥95% from sources like Dimorphandra mollis) are classified as novel foods under Regulation (EU) 2015/2283 when incorporated into food supplements, requiring pre-market authorization to ensure compliance with safety standards.^[65] Labeling regulations for quercetin-containing products mandate clear disclosure of the ingredient's identity and quantity on supplement labels in both the US and EU; for instance, FDA guidelines require it to be listed by name and quantity in the Supplement Facts panel, while EU rules under Regulation (EC) No 1925/2006 prohibit unsubstantiated health claims, as EFSA has not approved any for quercetin.^[66]^[67] Purity standards for quercetin extracts emphasize high content (typically ≥95% by HPLC) and strict limits on contaminants to mitigate risks; for example, United States Pharmacopeia (USP) monographs specify not less than 98% quercetin and general chapter limits for heavy metals (e.g., lead <0.5 ppm, arsenic <1 ppm, cadmium <0.5 ppm, mercury <0.1 ppm) in dietary ingredients.^[68] These standards, along with testing for microbiological contaminants, ensure product safety across food and supplement applications.^[69]

Toxicity and Side Effects

Quercetin demonstrates low acute oral toxicity in rodent models, with an LD50 value of approximately 160 mg/kg in rats, indicating it is not highly toxic at moderate exposure levels.^[3] No severe adverse effects have been observed at typical dietary intake levels, which are substantially lower than doses used in toxicity testing. In chronic exposure studies, high doses of quercetin exceeding 100 mg/kg body weight have exhibited potential estrogenic activity in animals, including increased serum estradiol levels and modulation of estrogen-responsive pathways.^[70] Additionally, long-term administration in male rats has been associated with kidney strain, evidenced by an elevated incidence of renal tubule cell adenomas at dietary concentrations up to 40,000 ppm.^[71] Human side effects from quercetin supplementation are uncommon and typically mild, with rare reports of gastrointestinal upset such as nausea or stomach discomfort, and headaches occurring at doses greater than 1 g per day.^[72] Hypersensitivity reactions, including tingling sensations or allergic responses, have been noted in susceptible individuals.^[73] Caution is recommended for special populations, including pregnant individuals, due to limited data on its safety during gestation or lactation.^[72] Those with hormone-sensitive conditions, such as estrogen receptor-positive breast cancer, should avoid high doses given quercetin's potential estrogenic effects observed in animal models.^[74] Quercetin may also interact with certain chemotherapy agents by interfering with their oxidative mechanisms, potentially reducing treatment efficacy.^[75]

Health Effects and Research

Antioxidant and Anti-inflammatory Properties

Quercetin exhibits potent antioxidant activity primarily through direct scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS), thereby mitigating oxidative stress in cellular environments.^[76] This scavenging capability is attributed to its polyphenolic structure, particularly the B-ring hydroxyl groups, which donate hydrogen atoms or electrons to neutralize free radicals such as superoxide and peroxynitrite.^[76] Additionally, quercetin acts as a metal chelator, binding ions like iron and cadmium to prevent Fenton-type reactions that generate harmful ROS.^[76] Quercetin further enhances endogenous antioxidant defenses by upregulating the Nrf2 signaling pathway, which translocates to the nucleus and activates antioxidant response elements (ARE) to increase expression of enzymes such as superoxide dismutase (SOD) and catalase.^[76] This indirect mechanism complements its direct radical scavenging, promoting cellular resilience against oxidative damage in various models.^[76] In vitro assays demonstrate quercetin's efficacy as an antioxidant, with an IC50 value of approximately 4.5 μM for DPPH radical scavenging, indicating strong free radical quenching potential at low concentrations.^[77] Quercetin's anti-inflammatory properties stem from its inhibition of key pro-inflammatory pathways, including NF-κB activation triggered by TNF-α, which suppresses the transcription of inflammatory genes.^[16] It also downregulates COX-2 expression in epithelial cells via blockade of PI3K signaling, reducing prostaglandin synthesis.^[16] Furthermore, quercetin attenuates production of cytokines such as IL-6 and TNF-α in immune cells like macrophages and mast cells by interfering with p38 MAPK and PKC-theta pathways.^[16] Quercetin modulates mast cell degranulation by stabilizing these cells and inhibiting calcium influx and histamine release, offering potential benefits in allergic responses.^[16] At the cellular level, quercetin influences signaling cascades such as MAPK (e.g., ERK1/2) and PI3K/Akt, inhibiting their activation to curb inflammation and oxidative stress in models of allergy and cardiovascular dysfunction.^[78] In atopic dermatitis models, it reduces cytokine release via NF-κB and MAPK suppression, while in endothelial cells, it enhances function through PI3K/Akt-mediated eNOS activation, supporting vascular protection.^[78]

Clinical Evidence and Health Claims

Quercetin has garnered attention for potential health benefits in various conditions, but clinical evidence from human trials remains limited and of low to moderate quality, with most studies being small-scale or short-term. Systematic reviews indicate that while preclinical data suggest antioxidant and anti-inflammatory mechanisms may contribute to therapeutic effects, robust randomized controlled trials (RCTs) confirming efficacy in humans are scarce, and no therapeutic uses have been approved by regulatory agencies such as the FDA. Clinical trials investigating neurodegeneration, such as the completed phase 1 trial NCT04063124 for early Alzheimer's disease (results published in 2025 showing safety, feasibility, central nervous system penetration of dasatinib plus quercetin, and preliminary improvements in fluid biomarkers and cognition), and the ongoing NCT04785300 for mild cognitive impairment, continue to explore its potential as a senolytic agent.^[79]^[80]^[81]^[82] In cancer research, quercetin demonstrates preclinical promise through in vitro and animal studies showing inhibition of cell proliferation, induction of apoptosis, and modulation of signaling pathways in various cancer types, including prostate and breast. However, human clinical evidence is weak, with preliminary phase 1 trials (e.g., for Fanconi anemia) reporting safety but no definitive efficacy in tumor reduction or survival outcomes. The FDA has not authorized health claims for quercetin in cancer prevention or treatment, aligning with broader 2000s rulings rejecting unsubstantiated antioxidant-related claims for disease risk reduction due to insufficient evidence.^[83]^[84] For cardiovascular health, meta-analyses of RCTs report modest reductions in blood pressure with quercetin supplementation, typically at doses around 500 mg/day, with systolic blood pressure decreasing by 2-4 mmHg in hypertensive and normotensive individuals over 4-8 weeks. These effects appear more pronounced in those with elevated baseline pressure, potentially linked to improved endothelial function, though larger trials are needed to confirm clinical significance. Evidence for broader cardiovascular benefits, such as cholesterol reduction, is inconsistent across studies.^[85]^[86]^[87] Regarding allergy relief, clinical trials in humans are limited, with small RCTs showing minor symptom improvements, such as reduced nasal congestion and eye itching in seasonal allergic rhinitis at doses of 200 mg/day over 4 weeks. However, these findings are preliminary and inconsistent, with no strong evidence supporting quercetin as a reliable alternative to standard antihistamine therapies.^[88]^[89]^[90] Research on quercetin for COVID-19, primarily from 2020-2023 trials, yields mixed results; some small RCTs reported reduced inflammatory markers (e.g., LDH, CRP) and shorter hospital stays with supplementation, but others found no significant impact on viral clearance or symptom resolution. As of 2025, major health authorities, including the NIH, do not endorse quercetin as a preventive or therapeutic agent for COVID-19 due to insufficient high-quality evidence from large-scale trials.^[91]^[92]^[93]

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https://pmc.ncbi.nlm.nih.gov/articles/PMC9326669/
[26]
Quercetin: A Molecule of Great Biochemical and Clinical Value ... - NIH
Quercetin, like other flavonoids, binds to monosaccharides, disaccharides, and sugars with more than three molecules, such as glucose, galactose, rhamnose, ...
[27]
A Systematic Review: Quercetin—Secondary Metabolite of ... - MDPI
Rutoside, also known in the literature as rutin [11,282,283], isoquercitrin, and quercitrin are the most commonly occurring glycosidic forms of quercetin in ...
[28]
Flavonoids as Aglycones in Retaining Glycosidase-Catalyzed ...
The specific activity for flavonoid glycosides followed the order of isoquercitrin > quercitrin > rutin. The conversion of rutin to quercetin was optimal at ...
[29]
Enzymic Glycosylation of Quercetin to Rutin* | Biochemistry
Quercetin–iron chelates are transported via glucose transporters. ... The synthesis of guanosine 5′-diphosphate d-rhamnose by enzymes of a higher plant.Missing: rutinose | Show results with:rutinose
[30]
Functional Characterization of a Flavonoid Glycosyltransferase in ...
Feb 15, 2018 · The results demonstrated that the recombinant UGT can only accept UDP-rhamnose to rhamnosylate the 7-hydrogen position of quercetin and ...
[31]
Breeding Buckwheat for Increased Levels of Rutin, Quercetin and ...
Exposure of buckwheat grain to moisture results in enzymatic breakdown of rutin to quercetin by rutinosidase (Figure 1), as happens also after milling and ...
[32]
Structural insights and biological activities of flavonoids: Implications ...
Oct 16, 2024 · Glycosylation of flavonoids significantly increases their water solubility and stability, which endows flavonoids with special biological ...<|separator|>
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The Biomarker Flavonoid “Rutin” in Morus Species - IntechOpen
In addition to their visual attractiveness, flavonoids serve vital functions in plant defense systems against UV radiation, pests, and diseases ...
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Therapeutic Potential of Quercetin: New Insights and Perspectives ...
May 14, 2020 · Quercetin, a plant pigment is a potent antioxidant flavonoid and more specifically a flavonol, found mostly in onions, grapes, berries ...
[35]
Quercetin: discover the bioactive compounds from the Cerrado
Feb 9, 2024 · Quercetin is a flavonoid from fava d’anta, a source of rutin, with antioxidant, antimicrobial, and anti-inflammatory properties. It is a strong ...
[36]
[PDF] A Review on Onion Skin, a Natural Dye Source Ozan Deveoglu
These skins have historically been used in coloring textiles to produce dark yellow and orange tones in Europe and Arab countries [35]. Quercetin dyestuff work ...
[37]
US5445842A - Quercetin-containing coloring - Google Patents
Quercetin is an aglycon of rutin and quercitrin, and it is widely distributed among plants, imparting a bright yellow color thereto under alkaline conditions.
[38]
Quercetin extraction from small onion skin (Allium cepa L ... - PubMed
May 1, 2023 · Ethanol: water ratio produced the highest quercetin from the onion skin. RP-HPLC analysis of the extracted material showed 2, 122 mg/g of ...
[39]
Development of Green and Efficient Extraction Methods of Quercetin ...
However, ethanol extract has the highest yield of quercetin (62.39 ± 1.22 mg/g extract) [32]. Deep eutectic solvent-based extraction of antioxidants from onion ...
[40]
Extraction of Rutin and Quercetin Antioxidants from the Buds of ...
Mar 7, 2018 · An environmentally friendly method for the static extraction of rutin and quercetin from the flower buds of Sophora japonica L. by subcritical water is ...
[41]
an effective solvent for the extraction of quercetin from South African ...
Jun 23, 2022 · Our study aimed to optimize the environmentally friendly carbon dioxide-based method for the extraction of quercetin from quince fruit
[42]
Novel extraction, rapid assessment and bioavailability improvement ...
2. Novel techniques for the extraction of quercetin. Conventional extraction methods such as maceration, soxhlet, hydro distillation, and heat-reflux extraction ...
[43]
Quercetin extraction from Rosa damascena Mill via supercritical CO2
In this study, the extraction of quercetin from Rosa damascena Mill was carried out by modified supercritical CO2 with ethanol an entrainer and Soxhlet ...
[44]
Isolation, purification and characterization of quercetin from Cucumis ...
Jan 12, 2023 · Extraction of CSP was carried out using 80% ethanol (SRL, India). Peel of C. sativus were collected from the hostel mess hall, Banasthali ...
[45]
Purification of quercetin in Anoectochilu roxburghii (wall) Lindl using ...
Column chromatography is the conventional method for isolation and purification of quercetin from natural sources. Therefore, quercetin has been isolated ...
[46]
Single-Step Process for Isolation of Pure Quercetin from Aqueous ...
Nov 7, 2024 · The purity of quercetin obtained from LLE was better at 93 ± 2% than the purity obtained from column chromatography (86 ± 2%). Optimization of ...
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https://doi.org/10.1021/jo01361a618
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https://doi.org/10.1039/JR9262902334
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https://doi.org/10.1021/acs.jafc.9b01329
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https://doi.org/10.1186/s40643-024-00825-w
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Pharmacokinetics of Quercetin - IntechOpen
The absorption of QUE, such as other flavonoids, is considered poor, resulting in its variably limited bioavailability [29]. QUE absorption is influenced by ...3. Absorption Of Quercetin · 5. Metabolism Of Quercetin · 7. Excretion Of Quercetin
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A Pharmacokinetic Study of Different Quercetin Formulations ... - NIH
Aug 10, 2023 · Participants received three different doses (250 mg, 500 mg, or 1000 mg) of quercetin aglycone orally. In the single-dose study, blood ...
[54]
The Pharmacological Activity, Biochemical Properties, and ...
Mar 23, 2020 · Previous animal and human research have reported poor oral bioavailability of quercetin after a single oral dose due to macronutrient absorption ...
[55]
Glucuronidated and sulfated metabolites of the flavonoid quercetin ...
However, quercetin (aglycone) is usually not present in plasma, but it is rapidly metabolized during absorption by methylation, glucuronidation and sulfation.
[56]
Contribution of Biotransformations Carried Out by the Microbiota ...
The 3 main Phase II reactions involved in the metabolism of dietary phenols are sulfation ... quercetin 3-O-glucuronide; isorhamnetin-3-glucuronide, Sulfation and ...
[57]
Transit and Metabolic Pathways of Quercetin in Tubular Cells
Jun 3, 2021 · The main glycosylated forms of quercetin are O-glucosides, which are formed from an O-glycosidic bond between the hydroxyl group in position 3 ...Missing: pigmentation | Show results with:pigmentation
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Enzymatic Metabolism of Flavonoids by Gut Microbiota and Its ... - NIH
After ingestion, quercetin reaches the small intestine to undergo deglycosylation by Lactate phlorizin hydrolase enzyme, yielding quercetin aglycone [42].
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The Interaction between Flavonoids and Intestinal Microbes: A Review
Rutin is a glycoconjugate form of quercetin and is poorly absorbed in the small intestine. It is usually hydrolyzed by several gut microbes such as ...
[60]
Evaluation of inhibitory effects of caffeic acid and quercetin on ...
Quercetin was a potent competitive inhibitor of CYP 2C19 and CYP3A4 (Ki = 1.74 and 4.12 μM, respectively) and a moderate competitive inhibitor of CYP2D6 (Ki = ...
[61]
Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and ...
Jul 31, 2020 · Interaction of Quercetin and Its Metabolites with Warfarin: Displacement of Warfarin from Serum Albumin and Inhibition of CYP2C9 Enzyme.
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Interaction of quercetin and its metabolites with warfarin - PubMed
Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy.
[63]
METABOLIC CONVERSION OF DIETARY FLAVONOIDS ALTERS ...
Quercetin-3-O-glucuronide and quercetin-3′-O-sulphate do not inhibit cellular adhesion molecule expression. After first-pass metabolism of quercetin by ...
[64]
Hepatoenteric recycling is a new disposition mechanism for orally ...
Jul 1, 2021 · Many orally administered phenolic drugs undergo enterohepatic recycling (EHR), presumably mediated by the hepatic phase II enzymes.
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Safety Aspects of the Use of Quercetin as a Dietary Supplement
Nov 11, 2017 · The present review is dedicated to safety aspects of isolated quercetin used as single compound in dietary supplements.Missing: labeling | Show results with:labeling
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Consultation process on novel food status - Food Safety
Consultation process on novel food status ; Q ; Quercetin (95 %) derived from the pods and seeds of Dimorphandra mollis, 9 November 2021, Novel when used as or in ...
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Dietary Supplement Labeling Guide - FDA
Apr 1, 2005 · This FDA guide helps ensure proper labeling of dietary supplements, covering identity, nutrition, ingredient labeling, and claims, and applies ...Nutrition Labeling · Other Labeling Information · Chapter V. Ingredient LabelingMissing: quercetin | Show results with:quercetin
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Quercetin related health claims - EFSA - European Union
Apr 8, 2011 · Scientific Opinion on the substantiation of health claims related to quercetin and protection of DNA, proteins and lipids from oxidative damage.
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Quercetin - USP-NF ABSTRACT
Quercetin contains NLT 98.0% and NMT 102.0% of quercetin (C 15H 10O 7) ... United States Pharmacopeia (). Dietary Supplement Monographs, Quercetin. USP ...
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Quercetin & Rutin Supplements Review - ConsumerLab.com
Heavy metals: Rutin products and any quercetin product claiming to contain whole herbs and/or 250 mg or more of minerals per daily serving must not exceed ...
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Quercetin and Ferulic Acid Elicit Estrogenic Activities In Vivo and In ...
Jun 29, 2023 · Additionally, quercetin and ferulic acid caused significant estrogenic effects evidenced by an increase of 8.7 to 22.48% in serum estradiol, ...Missing: chronic | Show results with:chronic
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Abstract for TR-409 - National Toxicology Program - NIH
May 13, 2025 · There was some evidence of carcinogenic activity of quercetin in male F344/N rats based on an increased incidence of renal tubule cell adenomas.
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Quercetin – Uses, Side Effects, and More - WebMD
It's not known if long-term use or higher doses are safe. When applied to the skin: There isn't enough reliable information to know if quercetin is safe or what ...
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Safety Aspects of the Use of Quercetin as a Dietary Supplement
Published adequate scientific data for safety assessment in regard to the long-term use (>12 weeks) of high supplemental quercetin doses (≥1000 mg) are ...Missing: EFSA g/
[75]
Dietary Quercetin Exacerbates the Development of Estrogen ... - NIH
Inhibition of COMT activity by quercetin may expose breast cells chronically to E2 and catechol estrogens. This would permit longer exposure times to the ...
[76]
Quercetin - Memorial Sloan Kettering Cancer Center
Oct 10, 2023 · Because of its antioxidant effects, quercetin may interfere with the actions of certain chemotherapy drugs.
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Quercetin: Its Antioxidant Mechanism, Antibacterial Properties and ...
This review aims to summarize and analyze the preventative effects of quercetin on heavy metal poisoning, pesticide poisoning, mycotoxin poisoning, and ...Missing: standards | Show results with:standards
[78]
Online RP-HPLC-DPPH screening method for detection of radical ...
Jan 23, 2008 · The IC50 values of quercetin, compound 2, compound 5, and compound 3 were 46.7, 88.5, 90.7, and 124.6 microM, respectively. These results ...
[79]
The Effects of Quercetin on Vascular Endothelium, Inflammation ...
Mechanistically, it modulates multiple signaling pathways, including the p53, PI3K/Akt, and MAPK pathways [11,12]. It also exhibits anti-angiogenic ...
[80]
Senolytic Therapy to Modulate Progression of Alzheimer's Disease ...
The purpose of this pilot study is to evaluate whether a combination of two drugs, dasatinib (D) and quercetin (Q) [D+Q], penetrate the brain using ...
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https://pubmed.ncbi.nlm.nih.gov/40274471/
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Phase 1 study of quercetin, a natural antioxidant for children and ...
Apr 22, 2025 · In this dose-finding phase 1 study, quercetin, a natural antioxidant was found to be safe and well tolerated in patients with FA.
[83]
Prostate Cancer Prevention Trial With Quercetin and Genistein
May 15, 2012 · The isoflavone genistein and the flavonoid quercetin have been identified as likely preventive candidates.
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Food Labeling: Health Claims and Labeling Statements; Dietary ...
Oct 3, 2000 · The Food and Drug Administration (FDA) is revoking its regulations codifying the agency's decision not to authorize the use of health claims for ...Missing: quercetin | Show results with:quercetin
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Effects of Quercetin on Blood Pressure: A Systematic Review and ...
Jul 12, 2016 · The results of the meta‐analysis showed significant reductions both in systolic BP (WMD: −3.04 mm Hg, 95% CI: −5.75, −0.33, P=0.028) and ...
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Effects of Quercetin on Blood Pressure: A Systematic Review and ...
Jul 12, 2016 · The results of the meta-analysis showed a statistically significant effect of quercetin supplementation in the reduction of BP, possibly limited to, or greater ...Missing: benefits | Show results with:benefits
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Abstract 13683: Deciphering the Effects of Quercetin on Blood ...
Nov 6, 2023 · Conclusions: The results indicate that quercetin supplementation notably lowers systolic blood pressure in hypertensive and normotensive ...
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https://examine.com/research-feed/study/1lB3L9/
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Effects of repeated oral intake of a quercetin-containing supplement ...
Jun 28, 2022 · The results indicated that oral intake of quercetin-containing supplements might effectively reduce some allergy symptoms derived from pollinosis.
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Quercetin with the potential effect on allergic diseases
May 14, 2020 · Quercetin has a main role in anti-inflammatory and immunomodulatory function which makes it proper for the management of different diseases.
[91]
The effect of quercetin supplementation on clinical outcomes in ...
Sep 26, 2023 · Our findings demonstrate that quercetin administration significantly reduced LDH activity, decreased the risk of hospital and ICU admission ...
[92]
The effect of quercetin on the prevention or treatment of COVID-19 ...
Jul 30, 2020 · There is currently insufficient evidence to recommend quercetin supplementation as a therapy for the treatment or prevention of COVID-19.
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Dietary Supplements in the Time of COVID-19
Sep 20, 2024 · Overview for health professionals of dietary supplements and COVID-19. Research evidence, safety, and use here.