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Quercetin

Quercetin is the most well researched of all bioflavonoids. It is not actually that good of a supplement on its own, but is an interesting research topic. Tons of interactions, and synergistic with other bioflavonoids and increases absorption of Resveratrol and Green Tea Catechins.

Our evidence-based analysis on quercetin features 79 unique references to scientific papers.

Kamal Patel
Research analysis led by Kamal Patel.
All content reviewed by the Examine.com Team. Published:
Last Updated:

Summary of Quercetin

Primary Information, Benefits, Effects, and Important Facts

Quercetin is a bioflavonoid found in fruits and vegetables, but highest levels are found in apples and onions.

Like many other bioflavonoids, Quercetin has anti-oxidant, anti-artherogenic, and anti-carcinogenic properties. Quercetin is also neuroactive, with some of the same abilities as caffeine but less potent.

There is a divide between the effects seen in quercetin in in vitro (cell cultured) studies and in vivo (in living) studies, with cell studies showing great results that are not that amazing in humans or animals. This is mostly due to quercetin having low oral bioavailability (low percentage of the compound is absorbed and put to use), but could also be due to in vitro studies using a form of quercetin called 'quercetin aglycone' whereas this particular form is never found in the blood, even after ingested, as it it gets changed in the liver.

Many studies also note a high range of differences between people who ingest the same amount of quercetin, suggesting a large degree of variability is possible with supplementation.

Quercetin has GRAS (Generally Recognized As Safe) status, and no side-effects have yet been noted in doses of a few grams a day in either humans or animals.


Things To Know & Note

Is a Form Of

Primary Function:

Also Known As

Apple extract, 3, 4, 5, 7-pentahydroxylflavone

Goes Well With

  • Other bioflavonoids such as Genistein and Resveratrol, due to AMPK activation (in the cell) or by increasing bioavailability (in the gut)

  • Green Tea due to catechol-o-methyl transferase inhibition, and increasing bioavailability of Green Tea Catechins

  • Apigenin in regards to reducing Aromatase transcription

Caution Notice

Examine.com Medical Disclaimer

  • Quercetin (as dehydrated powder) is yellow colored

How to Take Quercetin

Recommended dosage, active amounts, other details

Dosages of quercetin used are in the range of 12.5 to 25mg per kg body weight, which translates to a range of 1,136-2,272mg daily consumption of quercetin when in isolation.

It is suggested to supplement with other bioflavonoids such as resveratrol, genistein, or green tea catechins to increase the potency synergistically and theoretically get the benefits at a reduced level of intake.

When looking for quercetin, the form of dihydrate has the apparent best bioavailability followed by glycosides, aglycone, and finally rutinoside.

Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects quercetin has on your body, and how strong these effects are.
Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
grade-b Blood Pressure - High See all 3 studies
No acute alterations in blood pressure following Quercetin supplementation
grade-c Exercise-induced Stress Response Notable - See study
The exercise-induced increase in HSP70 expression is abolished with quercetin preloading
grade-c General Oxidation Minor Moderate See 2 studies
May reduce oxidative biomarkers in serum and urine, but is a tad unreliable in doing so.
grade-c HDL-C Minor - See 2 studies
An increase in HDL-C has been noted following quercetin supplementation
grade-c Intestinal Permeability Minor - See study
An increase in the amount of intestinal permeability induced by training in the heat has been noted with quercetin supplementation, which is an adverse event; the influence of quercetin at rest is uncertain
grade-c LDL-C Minor - See 2 studies
A decrease in LDL-C has been noted in persons with high blood lipids, although this decrease is not observed in persons who do not have high LDL-C concentrations.
grade-c 8-isoPGF2a - - See study
Urinary 8-isoPGF2α is unchanged with prolonged quercetin supplementation.
grade-c Anaerobic Running Capacity - Very High See 2 studies
No significant influence on anaerobic exercise capacity when preloaded
grade-c Blood Glucose - - See study
No significant alterations in blood glucose are detected with quercetin supplementation.
grade-c Fat Oxidation - - See study
No significant alterations in fat oxidation noted with quercetin supplementation
grade-c Fatigue - - See study
No significant influence on fatigue nor vitality in otherwise healthy persons
grade-c Heart Rate - - See study
No significant influence on heart rate either acutely or with prolonged supplementation.
grade-c Hydration (Total Body Water) - - See study
Hydration during exercise in the heat is unaffected by quercetin supplementation.
grade-c Inflammation - - See study
Mixed influence on inflammation, but does not appear to at all be practically significant
grade-c Interleukin 6 - - See study
The alterations in IL-6 concentrations seen with exercise are unchanged with quercetin supplementation.
grade-c Metabolic Rate - - See study
No significant influence on metabolic rate following acute Quercetin supplementation
grade-c Rate of Perceived Exertion - - See 2 studies
grade-c Sleep Quality - - See study
No significant influence on sleep quality
grade-c Training Volume - - See study
Training volume does not appear to be significantly influenced with quercetin supplementation.
grade-c Uric Acid - - See study
No significant influence on uric acid concentrations
grade-c Weight - - See study
No significant alterations detected in body weight with quercetin supplementation.
grade-c vLDL-C - - See study
No significant changes in vLDL-C are detected with quercetin supplementation.
grade-d Total Cholesterol Minor - See study
An increase in total cholesterol has been noted, but mostly attributed to HDL

Studies Excluded from Consideration

  • Confounded with other nutraceuticals[1][2]

Scientific Research on Quercetin

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1Sources and Structure

1.1Food Sources

Quercetin is one of the most prominent bioflavonoid compounds in plants, and is found in the food products:

  • Onions, commonly seen as the best source of Quercetin[3] at 60-100mg/100g fresh weight[4]

  • Grapes,[5] and due to that Wine also has a Quercetin content

Dietary supplements (fruits, leaves, or herbal compounds) may also confer a Quercetin content either as free Quercetin or one of its glycosides; popular or particularly good sources of Quercetin include:

1.2Structure

Quercetin possesses the basic flavonol backbone (hydroxylation on the 3 carbon of the central ring) with two other hydroxylations on the outer ring. Removal of one of these hydroxy groups creates Kaempferol, which is the backbone for the active metabolite of Horny Goat Weed, Icariin. Substitution of the removed group with a methoxy group creates the metabolite isorhamnetin. A glycoside of quercetin, called quercetin 3-O-beta-rutinode, is more commonly referred to as rutin.[10]

2Molecular Targets

2.1Xanthine Oxidase

Like some other bioflavonoids, quercetin has the ability to inhibit the xanthine oxidase enzyme[11]

2.2COMT

Quercetin has its antioxidant potential reduced via the enzyme catechol-o-methyl transferase[12] which is strongly inhibited by green tea catechins.

2.3SIRTs

SIRT6 appears to be a direct molecular target of quercetin as it directly binds to the protein[13] where it has been noted to inhibited the deacetylase function in silico[14] yet at 100µM in DT40 cells quercetin has failed to modify its activity significantly.[14]

3Pharmacology

3.1Absorption

After oral ingestion of quercetin, it is taken up from the gut into the liver. The conjugate of quercetin influences its absorption rates. At least intestinally, quercetin glycosides (food source) were found to have a 52+/-15% uptake, quercetin rutinoside (tea) has a 17+/-15% uptake, and supplemental quercetin aglycone had a 24+/-9% uptake.[15]

One pharmacokinetic study in humans following consumption of 500mg Quercetin (as aglycone) noted that the delivery of Quercetin chews had a Cmax of 1051.9+/-393.1ug/mL at Tmax of 3.66 hours, with the Cmax and Tmax of Food bar format and juice suspension reaching 698.1+/-189.5μg/L (in 2.3h) and 354.4+/-87.6μg/L (4.7h), respectively.[16] This study had all forms using QU995, and was unable to conclude any significant differences between groups due to higher variability (just different average).[16]

Appears to per se have a moderate to low bioavailability, depending on the source

Due to enhanced lymphatic release of Quercetin following administration of Long-Chain Fatty acids (LCFAs), it is thought that the formation of micelles from LCFAs can enhance the apparent bioavailability of Quercetin.[17]

Quercetin is a potent inhibitor of intestinal sulfurotransferases, and has some activity on hepatic sulfurotransferases as well.[18] This mechanism may increase bioavailability of compounds that undergo extensive intestinal metabolism via this method, like Resveratrol.[19]

Interacts with intestinal conjugation enzymes, which may predispose Quercetin to nutrient-nutrient interactions

3.2Circulating Quercetin

Acute administration of 2,000mg quercetin aglycone (in a food matrix) increases circulating quercetin aglycone to a concentration of 4.76+/-2.56μM at one hour.[20]

250-500mg of the aglycone has been detected in the blood within 15-30m and peaks in the 120-180m range, reaching baseline concentrations within 24 hours.[21] 730mg of the aglycone has been noted to increase plasma concentrations from 695+/-103nM to 1419+/-189nM.[22]

Supplementation of 50, 100, and 150mg quercetin (as dihydrate) can increase blood concentrations of quercetin to 92.2nM, 171.8nM, and 316.2nM respectively; the largest dose was also associated with a large range of serum concentrations, from 240–1292nM[23]

Basal concentrations of quercetin in the blood (from food intake) average 53.6nM, with a large range of 30–163nM.[23]

3.3Metabolism

After the liver, quercetin exists in the blood solely as quercetin glucuronides.[24] Regardless of initial source, all forms of quercetin undergo hydrolysis and get glucuronidated in the liver before being released into systemic circulation.

3.4Neural Pharmacology

In pigs, feeding of quercetin aglycone at 50mg/kg BW increased neurological concentrations to 0.02uM,[25] while another study noted levels of 0.22uM with a dosage of 500mg/kg BW.[26]

Quercetin is a highly polar (water-soluble) compound, but seems to be able to cross models of the blood brain barrier.[27][28] Mixed onion flavanoids (of which Quercetin comprises a large amount) appear to have around a 60% efficacy in crossing the BBB.[29]

4Neurology

4.1Adenosinergic Neurotransmission

Quercetin is an adenosine receptor antagonst (similar to caffeine), with a Ki value of approximately 2.5μM.[30] Although this is approximately 10-fold more potent than caffeine (25μM[31]) quercetin has failed to confer caffeine like effects when orally dosed at 200mg (despite caffeine being active).[32] This is thought to be related to the poor neural bioavailability of quercetin, where 50-500mg/kg in animals increases neural quercetin to 0.02-0.22μM.[26][25]

Although technically a potent adenosine receptor antagonist, it does not appear to be very effective in living models due to its poor absorption into the brain

4.2Neuroprotection

In vitro studies at 25-100uM show that quercetin is able to protect PC-12 neurons from oxidative stress induces from toxins and peroxides[33][34] as well as inhibiting formation of beta-amyloid pigmentation.[35] Protective effects against some ROS has been reported as low as 0.5uM of quercetin-3-glucuronide, which may be the only effects notable with basic quercetin supplementation due to low oral bioavailability and brain concentrations.[36]

On the other side of things, quercetin can be a potential neurotoxic substance in supraphysiological levels. Quercetin has been noted in some studied to initially protect the neuron and later act as a toxin in in vitro studies.[37] Quercetin seems to, in pure in vitro neuronal cultures, to induce toxicity at a concentration of 1-10uM[38] but is protected to a degree in vivo by metabolization by glial cells around neurons.[39] Inducing supraphysiological concentrations of quercetin in the range of 30uM-100uM in cultures with glia cells shows no signs of toxicity and increased survivial of neurons, however the effectiveness of the quercetin per unit is reduced by the protecting metabolization.[40][41]

4.3Inflammation

In regards to neuroinflammation, quercetin is able to act as an anti-inflammatory in the brain (and thus protectant of Alzheimers and Parkinsons, of which inflammation is an exacerbating factor) by increasing heme-oxygenase-1 expression which suppresses nitric oxide release induced from an inflammation response at concentrations as low as 10uM.[42][43] Suppression of other pro-inflammatory markers, TNF-alpha and IL-1alpha, occurred with quercetin (and resveratrol) at concentrations as low as 0.1uM.[44]

4.4Stimulation

When fed to rats at doses between 10-40mg/kg bodyweight, Quercetin does not seem to influence movement or stimulation any more than control.[45]

4.5Learning

One animal model noted that Quercetin, dosed at 10,20, or 40mg/kg bodyweight taken orally, was able to reduce learning as assessed by the Y-Maze and Morris Water maze task[45] yet no dose-dependence was noted. Only one other study has focused on cognition in healthy animals, and it was found that Quercetin was capable of deteriorating anterograde cognitive functions as assessed by the inhibitory avoidance task.[46] The lowest dose used (10mg/kg), after body surface area conversions,[47] correlated to 48.6mg Quercetin in an adult male human.

In these rats, lowered levels of phosphorylated CREB were noted.[45] This protein (CREB) is activated when short-term memories are translated to long term memories via creating proteins[48] and these proteins appear to be crucial to long-term memory storage.[49][50] These may be downstream to a reduction in Akt phorphorylation also noted[45] which appears to be a regulator of CREB.[51] CREB phorphorylation was decreased by 28%, 37%, and 35% at 10,20,40mg/kg bodyweight and Akt by 29% (20mg/kg) and 53% (40mg/kg).[45] The decreased phosphorylation of CREB paralleled that of CaMKII much more than it did Akt, and all results were recorded 1 hour after consumption.[45] The authors hypothesized that Quercetin affects acquisitional memory.[45]

Possible that Quercetin could adversely affect memory in healthy humans, but insufficient studies have been conducted

5Cardiovascular Health

5.1Blood Pressure

In persons with stage I hypertension given 730mg quercetin (aglycone in two divided doses) over a month, supplementation was associated with reductions in both systolic (−7+/-2mmHg) and diastolic (-5+/-2mmHg) independent of improvements in oxidative status; this benefit was not seen in nonhypertensive persons.[22] The changes in blood pressure did not persist following supplement cessation.[22]

6Effects on Exercise Performance

6.1Exercise Endurance

In mice, mitochondrial biogenesis associated with exercise is increased with oral supplementation of 12.5-25mg/kg quercetin.[52]

In mice, exercise induced mitochondrial biogenesis appears to be increased

500mg quercetin (as 3-O-glucoside) twice daily via gatorade to athletes subject to twelve 30m sprints after a week of supplementation failed to influence sprint performance, fatigue, or the rate of percieved exertion (RPE)[11] and a single acute dose of 2,000mg quercetin (aglycone via energy bars) prior to a cycling test (15m time trial on an erg bike) failed to influence performance.[20]

Studies that use quercetin in isolation for power output tend to note failures with supplementation

One study using quercetin (300mg) alongside green tea catechins (300mg) and caffeine (45mg) has noted improvements in exercise performance in trained cyclists[1] and the addition of quercetin (300mg twice daily) to an antioxidant cocktail that was given to the placebo group is associated with improved performance on a 30km time trial (improved power output in the final stretch with no changes in RPE) after six weeks of supplementation.[2] This latter study has been somewhat replicated, with the addition of quercetin (500mg twice daily) to a vitamin drink also given to placebo being associated with an improved VO2 max and time to fatigue on a cycling test after seven days.[53]

Studies that note benefit tend to use prolonged supplementation of quercetin (over a week at minimum) and are usually confounded with the inclusion of other antioxidants. That being said, the inclusion of quercetin to the antioxidants tends to outperform the antioxidants by themselves

6.2Hydration

Supplementation of 2,000mg quercetin (aglycone delivered via energy bars) has failed to outperform placebo in regards to preserving hydration during an exercise session in the heat.[20]

Does not appear to support hydration during exercise

6.3Heat Response

Quercetin appears to be an inhibitor of the Heat Shock Response, a response to heat exposure that results in activation of heat-shock and heat-response proteins[54][55] that can have wide-reaching effects such increasing intestinal permeability.[56] Specifically, Quercetin has shown inhibition at the level of phosporylation and trimerization in the cytosol[57][58][59] and downstream effects on promoter binding[60] and results of genetic signalling (mRNA expression and protein accumulation).[55] Through these effects, it may mitigate the anti-inflammatory effects of Heat-Shock Protein 70 (HSP70).[61] In humans, 30mg/kg quercetin a day (averaged to 2,000mg Quercetin daily) taken with exercise was shown to increase urinary lactulose on day 1, and increase both lactulose and serum endotoxin on day 7 after heat acclimatization should have occurred.[57] These results suggest impairment of intestinal permability acutely, and prevention of beneficial adaptations to heat over continual heat exposure associated with 2g Quercetin supplementation.[57]

7Interactions with Hormones

7.1Testosterone

Quercetin, at 20mg/kg bodyweight, can prevent testicular damage from Dioxins and thus prevent a decline in testosterone levels;[62] the mechanism seems to be through being an anti-oxidant present in the testes[63] as it is the same mechanism by which quercetin protects the kidneys from Dioxins.[64] Quercetin may also protect against physical injuries, as evidenced by rotating rat testicles 720 degrees clockwise.[65]

Quercetin can increase aromatase activity 4x at a concentration of 100uM,[66] but possesses inhibitory actions at a lower dosage (0.026uM).[67] It shows some suppressive effects on mRNA transcription of aromatase in the corpus luteum[68] and in a seemingly dose dependent manner, with 10uM being more potent than 100nM. Quercetin shows synergism with Apigenin in this regard.[68] In intestinal cells, they do not influence mRNA levels but induce aromatase activity.[69]

Using onion juice, a good source of Quercetin, testosterone levels can increase in rats after 4g/kg bodyweight daily for 20 days.[70]

The biochemistry seems to be in line with an estrogen modulator; having the ability to regulate estrogen and androgen levels depending on its concentration.

8Quercetin Glycosides and Derivatives

A glycoside is a term used to refer to a molecule connected to sugar molecules. Glycosides tend to exist in plants as a storage form, and upon human consumption they can either be hydrolyzed into the molecule and sugars (two separate things to make note of) or remain bound together. For example, Cyanidin is a molecule while Cyanidin-3-O-Glucoside is a glycoside thereof that has some unique properties and can be detected in the blood after oral ingestion
Glycoside is a term that does not discriminate the sugar in concern, whereas the term glucoside may be used to refer to the same thing if the sugar is glucose; looking at the following list, Isoquercetin is both a glycoside (bound to sugar) and a glucoside (the sugar is glucose) but Rutin is only a glycoside and not a glucoside. The molecule with no sugars attached can be referred to an aglycone (without sugar) or aglucone (without glucose)

8.1Quercetin-3-O-Rutinoside (Rutin)

Quercetin-3-O-Rutinoside is more commonly called Rutin, and consists of a Quercetin molecule bound to the sugar rutinose; rutinose is a disaccharide of rhamnose and glucose (6-O-L-rhamnosyl-D-glucose). It can be found in a variety of plants alongside Quercetin, but is in high amounts in Ziziphus Jujuba leaves.

8.2Quercetin-3-O-Rhamnoside

Quercetin-3-O-Rhamnoside is a glycone where Quercetin is attached to the sugar Rhamnose, found in high levels in Irvingia Gabonensis

8.3Quercetin-3-Glucoside (Isoquercetin)

Quercetin-3-Glucoside is a Quercetin molecule with a lone glucose sugar bound to the 3 carbon, and has the common name of Isoquercetin; it commonly co-exists with Quercetin in food products.

8.4Quercetin 3-O-β-D-glucoside

Quercetin 3-O-β-D-glucoside is structurally similar to Isoquercetin, but with modifications on the glucose moiety.

8.5Quercetin-4'-O-Glucoside (Spiraeoside)

Another glucoside of Quercetin, where the glucose is attached to the 4' carbon rather than the common 3 carbon; this conjugate is sometimes referred to as Spiraeoside, and is found in the herb Filipendula ulmaria as well as common onions.

8.6Quercetin 3-D-galactoside (Hyperin)

Quercetin bound to a galactose molecule (one of the two constituents of lactose) results in a glycoside known as Hyperin, with other names included Hyperoside; this glycoside is in relatively high levels in the leaves of the plant bearing Chinese Hawthorn

8.7Quercetin-3,6-Malonylglucoside

Quercetin-3,6-Malonylglucoside (Q3MG) is a monoglucoside structure with a malonyl attachment on the glucose moiety, found in high concentrations in the leaves of Morus Alba (260mg/100g[71]) which exceeds that of onions, thought to be one of the best sources of Q3MG at 60-100mg/100g;[4] Morus Alba leaf extracts (tea) is commonly consumed as an anti-diabetic therapy, although this may be more related to non-quercetin structures (the iminosugars, with 1-deoxynojirimycin being particularly important to Morus Alba).

8.8Quercetin-3-O-robinobioside

Quercetin-3-O-robinobioside is a glycoside where Quercetin is attached to Robinose, Robinose being a rhamnose sugar attached to a galactose sugar and Robinoside being interchangeable with 6″-O-α-rhamnopyranosyl-β-galactopyranoside. This glycsoide is found in high levels in the leaves of Boerhaavia Diffusa.

8.9Quercetin Rhamnohexoside

Quercetin Rhamnohexoside is a glycoside found in high levels in the leaves of Gynostemma pentaphyllum, alongside Quercetin Dirhamnohexoside (an additional Rhamnose sugar).

The following molecules are variants on Quercetin, where the structure is slightly modified but not due to the addition of a sugar molecule to the structure

8.10Methylated Quercetin Molecules

Pentamethylquercetin is a molecule where the Quercetin molecule has been methylated five additional times, and constitutes up to 0.391% of the dry weight of the leaves of Kaempferia Parviflora

3-O-Methylquercetin is a structure where the 3-carbon (where many glycosides attach) is methylated, and appears to be the main bioactive in Rhamnus Nakaharai

9Nutrient-Nutrient and Nutrient-Drug Interactions

9.1Yerba Mate

Yerba Mate is a form of tea with a caffeine content and a relatively unique blend of polyphenolic compounds. The saponin content of Yerba Mate synergistically works with Quercetin to suppress inflammation via NO and PGE(2).[72]

References

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