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.
Return to BIOFLAVONOIDS
Since 1-01-1998
|
