What is quercetin

Quercetin is a polyphenolic flavonoid widely distributed in many plants and fruits including red grapes, citrus fruit, tomato, broccoli and other leafy green vegetables, and a number of berries, including raspberries and cranberries ¹. Quercetin acutally belongs to a type of flavonols, which is a class of flavonoids that have the 3-hydroxyflavone backbone (3-hydroxy-2-phenylchromen-4-one) and present in a wide variety of herbs including licorice ². Quercetin is a licorice flavonoid and its IUPAC name is 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one.

Several studies demonstrated that quercetin had diverse bioactive effects such as antiviral activity, anti-asthmatic activity, anti-oxidant, monoamine-oxidase inhibitor, anti-tumor and anti-inflammatory activity and quercetin has been studied extensively as a chemoprevention agent in several cancer models ³, ⁴, ⁵. Quercetin has been used in medicine to decrease capillary fragility. It has also been used in dyes and as a veterinary drug ⁶. However, there is no reliable clinical evidence that quercetin has a protective effect on human cancer.

Quercetin itself (aglycone quercetin), as opposed to quercetin glycosides, is not a normal dietary component. Quercitin glycosides are converted to phenolic acids as they pass through the gastrointestinal tract. Quercetin has neither been confirmed scientifically as a specific therapeutic for any condition nor been approved by any regulatory agency. The U. S. Food and Drug Administration has not approved any health claims for quercetin. Nevertheless, the interest in dietary flavonoids has grown after the publication of several epidemiological studies showing an inverse correlation between dietary consumption of flavonols and flavones and reduced incidence and mortality from cardiovascular disease and cancer. In recent years, a large amount of experimental and some clinical data have accumulated regarding the effects of flavonoids on the endothelium under physiological and pathological conditions. The meta-analysis of seven prospective cohort studies concluded that the individuals in the top third of dietary flavonol intake are associated with a reduced risk of mortality from coronary heart disease as compared with those in the bottom third, after adjustment for known risk factors and other dietary components. A limited number of intervention studies with flavonoids and flavonoid containing foods and extracts has been performed in several pathological conditions.

Flavonoids are a large group of compounds (>4000) that occur naturally in fruits, vegetables, nuts, seeds, flowers and other plant matter and as such they are an integral part of the human diet ⁷. They all share a common three-ring structure but are subdivided into flavonols, flavons, flavanols and flavanons according to their substituents ⁸. Epidemiological studies indicate that diets rich in flavonoids are associated with reduced incidences of several chronic diseases including cardiovascular disease, asthma, type II diabetes and certain types of cancer ⁹. The cardioprotective properties of flavonoids are multi-faceted involving antioxidant, anti-hypercholesterolaemia, anti-inflammatory and inhibition of platelet aggregation effects ⁹. The antioxidant property of flavonoids was thought, until relatively recently, to underlie the majority of their protective cellular effects. However, it is becoming increasingly apparent that flavonoids also influence cellular function by modulating the activity of many enzymes including the inhibition of protein kinases and lipid kinases ¹⁰.

The inhibitory effect of flavonoids on protein kinase activity is primarily due to their ability to function as competitive inhibitors of the ATP-binding domain located in the active site of these enzymes ¹⁰. Protein kinases directly inhibited by flavonoids include protein kinase C (PKC), myosin light chain kinase (MLCK) and MEK1 ¹⁰. MEK1 is an upstream kinase responsible for the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase (MAPK) family of protein kinases ¹¹. This family also includes p38 MAPK and JNK signalling pathways, both of which are targets for modulation by flavonoids ¹². It is also notable that flavonoids such as quercetin also inhibit (via competitive inhibition of the ATP-binding site) the lipid kinase PI-3Kγ ¹³, which plays a prominent role in the activation of protein kinase B (PKB; also known as Akt).

The MEK/ERK1/2 and the PI-3K/PKB pathways are important signalling pathways which mediate cell survival and cardioprotection against ischaemia/reperfusion injury ¹⁴. In contrast, p38 MAPK and JNK cascades are typically associated with inflammation and cell death; however, there is also evidence that they mediate cardioprotection ¹⁴. Hence, the cardioprotective effects of flavonoids may relate to their ability to modulate MAPK and PI-3K/PKB signalling cascades. Indeed, recent studies have shown that grape seed proanthocyanidin extract protects cardiomyocytes from ischaemia/reperfusion injury via PKB activation ¹⁵. Similarly, quercetin (the most abundant dietary flavonoid) protected H9c2 cardiomyoblasts from H2O2-induced cell death via enhancement of ERK1/2 and PI-3K/PKB signalling ¹⁶. In contrast, isorhamnetin (a flavonol isolated from sea buckthorn) prevented H2O2-induced activation of apoptosis in H9c2 cells through ERK1/2 inactivation ¹⁷.

Figure 1. Quercetin

Figure 2. Molecular structure of quercetin, quercetin glycoside, quercetin glucuronide, quercetin sulfate and methylated quercetin

Note:

Quercetin (C15H10O7) is an aglycone, lacking an attached sugar. It is a brilliant citron yellow needle crystal and entirely insoluble in cold water, poorly soluble in hot water, but quite soluble in alcohol and lipids. A quercetin glycoside is formed by attaching a glycosyl group (a sugar such as glucose, rhamnose, or rutinose) as a replacement for one of the OH groups (commonly at position 3). The attached glycosyl group can change the solubility, absorption, and in vivo effects. As a general rule of thumb, the presence of a glycosyl group (quercetin glycoside) results in increased water solubility compared to quercetin aglycone ¹⁸.

A quercetin glycoside is unique by the attached glycosyl group. Generally, the term quercetin should be used to describe the aglycone only; however, the name is occasionally used to refer to quercetin-type molecules, including its glycosides in research and the supplement industry.

Quercetin Absorption

Quercetin glycosides might be differently absorbed based on the type of sugar attached ¹⁹. Available evidence indicates that quercetin glucosides (like those found predominantly in onion or shallot flesh) are far better absorbed than its rutinosides (the major quercetin glycoside in tea). The glucosides are efficiently hydrolyzed in the small intestine by beta-glucosidases to the aglycone form, much of which is then absorbed ²⁰. Quercetin glucuronic acid and its sulfuric acid derivatives were more easily absorbed than quercetin ²⁰. Thereafter, its absorption is affected by differences in its glycosylation, the food matrix from which it is consumed, and the co-administration of dietary components such as fiber and fat ²¹. Thus different sugar types and sugar group conjugation sites will result in absorption variation.

Quercetin and derivatives are stable in gastric acid; however, there were no reports whether they can be absorbed in stomach. Studies suggest that quercetin is absorbed in the upper segment of small intestinal ²².

Among quercetin’s derivatives, conjugated forms of its glycosides are better absorbed than quercetin. Purified quercetin glucosides are capable of interacting with the sodium dependent glucose transport receptors in the mucosal epithelium and may therefore be absorbed by the small intestine in vivo ²³.

Quercetin foods

Quercetin-type flavonols (primarily as quercetin glycosides), the most abundant of the flavonoid molecules, are widely distributed in plants. They are found in a variety of foods including apples, berries, Brassica vegetables, capers, grapes, onions, shallots, tea, and tomatoes, as well as many seeds, nuts, flowers, barks, and leaves. Quercetin is also found in medicinal botanicals, including Ginkgo biloba, Hypericum perforatum, and Sambucus canadensis ²⁴, ²⁵, ²⁶. In red onions, higher concentrations of quercetin occur in the outermost rings and in the part closest to the root, the latter being the part of the plant with the highest concentration ²⁷. One study found that organically grown tomatoes had 79% more quercetin than chemically grown fruit ²⁸. Quercetin is present in various kinds of honey from different plant sources ²⁹. Food-based sources of quercetin include vegetables, fruits, berries, nuts, beverages and other products of plant origin ³⁰. In the determined food, the highest concentration is 234 mg/100 g of edible portion in capers (raw), the lowest concentration is 2 mg/100 g of edible portion in black or green tea (Camellia sinensis) ³¹.

Dietary intake of quercetin was different in several countries. The estimated flavonoid intake ranges from 50 to 800 mg/day (quercetin accounts for 75%), mostly depending on the consumption of fruits and vegetables and the intake of tea ³². In the Suihua area of northern China, quercetin intake was reported to be 4.37 mg/day, where the main food sources of flavonol was apples (7.4%), followed by potatoes (3.9%), lettuce (3.8%) and oranges (3.8%) ³³, whereas the average quercetin intake was 4.43 mg/day, with apple (3.7%), potato (2.5%), celery (2.2%), eggplant (2.2%), and actinidia (1.6%) being the main food sources of quercetin in Harbin, China ³⁴. The most recent study showed that quercetin intake is about 18 mg/day for Chinese healthy young males. In the USA, flavonol intake is about 13 mg/day for U.S. adults, while quercetin represents three-quarters of this amount. The mean quercetin intake was approximately 14.90 to 16.39 mg per day. Onions, tea, and apples contained high amounts of quercetin ³⁵. In Japan, the average and median quercetin intakes were 16.2 and 15.5 mg/day, respectively; the quercetin intake by men was lower than that by women; and the quercetin intakes showed a low correlation with age in both men and women. The estimated quercetin intake was similar during summer and winter. Quercetin was mainly ingested from onions and green tea, both in summer and in winter. Vegetables, such as asparagus, green pepper, tomatoes, and red leaf lettuce, were good sources of quercetin in summer ³⁶. In Australia, black and green teas were the dominant sources of quercetin. Other sources included onion, broccoli, apple, grape, and beans ³⁷. Analysis of the 24-h recall data indicated an average adult intake of total flavonoids (>18 years) of 454 mg/day. Apple was the most important source of quercetin until age 16–18 years, after which onion became an increasingly important prominent source ³⁷. In Spain, the average daily intake of quercetin is 18.48 mg/day, which is significantly higher than that in the United States (9.75 mg/day), based on sources like tea, citrus fruits and juice, beers and ales, wines, melon, apples, onions, berries and bananas ³⁸.

Table 1. Foods containing quercetin

[Sources ³⁹; ⁴⁰]

Quercetin benefits

Pharmacological reports have demonstrated that quercetin has pronounced pharmaceutical effects, including anti-inflammatory, antioxidant, and antiviral activity ⁴¹. In addition, quercetin is included in a novel class of chemotherapeutic drugs for the treatment of various cancers ⁴² and can also be combined with ultrasonic pretreatment to increase the concentration of quercetin to inhibit the growth of the prostate and skin cancer cell lines ⁴³. However, quercetin has low aqueous solubility, poor absorption, and rapid metabolism (bioavailability approximately 1%–5%) ⁴⁴, all of which can generate in vivo (animal & human study) results that differ from the powerful in vitro (test tube study) efficacy of quercetin. Most of the studies which have shown the antitumor activity of quercetin were performed with a high concentration of quercetin, rangin from 25 μM to 200 μM. But pharmacokinetic research reveals that the peak concentration of quercetin in blood after food uptake reaches to a peak of around 10 μM ⁴⁵.

Quercetin has been shown to inhibit the proliferation of a wide range of cancers such as prostate, cervical, lung, breast, and colon. Recent studies have revealed that quercetin inhibits cell proliferation by causing apoptosis and/or cell cycle arrest ⁴⁶. It has been shown that quercetin treatment causes cell cycle arrests such as G2/M arrest or G1 arrest in different cell types ⁴⁷. Moreover, quercetin-mediated apoptosis may result from the induction of stress proteins, disruption of microtubules and mitochondria, release of cytochrome c, and activation of caspases ⁴⁸. Quercetin is a strong antioxidant because it can chelate metals, scavenge oxygen free radicals ⁴⁹ and inhibit xanthine oxidase and lipid peroxidation in vitro ⁵⁰.

Quercetin has also been shown to impair an oncoviral replication. Quercetin inhibited HBsAg (hepatitis B surface antigen) and HBeAg (hepatitis B e antigen) secretion in the HBV (Hepatitis virus B)-producing 2.2.15 cells ⁵¹. In addition, quercetin appeared to be the most effective inhibitor for HCV (hepatitis C virus) replication among all flavonoids, demonstrating a strong anti-hepatitis C virus activity in hepatitis C virus replicon-containing cells when combined with interferon (IFN)α ⁵². Quercetin and its analog quercetin showed stronger inhibition on HIV-1 reverse transcriptase, all with IC50 values of 60 μM than HIV-1 protease and α-Glucosidase ⁵³. Quercetin was shown to inhibit other three reverse transcriptases from avian myeloblastosis, Rous-associated virus-2 and Maloney murine leukemia virus when poly(rA)oligo(dT)12-18 or rabbit globin mRNA were used as template ⁵⁴. Several studies investigated potential use for quercetin as anti-cancer agent ⁵⁵. A couple of cell culture studies showed that quercetin has an anti-cancer activity due to its antioxidant or anti-inflammatory properties ⁵⁶. Quercetin also inhibits the growth of cancer cells and helps induction of apoptosis ⁵⁷. Some studies using animal models have shown that quercetin could protect against colon cancer ⁵⁸.

Quercetin Clinical Studies

Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduces cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes in healthy seniors and hypercholesterolemic subjects ⁵⁹.

In a randomized, double-blinded, placebo-controlled trial, 1002 subjects took 500 or 1000 mg/day quercetin or a placebo for 12 weeks. For the group as a whole, quercetin supplementation had no significant influence on rates of upper respiratory tract infections (URTI) compared to placebo. In a subgroup of subjects age 40 or older who self-rated themselves as physically fit, 1000 mg/day quercetin resulted in a statistically significant reduction in total sick days and symptom severity associated with URTI ⁶⁰. Female subjects were supplemented with 500 or 1000 mg/day quercetin or placebo for 12 weeks. While quercetin supplementation significantly increased plasma quercetin levels, it had no influence on measure of immune function ⁶¹. Quercetin (100 mg/day) did not alter exercise-induced changes in several measures of immune function following three days of intense exercise in trained athletes, but it significantly reduced URTI incidence (1 of 20 subjects in active versus 9 of 20 in placebo group) during the two-week post-exercise period ⁶². A similar lack of effect on strenuous exercise-induced immune system perturbation was found in subjects who took 1000 mg/day of quercetin for three weeks before, during, and continuing for two weeks after the 160-km Western States Endurance Run. In this study, however, there were no differences in the post-race illness rates between quercetin and placebo groups ⁶³.

There are several studies in humans investigating the correlation of quercetin and its immunomodulatory effects. Quercetin does indeed reduce illness after intensive exercise. Again, under double-blind conditions, Nieman et al. showed that a supplement of 1000 mg of quercetin alone three weeks before, during and two weeks after a three-day period of 3 h of cycling in the winter resulted in a markedly lower incidence of URTI in well-trained subjects in the two weeks after the intensified training, but had no effect on exercise-induced immune dysfunction, inflammation and oxidative stress ⁶⁴.

The literature is supportive of the anti-pathogenic capacities of quercetin when it is cultured with target cells and a broad spectrum of pathogens including URTI-related rhinoviruses, adenoviruses and coronaviruses. The impact of the co-ingestion of two or more flavonoids increases their bioavailability and the outcomes on immunity. Nieman et al. determined the influence of two weeks of 1000 mg/day quercetin compared with placebo supplementation on exercise performance and skeletal muscle mitochondrial biogenesis in untrained, young adult males. It resulted in significantly reduced post-exercise measures for both inflammation and oxidative stress, with a chronic augmentation of granulocyte oxidative burst activity ⁶⁵. When taken together, quercetin showed a successful reduction in the illness rates of exercise-stressed athletes as well as a chronic augmentation of their innate immune function.

Most in vitro research suggests that quercetin possesses anti-inflammation and immunological improvement. However, the results from a double-blinded, placebo-controlled, randomized trial indicated that quercetin supplementation at 500 and 1000 mg/day for 12 weeks significantly increased plasma quercetin levels but had no influence on measures of innate immune function or inflammation in community-dwelling adult females ⁶¹.

The main action of quercetin on inflammation and immune function in vivo is summarized in the Table 2.

• These results suggest that quercetin studies in human did not totally support these results from cells and animals. The effect, in which quercetin acts as an immune booster in humans, needs to be further verified for future broad application.

Table 2. Summary of the main effects of quercetin on inflammation and immune function in human

Quercetin side effects

Evaluation: There is inadequate evidence in humans for the carcinogenicity of quercetin. There is limited evidence in experimental animals for the carcinogenicity of quercetin ⁷³. Groups of 50 male and 50 female Fischer 344/DuCrj rats, six weeks of age, were fed quercetin (purity, at least 99.4%) in the diet at concentrations of 0 (control), 1.25 or 5% for 104 weeks and were maintained for a further eight weeks without quercetin. The high dose was the maximum tolerated. At the end of the 112-week study, the survival rates for males were 56, 66 and 68% and those for females were 66, 62 and 72% for the three groups, respectively. No statistically significant increase in incidence of tumors was seen, but males at the high dose showed a significant increase in the incidence of non-neoplastic hyperplastic polyps of the cecum, and one adenoma and two adenocarcinomas of
the cecum were found in males at this dose and two adenomas of the colon occurred in females ⁷⁴.

Groups of 70 male and 70 female Fischer 344/N rats, seven weeks of age, were given quercetin (purity, > 95%; ellagic acid was the predominant impurity at 1.1–2.6%) in the diet at concentrations of 0, 1000, 10 000 or 40 000 mg/kg (ppm) for 104 weeks. Ten animals per group were killed at 6 and 15 months. The high dose approached the maximum tolerated. Treatment did not affect the survival of either male or female rats, but the decreased body-weight gain of animals at the high dose was attributed to quercetin. Males at the high-dose had an increased incidence of renal tubular tumours (three adenomas and one adenocarcinoma) with none in control males, but the increase did not achieve statistical significance. After step-sectioning, a total of nine renal tubular tumours were found in these animals, and the increase was statistically significant. The severity of spontaneous progressive nephropathy was exacerbated in male rats by exposure to quercetin ⁷⁵.

Overall evaluation: Quercetin is not classifiable as to its carcinogenicity to humans (Group 3) ⁷³.

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