Quercetin: A Review of Clinical Applications
 
   

Quercetin: A Review
of Clinical Applications

This section was compiled by Frank M. Painter, D.C.
Send all comments or additions to:
  Frankp@chiro.org
 
   

Thanks to the Natural Medicine Online for the use of this article!

By L. Stephen Coles, M.D., Ph.D.

Los Angeles Gerontology Research Group


Introduction

Quercetin (3,3',4',5-7-pentahydroxyflavone), a chemical cousin of the glycoside rutin, is a unique flavonoid that has been extensively studied by researchers around the world, starting with the discovery of both vitamin C and flavonoids by Albert Szent-Gyorgyi who received the Nobel Price in 1937 for research in this area. Flavonoids, by the way, are plant polyphenolics found as the pigments in leaves, barks, rinds, seeds, and flowers-frequently closely associated with Vitamin C and offering synergistic effects. Both flavonoids and Vitamin C benefit plants by providing them with antioxidant protection and also confer protection against climatic variations (in wind, rainfall, temperature, and sunlight). Flavonoids are also important for human health. Like vitamins, these compounds are not produced endogenously by the body and must be supplied either through the diet or nutritional supplements. Quercetin has been the subject of dozens of scientific reports over the past 30 years. It has shown the greatest activity among the flavonoids studied in experimental models. Quercetin is frequently used therapeutically in allergic conditions, including asthma and hayfever, eczema, and hives. Additional clinical uses include treatment of gout, pancreatitis and prostatitis, which are also, in part, inflammatory conditions. The common link is its ability to mediate production and manufacture of pro-inflammatory compounds.

However, its uses also may be important in cancer therapeutics. Quercetin is a recognized antioxidant and has been studied for its gastro-protective effects, inhibition of carcinogenicity either alone or in combination with chemotherapeutic agents, reducing risk of cataract. Again, the ability of quercetin to inhibit inflammatory leukotriene production may be a key to its beneficial impacts. Sources of quercetin include green vegetables, berries, onions, parsley, legumes, green tea, citrus fruits, and red grape wines.

Understanding the Role of Quercetin in Asthma and Hay Fever Therapeutics Perhaps the most extensive clinical use of quercetin at this time is in asthma and hay fever therapeutics. Asthma may be divided into two types: extrinsic and intrinsic. Extrinsic asthma, also known as atopic asthma, is thought to be due to allergenic physiological reactions, characterized by increases in serum levels of IgE-the allergic antibody. Intrinsic asthma, on the other hand, is thought to be caused by toxic chemicals, cold air, exercise, infection, and emotional upset.

Both extrinsic and intrinsic asthma share common pathologies by which the asthma sufferer's body releases chemicals from mast cells that produce or control inflammation. Mast cells are a type of white blood cell, found throughout the body, lining the respiratory passages in particular.

The chemicals released by mast cells are mediators of bodily inflammatory processes. They account for the major symptoms of asthma. These mediators are found within mast cells in tiny packages (granules) and also are produced by various fatty acids that compose cellular membranes.

Among the most well-studied chemical mediators are histamines and leukotrienes. It should be recognized that leukotrienes are far more potent than histamines as stimulators of bronchial constriction and allergy. Some leukotrienes are as much as 1,000 times more potent than histamine.

Asthmatics tend to have markedly high leukotriene levels. In particular, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can cause highly increased leukotriene levels in susceptible individuals. Other stimulants of leukotriene release include tartrazine (yellow dye #5), which is used as a food coloring in a wide range of foods, particularly candy. Also, ragweed pollen, as well as various grass and tree pollens can induce bodily production of pro-inflammatory leukotrienes.

Obviously, reducing the overall allergic threshold is a key to treating asthma naturally. That is because allergens become more dangerous as exposure intensifies and increases. Highly increased exposures to recognized allergens, either in food, medications, or the environment, increase the risk for asthmatic and/or hay fever attacks. Thus, some of the most practical ameliorating considerations include reducing exposure to airborne and food allergens, including dust mites in the home and office, as well as other allergenic agents such as formaldehyde that may be present in furniture.

However, quercetin-based therapy may also be important. One reason for the marked increase in asthma rates in the last two to three decades can be explained partially by increasing exposure to potential allergens, while dietary intake of antioxidants has markedly decreased. It is thought that antioxidants are an important defense mechanism for protecting normal lung function. Antioxidants scavenge free radicals and other oxidizing agents that are known to stimulate bronchial constriction and increase reactivity to other potential pro-inflammatory compounds. Thus, supplemental intake of fundamental antioxidants, including beta-carotene, Vitamins C and E, zinc, selenium, and copper, is important. Auxiliary botanical antioxidants are also important. This would include quercetin

Flavonoids, particularly quercetin, appear to be key antioxidants in the treatment of asthma. Quercetin is known to inhibit mast cells from releasing pro-inflammatory compounds that cause allergy symptoms. In particular, quercetin is an inhibitor of allergic (IgE-mediated) mediator release from mast cells and basophils (another type of white blood cell involved in immune reactions).

Other research has shown that quercetin inhibits not only IgE-mediated allergic mediator release from mast cells but also IgG-mediated histamine and SRS-A (peptido-leukotriene) release from chopped lung fragments from actively sensitized guinea pigs. Interestingly, quercetin was shown to be much more potent as an inhibitor of the release of SRS-A than histamine, suggesting that it might also inhibit the biosynthesis of SRS-A. Subsequently, it has been demonstrated that quercetin is an effective inhibitor of 5-lipoxygenase. This property of the compound most likely accounts for its effect on peptido-leukotriene biosynthesis. It is thought that compounds such as quercetin, which exhibit both allergic mediator release activity and selective inhibition of the biosynthesis of pro-inflammatory arachidonic acid metabolites, may be interesting prototypes which will lead to the discovery of very effective antiallergic and anti-inflammatory agents. Quercetin also spares vitamin C and stabilizes cell membranes, including those of mast cells.

Eczema

Once again, natural agents that address excessive histamine release may be beneficial in enhancing the healing response among eczema patients. This is because, as with asthma and other allergic conditions, serum IgE levels are highly elevated in eczema patients, and virtually all eczema patients are positive for allergy testing. Also, many eczema patients either suffer from or go on to develop asthma and/or hay fever. Certainly quercetin is one of the more important of such natural compounds in eczema therapeutics.

Hives

Because quercetin inhibits manufacture and release of histamine and other allergic inflammatory mediators by mast cells and basophils, it may be quite useful in treating hives, another condition characterized by increased serum IgE levels. , The drug sodium cromoglycate is quite similar to quercetin in chemical structure. Because sodium cromoglycate offers protection against the development of hives in response to heightened food allergens, it can be speculated that quercetin may prove useful in enhancing the healing response.

Pancreatitis

Limited evidence suggests quercetin may be used in the therapy of pancreatitis. The results of the use of inhibitors of biosynthesis of leukotrienes in the treatment of acute pancreatitis were studied in 68 patients, of whom 29 were operated on. According to the researchers, "A high effectiveness of the method in preventing aggravation or destruction of the pancreatic gland was shown." Again, this may well be due, in part, to quercetin's unique anti-inflammatory activity.

Prostatitis

The National Institutes of Health (NIH) Category III Chronic Prostatitis Syndrome (nonbacterial chronic prostatitis and prostatodynia) is a common disorder with few effective therapies. Bioflavonoids have recently been shown in an open-label study to improve the symptoms of these disorders in a significant proportion of men. The aim of a recent study was to confirm these findings in a prospective randomized, double-blind, placebo-controlled trial. Thirty men with category IIIa and IIIb chronic pelvic pain syndrome were randomized in a double-blind fashion to receive either placebo or the bioflavonoid quercetin (500 mg twice daily) for one month. The NIH Chronic Prostatitis Symptom Score was used to grade symptoms and the quality-of-life impact at the start and at the conclusion of the study. In a follow-up non-blinded, open-label study, 17 additional men received one month of a supplement containing quercetin, as well as bromelain and papain, which enhance bioflavonoid absorption. Two patients in the placebo group refused to complete the study because of worsening symptoms, leaving 13 placebo and 15 bioflavonoid patients for evaluation in the blind study. Both the quercetin and placebo groups were similar in age, symptom duration, and initial symptom score. Patients taking placebo had a mean improvement in NIH symptom score from 20.2 to 18.8 (not significant), while those taking the bioflavonoid had a highly significant mean improvement from 21.0 to 13.1. Twenty percent of patients taking placebo and 67 percent of patients taking the bioflavonoid had an improvement of symptoms of at least 25 percent. Therapy with the bioflavonoid quercetin was shown to be well tolerated and provide significant symptomatic improvement in most men with chronic pelvic pain syndrome.

Canker Sores

Very similar in structure and function to quercetin is the anti-allergy drug disodium cromoglycate that has been shown to be effective in the treatment of recurrent canker sores. Thus, Quercetin may offer similar benefits.

Gout

Another possible benefit of quercetin is in the treatment of gout. Quercetin has been experimentally shown to inhibit uric acid production in a manner similar to the drug Allopurinol, as well as inhibit the manufacture and release of inflammatory compounds.

Anti-ulcer and Gastro-protective Effects In an experimental study, the cell-protective properties of quercetin and the involvement of endogenously produced prostaglandins in mucosal injury produced by absolute ethanol were examined. Oral pretreatment with the highest dose of quercetin (200 mg/kg), 120 minutes before absolute ethanol, was most effective in preventing cell death (necrosis). However, subcutaneous administration of indomethacin (10 mg/kg) to the animals treated with quercetin partially inhibited gastric protection. All treated groups showed a marked increase in the amount of gastric mucus, although this increase was less in animals pretreated with indomethacin. Evaluation of gastric damage confirmed a significant increase in mucus production accompanied by a parallel reduction of gastric lesions with the highest dose of quercetin tested. These benefits may be due to inhibition of lipid peroxidation of gastric cells or inhibition of gastric acid secretion. Clinical studies are required to validate whether quercetin may be clinically useful in prevention of ulceration.

Inhibition of Carcinogenicity

It is in cancer prevention, and possibly therapeutics, wherein many future uses of this natural medicine may be directed. It has been demonstrated that quercetin inhibits the growth of several cancer cell lines and that the anti-proliferative activity of this substance is mediated by a so-called Type II Estrogen-Binding Site (Type II EBS).

In an in vitro study, the effects of Quercetin and cisplatin alone and in combination on the proliferation of the ovarian cancer cell line (OVCA 433) were examined. Both drugs exhibited a dose-related growth inhibition in a range of concentrations between [0.01 - 2.50] mcM and [0.01 - 2.50] mcg/ml for quercetin and cisplatin, respectively. The combination of the two drugs resulted in a synergistic anti-proliferative activity. It should be noted that two other flavonoids tested, i.e., rutin (3-rhamnosylglucoside of Quercetin) and hesperidin (7-b rutinoside of hesperetin [3'-5-3-hydroxy-4-methoxyflavone]) were ineffective both alone and in combination with cisplatin. Since both rutin and hesperidin do not bind to Type II EBS it can be hypothesized that quercetin synergizes cisplatin by acting through an interaction with these binding sites.

Other studies have shown quercetin to possess cisplatin-sensitizing properties in cancer cells. In a recent study, researchers studied the effects of various bioflavonoids on cisplatin toxicity in an in vitro model of cultured tubular epithelial cells. Pretreatment of cells with quercetin for three hours significantly reduced the extent of cell damage. The protective activity of quercetin was concentration dependent. Other bioflavonoids (i.e., catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations. Quercetin itself showed some intrinsic cytotoxicity at higher concentrations exceeding 75 mcM.

In another study, the effect of resveratrol and quercetin on growth of human oral cancer cells was studied. Resveratrol and quercetin, in concentrations of [1 - 100] mcM, were incubated in triplicate with human oral squamous carcinoma cells. Resveratrol at 10 and 100 mcM induced significant dose-dependent inhibition in cell growth, as well as in DNA synthesis. Quercetin exhibited a biphasic effect, stimulation at 1 and 10 mcM, and minimal inhibition at 100 mcM in cell growth and DNA synthesis. Combining resveratrol with quercetin resulted in a gradual and significant increase in the inhibitory effect of quercetin on cell growth and DNA synthesis. Thus, it can be shown that resveratrol or a combination of resveratrol and quercetin, in concentrations equivalent to that present in red wines, are effective inhibitors of oral squamous carcinoma cell (SCC-25) growth and proliferation. They certainly warrant further investigation as cancer chemo-preventive agents.

Cataract

Cataracts result from oxidative damage to the lens. The mechanism involves disruption of the redox system, membrane damage, proteolysis, protein aggregation, and a loss of lens transparency. Diet has a significant impact on cataract development, but the individual dietary components responsible for this effect are not known. In a study, it was shown that low micromolar concentrations of quercetin inhibit cataractogenesis in a rat lens organ-cultured model exposed to the endogenous oxidant hydrogen peroxide. Other phenolic antioxidants, (+)epicatechin and chlorogenic acid, were much less effective. Quercetin was active both when incubated in the culture medium together with hydrogen peroxide, and was also active when the lenses were pre-treated with quercetin prior to oxidative insult. Quercetin protected the lens from calcium and sodium influx, which are early events leading to lens opacity, and this implies that the non-selective cation channel is protected by this phenolic. It did not, however, protect against formation of oxidized glutathione resulting from H2O2 treatment. The results demonstrate that quercetin helps to maintain lens transparency after an oxidative insult.

Absorption

It is known that oral doses of quercetin are absorbed. In one study, plasma quercetin concentration in subjects with an intact colon, after ingestion of fried onions, apples, and pure quercetin rutinoside, decreased slowly with an elimination half-life of about 25 hours. Thus, repeated dietary intake of quercetin will lead to accumulation in plasma. The relative bioavailability of quercetin from apples and rutinoside was one-third of that from onions. Dietary quercetin would appear to increase the antioxidant capacity of blood plasma. It is also thought that the combination of the proteolytic enzyme bromelain with quercetin enhances absorption and bioavailability of quercetin.

Available Forms

Quercetin is available in powder and capsule form. When quercetin is being used for its anti-inflammatory properties (which may even extend to cancer therapeutics), it should be combined with the pineapple enzyme bromelain for its own anti-inflammatory activity and possibly enhanced absorption of quercetin. If used in combination, then the amount of bromelain should equal the amount of quercetin. Most recently, a new water-soluble form of the quercetin molecule has been developed which may enhance absorption.

Dosages

Most dosages range from 200 to 500 mg, taken 20 minutes before meals. Asthma and Hay Fever: Take 400 mg 20 minutes before each meal. Canker Sores: Take 400 mg 20 minutes before each meal. Eczema: Take 400 mg 20 minutes before each meal. Gout: Take 200 to 400 mg of quercetin with bromelain between meals three times daily. Hives: Take [200 - 400] mg 20 minutes before each meal. A new water-soluble form of quercetin may be able to reduce dosages to 250- mg three times a day.

Side-effects/Drug Interactions

There are no known drug interactions. No long-term adverse effects from the use of quercetin are noted in the medical literature.


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