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Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge

Quercetin: A Versatile

Dr. Parul Lakhanpal*, MD and Dr. Deepak Kumar Rai†, MD

*Reader, Department of Pharmacology, SSR Medical College, Mauritius †SMHO, Department of Pediatrics, Ministry of Health & Quality of Life, Mauritius

(Received 04 January 2007 and accepted 29 March 2007)

ABSTRACT: Associative evidence from observational and intervention studies in human subjects shows that a diet including plant foods (particularly fruit and vegetables rich in ) conveys health benefits. There is no evidence that any particular nutrient or class of bioactive substances makes a special contribution to these benefits. occur naturally in fruits, vegetables and beverages such as tea and wine. Quercetin is the major flavonoid which belongs to the class called . Quercetin is found in many common foods including apples, tea, onions, nuts, berries, cauliflower, cabbage and many other foods. Quercetin provides many health promoting benefits, including improvement of cardiovascular health, eye diseases, allergic disorders, arthritis, reducing risk for cancers and many more. The main aim of this review is to obtain a further understanding of the reported beneficial health effects of Quercetin, its pharmacological effects, clinical application and also to evaluate its safety.

KEY WORDS: Quercetin, Flavonoid, , Health.

INTRODUCTION: on the basis of their molecular structures (Figure Quercetin is a unique bioflavonoid that has been 1)4. extensively studied by researchers over the past Six-member ring condensed with the benzene 30 years. Bioflavonoids were first discovered by ring is either a-pyrone (flavonols and Nobel Prize laureate Albert Szent Gyorgyi in the flavonones) or its dihydroderivative (flavanols year 1930. Flavonoids belong to a group of and ). The position of the benzenoid natural substances with variable phenolic substituent divides the flavonoid class into structure and are found in the fruits, vegetables, flavonoids (2-position) and (3- grains, bark roots, stem, flowers, tea and wine1. position). Flavonols differ from flavonones by These natural products were known for their hydroxyl group the 3-position and C2-C3 double beneficial effects on health long before bonds5. Flavonoids are often hydroxylated in flavonoids were isolated as the effective position 3, 5, 7, 2’, 3’, 4’, 5’. Methylethers and compounds. More than 4000 varieties of acetylesters of the group are known to flavonoids have been identified, many of which occur in nature. When are formed, the are responsible for their attractive colors of glycosidic linkage is normally located in flowers, fruits and leaves2. positions 3 or 7 and the carbohydrate can be L- Flavonoids occur as aglycones, glycosides and , D-glucose, glucor-hamnose, galactose methylated derivatives. The flavonoid aglycone or arabinose6. Flavonoids are mainly divided into consists of a benzene ring (A) condensed with a seven major groups (figure-2)7. One of the best six membered ring (C), which in the 2-position described flavonoids, Quercetin is a member of carries a phenyl ring (B) as a substituent3. The this group. Flavonoids can be divided into various classes

Corresponding Author: Dr. Parul Lakhanpal, Reader, Department of Pharmacology, SSR Medical College, Belle-Rive, Mauritius, Email: [email protected]

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Figure 1: Structures of the major classes of Flavonoid4

Figure 2: Major classes of Flavonoids7

Quercetin is found in abundance in onions, are mainly found in green and black tea and in broccoli, apples and berries. The second group is red wine, whereas, anthocyanins are found in flavanones, which are mainly found in strawberries, other berries, , wines and fruits. An example of a Flavonoid in this group is tea2. Flavonoid contents of different foods are naringinin. Flavonoids belonging to the shown in Table-1.

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Table 1: Main groups of flavonoids, compounds and food sources

Groups Compounds Food sources Quercetin Yellow onion, Curly , Leek, Cherry , Flavonols Broccoli, Apple, Green and black tea, Black grapes, Querctagetin Blueberry. Parsley, Celery, Capsicum Heptamethoxyflavone pepper. Quercetogetin Apegenin Disometin Orange juice, Grapefruit juice, Lemon juice. Flavanones Dihydroquercetin Dihydrofisetin Dihydrobinetin Cocoa, Cocoa beverages, Silymarin Chocolates. Flavanols Pinobanksin (+) Chocolate, Beans, Apricot, Gallocatechin Cherry, Grapes, Peach, Red Catechins (-) Epicatechin wine, Cider, , Black () Epigallocatechin tea, Blackberry. Epicatechin 3-gallate Epigallocatechin 3-gallate Soy cheese, Soy flour, Soy bean, Tofu. Cyanidin Blue berry, Blackcurrant, Delphinidin Black grapes, Cherry, Malvidin , Plum, Strawberry, Anthocyanins Pelargonidin Red wine, Red cabbage. Peonidin Petunidin

Quercetin, the most abundant of the flavonoids many other flavonoids including the citrus (the name comes from the Latin –quercetum, flavonoids like , hesperidins, Naringenin meaning oak forest, quercus oak) consists of 3 and tangeritin. It is widely distributed in the rings and 5 hydroxyl groups (Figure-3)8. plant kingdom in rinds and barks. Quercetin Quercetin is a member of the class of flavonoids itself is an aglycon or aglucone that does not called flavonoles and forms the backbone for possess a carbohydrate moiety in its structure.

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Quercetin is typically found in plants as glycone reconstituting membranes. These include lipases, or carbohydrate conjugates. Quercetin glycone proteases, DNA repair and conjugates include rutin and thujin. Rutin is also transferases12. known as Quercetin-3-rutinoside.Thujin is also known as , Quercetin-3-L-rhamnoside Direct scavenging action: and 3-rhannosyl qurcetin. Onions contain Free radical production in animal cells can either conjugates of Quercetin and carbohydrate iso be accidental or deliberate. With the increasing including Quercetin-3-4’-di-o-beta acceptance of free radicals as common place and , isorhamnetin-4’-o-beta glucoside and important biochemical intermediates, they have Quercetin-4’-o-beta glucoside. been implicated in a large number of human diseases13,14. Quercetin acting as free radical scavengers was shown to exert a protective effect in reperfusion ischemic tissue damage15,16,17. Quercetin prevents free radical induced tissue injury by various ways. One way is the direct scavenging of free radicals. By scavenging free radicals, Flavonoid; particularly Quercetin can inhibit LDL oxidation in vitro18. This action protects against atherosclerosis.

Inducible nitric oxide syntheses Inhibitory action: Quercetin results in a reduction in ischemia – 8 Figure-2 Molecular structure Quercetin reperfusion injury by interfering with inducible nitric oxide synthase activity19. Nitric oxide is MECHANISM OF ACTION: produced by several different types of cells Anti-oxidative action: including endothelial cells and . The best described property of Quercetin is its Although the early release of nitric oxide through ability to act as antioxidant. Quercetin seems to the activity of constitutive nitric oxide synthase be the most powerful flavonoids for protecting is important in maintaining the dilatation of the body against reactive oxygen species, blood vessels20, the much higher concentration of produced during the normal oxygen metabolism nitric oxide produced by inducible nitric oxide or are induced by exogenous damage9,10. One of synthase in macrophages can result in oxidative the most important mechanisms and the damage. In these circumstances the activated sequence of events by which free radicals macrophages greatly increase their simultaneous interfere with the cellular functions seem to be production of both nitric oxide and superoxide the lipid peroxidation leading eventually the cell anions. Nitric oxide reacts with free radicals, death. To protect this cellular death to happen thereby producing high damaging peroxynitrite. from reactive oxygen species, living organisms Peroxynitrite can directly oxidize LDLs resulting have developed antioxidant line of defense in irreversible damage to cell membranes. systems11. These include enzymatic and non- Quercetin causes scavenging of free radicals; enzymatic antioxidants that keep in check therefore can no longer react with nitric oxide, ROS/RNS level and repair oxidative cellular resulting in less damage21. Nitric oxide damage. The major enzymes, constituting the interestingly can be viewed as radical itself and first line of defence, directly involved in the can directly be scavenged by Flavonoids22. neutralization of ROS/RNS are: superoxide dismutase (SOD), catalase (CAT) and oxidase inhibitory action: peroxidase (GPx) The second line of The xanthine oxidase pathway has been defence is represented by radical scavenging implicated as an important route in the oxidative antioxidants such as , and injury to the tissues especially after ischemia- plant including quercetin that reperfusion23. Both xanthine dehydrogenase and inhibit the oxidation chain initiation and prevent xanthine oxidase are involved in the metabolism chain propagation .This may also include the of xanthine to . Xanthine dehydrogenase termination of a chain by the reaction of two is the form of the present under radicals. The repair and de novo enzymes act as physiological condition but its configuration the third line of defence by repairing damage and changed to xanthine oxidase during oxidative

25 Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge stress and ischemic conditions. Quercetin seems significantly inhibited TNF-α production and to inhibit xanthine oxidase activity thereby gene expression in a dose-dependent manner. A resulting in decreased oxidative injury19, 24, 25. decrease in endogenous TNF-α production in the presence of quercetin indicates that flavonoids Decreasing Leukocyte immobilization: have the capacity to modulate the immune The immobilization and the firm adhesions of response and have potential anti-inflammatory leukocytes to the endothelial wall is another activity. In addition to its well-known major mechanism responsible not only for the proinflammatory role, TNF-α has complex formation of oxygen derived free radicals but effects on the growth, differentiation, and death also for the release of cytotoxic oxidants and of immune cells. TNF-α inhibition is a validated inflammatory mediators and further activation of approach to treat several inflammatory complement system. Under normal conditions diseases28. Quercetin-induced suppression of leukocytes move freely along the endothelial TNF-α can result in the stimulation of anti- walls. However during ischemia and inflammatory cytokines via inhibiting the inflammation, various factors mainly endothelial activation of NF-κβ, and therefore, one can derived mediators and complement factors may anticipate that quercetin could be widely used as cause adhesions of the leukocytes to the an anti-TNF-α therapy. Kaneuchi et al33 endothelial walls, thereby immobilizing them showed that quercetin has anti-proliferative and stimulating degranulation of neutrophils. As activity and the mechanisms of quercetin action a result oxidants and inflammatory mediators are may be through modulation of cell cycle and cell released, resulting in injury to the tissues. Oral growth regulatory genes. Quercetin can suppress administration of purified micronized flavonoids proliferation of Ishikawa cells (endometrial fraction was reported to decrease the number of carcinoma) through down-regulation of EGF and immobilized leukocytes during reperfusion, cyclin D1. which may be related to its protective mechanism against inflammatory conditions26. Interaction with other enzyme systems: Quercetin interacts with calmodulin, a Modulation of gene expression: regulatory protein34. Calmodulin transports Recent studies indicate that the radical calcium ion across cellular membranes, initiating scavenger property of Quercetin is unlikely to be numerous cellular process. Quercetin appears to the sole explanation for their neuroprotective act as calmodulin antagonist. Through this capacity and in fact, a wide spectrum of cellular mechanism, Quercetin functions at cell signaling events may well account for their membrane level with a membrane stabilizing 35 biological actions27. action . Quercetin inhibits calmodulin Much recent interest has focused on the potential dependent enzyme present at cell membrane of Quercetin to interact with intracellular such as ATPases and phospholipases thereby 36 signaling pathways such as with the mitogen- influencing membrane permeability . Quercetin activated cascade. The strong affects other calmodulin dependent enzymes that neurotoxic potential of quercetin in primary control various cellular functions, including the 4 cortical neurons may occur via specific and secretions of histamine from mast cells . A sensitive interactions within neuronal mitogen- number of investigations have demonstrated the activated protein kinase and Akt/protein kinase B ability of Quercetin, to reduce histamine (PKB) signaling cascades, both implicated in secretion from mast cells in various tissues and 37-42 neuroal . Quercetin induced potent also from basophils . The enzyme inhibitory inhibition of both Akt/PKB and ERK action of Quercetin extends to phospholipases phosphorylation, resulting in reduced which catalyses the release of arachidonic acid phosphorylation of BAD and a strong activation from phospholipids stored in cell membranes. of caspase-327. Arachidonic acid serves as a key substrate for Tumor necrosis factor alpha (TNF-α) is one of substances such as thromboxane, inflammatory the major proinflammatory cytokines involved in prostaglandins and leukotrienes. In addition, the pathogenesis of chronic inflammatory Quercetin also inhibits the enzymes diseases and is modulated by oxidative stress28,29. cyclooxygenase and Lipooxygenase which TNF-α also triggers the cellular release of other catalyses the conversion of arachidonic acid to 42,43,44 cytokines, chemokines, or inflammatory its metabolites . Reducing levels of these mediators and displays antiviral and metabolites as well as histamine levels, is antimicrobial effects30,31,32. Quercetin beneficial in maintaining the normal comfort

26 Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge level of body tissue and structures. Quercetin has Studies have shown that Bromelain, an enzyme also been shown to limit the function of adhesion derived from pineapple, enhances the absorption molecules on endothelial cells45. Quercetin also of quercetin. Bromelain is a complex substance chelates ions of transition metals such as iron largely composed of proteolytic enzymes. which can initiate the formation of oxygen free Several studies have presented the evidence that radicals46,47. Direct inhibition of lipid bromelain is a fibrinolytic agent53, 54. Bromelain peroxidation is another protective measures48. is also known to have many of the same histamine and Leukotriene-inhibitory properties PHARMACOKINETICS: as quercetin. In this way they enhance each other The metabolism and pharmacokinetics of properties. flavonoids has been an area of active research in After getting absorbed in small intestine, the last decade. To date, approximately 100 quercetin is transported to the liver via portal studies have reported the pharmacokinetics of circulation, where it undergoes first pass individual flavonoids in healthy volunteers. The metabolism. Quercetin and its metabolites are data indicate considerable differences among the distributed to various tissues in the body. different types of dietary flavonoids so that the Quercetin is strongly bound to the albumin in most abundant flavonoids in the diet do not plasma. Peak plasma level reaches in 0.7 h to 7.0 necessarily produce the highest concentration of hours following its ingestion. The elimination flavonoids or their metabolites in vivo. Small half life of quercetin is approximately 25 hours55. intestinal absorption ranges from 0 to 60% of the The elimination of quercetin was significantly dose and elimination half-life (T1/2) range from 2 delayed after its application with fat-enriched to 28 h49. diets (P < 0.05)52. Quercetin is generally believed to be poorly absorbed. About 25 % of an injected dose of ADVERSE DRUG REACTION: quercetin is absorbed from small intestine. Adverse effects reported with oral quercetin Although a recent study by Hollman et al include gastrointestinal effects such as nausea concludes that humans absorb appreciable and rare reports of headache and mild tingling of amount of quercetin, contradicts the the extremities. Oral quercetin is generally well assumption50. However, it is found in human tolerated. Intravenous quercetin has been plasma as conjugates with glucuronic acid, associated with nausea, vomiting, diaphoresis, sulfate or methyl groups, with no significant flushing, and dyspnoea. amounts of free quercetin. Quercetin was found to reach 0.1-10 µmol/lit (micromole per liter) in Safety Profile: the circulation. The concentration of quercetin There is much controversy regarding the was mainly due to the presence of quercetin purported toxic or even mutagenic properties of metabolites rather than its aglycon as recently quercetin. Formica and Regelson gave an revised by Murota and Terao51. Regarding the interesting overview of quercetin in vivo and in pharmacokinetics of quercetin vitro56. The early data on toxic side effects are conjugates; it seems that the main determinant of mainly derived from in vitro studies. At a absorption of these conjugates is the nature of conference of the Federation of American the sugar moiety. For example quercetin societies for experimental biology in 1984 on glucoside is absorbed from small intestine, mutagenic food flavonoids, carcinogenicity was whereas quercetin rutinosides is absorbed from reported in just one out of 17 feeding studies the colon after the removal of carbohydrate conducted in laboratory animals57, 58. Dunnick moiety by bacterial enzymes. In addition to the and Hailey reported that high doses of quercetin chemical form of the flavonol, the fat content of over several years might result in the formation the diet also influences oral of of tumors in mice59. However, back in the 1970s, quercetin. Lesser et al investigated the influence quercetin was found to have mutagenic activity of dietary fat on oral bioavailability of quercetin. as determined by the in vitro Ames test, which According to the them, Quercetin bioavailability was developed by researcher Bruce Ames to test from each diet was always higher from the if a natural or synthetic substance will cause glucoside than from the aglycon but irrespective DNA mutations in bacteria60. However in other of the chemical form applied, the bioavailability long term study, no carcinogenicity was found61. of quercetin was also found to be higher in the In contrast to earlier studies several more recent 17% fat diet compared with the 3% fat diet (P < reports indicate that quercetin is antimutagenic in 0.05)52. vivo56, 62, 63. A large clinical study by Knekt et

27 Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge al, in which 9959 men and women were : followed for 24 years, showed an inverse Studies have shown that grapefruit juice relationship between the intake of quercetin and significantly increases levels in the lung cancer64. One possible explanation for these blood71,72. One of the flavonoids found in conflicting data is that quercetin is toxic to grapefruit juice is Quercetin. In a test tube study, cancer cells or immortalized cells but not toxic to quercetin was found to change normal cells. In other studies quercetin was also metabolism in human liver cells in a way that it recognized as genoprotective against mutagenic increases estradiol level and reduces other forms agents65, 66. Review of the total body of available of estrogens72. However the levels of quercetin data on quercetin as presented in several used to alter estrogen metabolism in the test tube published reviews indicates that quercetin, were much higher than the levels found in the although displaying mutagenic activity in vitro is body after supplementing with quercetin. not carcinogenic in the body. In a number of In a small controlled study of women with studies such as Formica and Regelson56, surgically removed ovaries, estradiol levels in Stavric58, Stoewsand67, and recently the blood were significantly higher after taking Okamoto68, a review of quercetin safety based estradiol with grapefruit juice than when on past animal toxicity studies, concluded that estradiol was taken alone71. These results have orally administered quercetin is unlikely to cause independently confirmed that women taking oral any adverse effects although specific dose levels estradiol should probably avoid grapefruits were not indicated. altogether72.

CONTRAINDICATIONS AND Cyclosporine: PRECAUTIONS: In a randomized study of nine adults with Contraindication of Quercetin is not known. cyclosporine treated auto-immune diseases, Quercetin has been shown to cause chromosomal grapefruit juice causes a significant increase in mutations in certain bacteria in test tube studies. cyclosporine blood levels compared with However the significance of this finding for cyclosporine with water74. In another study by humans is not clear Because of lack of the healthy human volunteers, supplementing availability of long term safety data, quercetin quercetin along with cyclosporine significantly should be avoided by pregnant women and increased blood level of cyclosporine compared nursing mothers. to when not taken quercetin75.

DRUG INTERACTIONS: Quinolones: Quercetin shows interaction with following Quercetin binds in vitro with DNA gyrase site in drugs: bacteria. Therefore theoretically it can serve as competitive inhibitor to the Quinolones, which Felodipine: also bind to the same site76. Quercetin (found in grapefruit juice, tea, onions, and other foods) has been shown in test tube Cisplatin: studies to inhibit enzymes responsible for Because of the theoretical risk of genotoxicity in breaking down of Felodipine into inactive forms. normal tissues, in those using cisplatin along This interaction may result in increased blood with quercetin, cisplatin users should avoid levels of felodipine that could lead to unwanted quercetin supplements. side effects69. Until more is known about this interaction, patients taking felodipine should Doxorubicin: avoid supplementing with quercetin. Regular Test tube and animal studies suggest that consumption of grapefruit juice can increase the quercetin may enhance the effect of doxorubicin. quantity of felodipine in the blood by reducing the breakdown of the drug. The inhibitory effect Digoxin: of grapefruit juice lasts up to 24 hours after Treatment with both Digoxin and Quercetin may ingestion and can increase the blood levels result in large amounts of digoxin in blood, nearly three times the expected amount. In order which may cause more side effects of digoxin to prevent the side effects, individuals taking than usual. This interaction has been reported in felodipine should avoid consuming grapefruits animals, but how it affects people, is unclear80. and its juice70. DIETARY SOURCES:

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Fruits and vegetables particularly citrus fruits, followed by semambu leaves, bird chillies, black apples, onions, parsley, tea, red wine, etc. are the tea, papaya shoots and guava. Major flavonoids primary dietary sources of Quercetin. Olive oil, content in these plant extract is quercetin, grapes, dark cherries, and dark berries such as followed by myricetin, and kaempferol. In blueberries and bilberries are also high in vegetables quercetin glycosides predominate but flavonoids including quercetin. glycosides of kaempferol, luteolin and Studies were conducted on the Flavonoids are also present. Fruits contain almost (Myricetin, Quercetin, Kaempferol, Luteolin and exclusively quercetin glycosides, whereas Apegenin) contents of 62 edible tropical plants. kaempferol and myricetin glycosides are found The highest total flavonoids contents were found only in trace quantities78. Table-2 shows in onion leaves (1497 mg/Kg Quercetin, 391 contents of Quercetin, Myricetin and Kaempferol mg/kg Luteolin and 832 mg/kg Kaempferol) in selected food79.

Table 2: Amount of Quercetin in selected food79

Quercetin Myricetin Kaempferol FOOD mg/100g mg/100g mg/100g Broccoli, Raw 2.8 0.0 6.3 Carrots, Raw 0.4 0.0 0.0 Celery, Raw 3.5 ------Cocoa powder, Unsweetened 20.1 ------, Raw 14.0 4.3 0.1 Kale, Raw 5.1 0.0 14.6 Lettuce, Looseleaf, Raw 2.0 0.0 0.0 Lingonberries, Raw 11.3 0.0 0.0 Onions, Raw 22.6 0.0 0.3 Tomatoes, Red ripe, Raw 0.5 0.0 0.1

In another study, content of quercetin was and a direct extraction method for the -3- estimated in 25 edible berries. Sixteen species of ols and flavanones. This study showed that the cultivated berries and nine species of wild berries variation in the flavonoid content of foods, as were collected in Finland in 1997. Quercetin was purchased by the U.S. consumer, is very large. found in all the berries such as bog whortleberry The relative standard deviation, averaged for (158 mg/kg fresh weight), lingon berry (74 and each flavonoid in each food, was 168%87. 146 mg/kg), (83 and 121 mg/kg), chokeberry (89 mg/kg), sweet rowan (85 mg/kg), THERAPEUTIC USES: rowanberry (63 mg/kg), sea buckthorn berry (62 Quercetin offers a variety of potential therapeutic mg/kg) and crowberry (53 and 56 mg/kg)80. uses primarily in the prevention and the Onions (Allium cepa L) ranked highest in treatment of the conditions listed below. quercetin content in a survey of 28 vegetables Quercetin seems to work better when it is used in and 9 fruits81, 82. Quercetin levels tend to be conjunction with bromelain, a digestive enzyme highest in red and yellow onions and lowest in found in pineapple. white onions83, 84. Amount of quercetin in onions vary with bulb color type and variety. Regardless Allergies, asthma, hay fever and hives: of onion bulb pigmentation, quercetin Quercetin might be useful in some of the concentration is highest in the outer rings85, 86. allergies such as hay fever, hives. It inhibits the However in another study, more than 60 fresh production and release of histamine and other fruits, vegetables, and nuts were collected from allergic/inflammatory substances possibly by four regions across the United States at two stabilizing cell membranes of mast cells86,88. times of the year. Sample collection was Mast cells have been proposed as an immune designed and implemented by the Nutrient Data gate to the brain, as well as sensors of Laboratory (USDA), using a hydrolysis method environmental and emotional stress, and are for the , flavones, and flavonols likely involved in neuropathologic processes

29 Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge such as multiple sclerosis. Among mast cell various cancers. Indeed it has been suggested products, the protease tryptase could be that about 7-31% of all cancers could be reduced associated with neurodegenerative processes by diets high in fruits and vegetables94. through the activation of specific receptors (PARs) expressed in the brain, while interleukin In various animal and test tube studies, quercetin (IL)-6 likely causes neurodegeneration and has been shown to inhibit the growth of cancer exacerbates dysfunction induced by other cells including those from breast, colon, prostate cytokines; or it could have a protective effect and lung cancers63. Quercetin by virtue of its against demyelinisation. In the year 2006 a study anti-oxidant property prevents reactive oxygen conducted by Kempuraj et al showed that species induced DNA damage, leading to quercetin, a natural compound able to act as an mutational changes. A large clinical study inhibitor of mast cell secretion, causes a decrease suggested the presence of an inverse association in the release of tryptase and IL-6 and the down- between quercetin intake and subsequent regulation of histidine decarboxylase (HDC) incidence of lung cancers64. In the study done by mRNA from human mast cell (HMC)-1. As Caltagirone et al, quercetin showed the quercetin dramatically inhibits mast cell tryptase, inhibitory effect on the growth of melanoma and IL-6 release and HDC mRNA transcription by also influenced the invasive and metastatic HMC-1 cell line, these results nominate potential in mice95. The bioflavonoid quercetin quercetin as a therapeutical compound in may be a potent alternative to reduce cisplatin association with other therapeutical molecules induced nephrotoxicity96. Furthermore quercetin for neurological diseases mediated by mast cell seems to inhibit angiogenesis97. Angiogenesis is degranulation89. normally a strictly controlled process in the human body. Pathological, unregulated Antibacterial activity: angiogenesis occurs in cancers98. Among the Quercetin seems to exert antibacterial activity angiogenesis inhibitors quercetin seems to play against almost all the strains of bacteria known an important role99. However the mechanism to cause respiratory, gastrointestinal, skin and behind the anti-angiogenic effect of flavonoids is urinary disorders90. unclear. A possible mechanism could be the inhibition of protein kinase100. As many of the Arthritis: PTKs are oncogenes, this raised the possibility of Quercetin inhibits both cyclo-oxygenase and quercetin being an effective anti-cancer lipo-oxygenase activities thus diminishing the compound. Quercetin was effective in inhibiting formation of inflammatory mediators91,92. In radiation-induced PKC activity. Activation of addition there are reports of people with PKC is one of the means of conferring rheumatoid arthritis, who experienced an radioresistance on a tumour cell. Suppression of improvement in their symptoms, when they PKC activity by Quercetin may be one of the switched from a typical western diet to a vegan means of preventing the development of diet with lots of uncooked berries, fruits, radioresistance following radiotherapy101. vegetables containing amongst other antioxidants, quercetin93. Coronary Heart Diseases: Anti-oxidant quercetin intake protects against Cancers: coronary heart disease (CHD), caused by Although the etiology of cancer may be oxidized LDL (bad cholesterol). Hertog et al multifactorial (e.g. diet, genetic, environment), stated that regular consumption of flavonoids in there is wide recognition that reactive oxygen the food might reduce the risk of deaths from and nitrogen species (ROS/RNS) play a pivotal CHD in elderly men102,103. Furthermore a role in the pathophysiological process. Japanese study reported an inverse correlation ROS/RON have been shown to be carcinogenic between quercetin intake and total plasma and may exert their deleterious effects by cholesterol concentration104. Quercetin was also causing DNA damage, alter cell signaling shown to be effective inhibitor of platelets pathways (MAPK, NFkB, AP-1, PLA, ASK-1) aggregation in dogs and monkeys105. The main and modulate gene expression (proto-oncogene, antiplatelet aggregating effect is because of the tumour suppressor gene). The evidence from in inhibition of thromboxane A2106. Quercetin vitro and in vivo laboratory studies, clinical trials inhibits the proliferation and migration of aortic and epidemiological investigations show that smooth muscle cells, and platelet aggregation plant-based diets have protective effects against along with the inhibition of mitogen–activated

30 Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge protein kinase phosphorylation. These findings always better sources of quercetin than cooked or provide new insights and a rationale for the processed apples because the compound is potential use of quercetin in the prevention of mainly concentrated in the skin of apples. In cardiovascular diseases107. general red apples tend have more of antioxidant than green or yellow ones. Quercetin, through its Diabetic complications: COMT and MAO enzymes inhibiting properties, Quercetin has been found to be an inhibitor of might potentiate the anticatabolic effect of L- the enzyme aldose reductase, which plays a role dopa plus carbidopa treatment. The results of the in converting glucose (sugar) to sorbitol (a sugar present study strongly suggest that quercetin alcohol) in the body. People with diabetes could serve as an effective adjunct to L-dopa develop secondary problems, such as therapy in Parkinson disease113. Quercetin has neuropathy, retinopathy, diabetic cataracts, and potential for the treatment of neuroleptic-induced nephropathy because of sorbitol buildup in the extrapyramidal side effects, such as from body. Quercetin may therefore be beneficial in haloperidol114. Quercetin also is a powerful the nutritional management of diabetes, but antioxidant that may protect brain cells from clinical studies need to be conducted to verify damage. these effects, which have been observed in non- human experiments108. Osteoporosis: In an English study, bone mineral was Eye disorders: compared between elder women, who consumed Free radicals are thought to contribute the tea and those who did not. Women in the study, development of certain disorders including who drank tea (quercetin), had higher bone cataracts and macular degeneration. Quercetin mineral density measurements than those who prevents and treats these eye conditions by did not drink tea. Quercetin in the tea might be neutralizing these free radicals. In a study of responsible for the prevention of osteoporosis115. 3,072 adults with the symptoms of macular degeneration, moderate red wine consumption (a Peptic Ulcer: source of quercetin) offered some protection Quercetin seems to play a very important role in against the development and the progression of the prevention and treatment of peptic ulcer. It the disease109. Regular consumption of dark acts by promoting mucus secretion, thereby berries offers benefits for preventing macular serves as gastroprotective agent. Apparently, degeneration110. many peptic ulcers can be caused by infectious bacteria, known as Helicobacter pylori. Gout: Quercetin has been shown to inhibit the growth Quercetin by virtue of its xanthine oxidase of this bacterium in in-vitro studies116,117. inhibitory nature prevents the production of uric acid, thereby easing the gout symptoms24, 25. Prostatitis: In a prospective double-blind placebo controlled Neurodegenerative disorders: study, quercetin was found to be helpful in According to a study conducted by researchers at category III chronic prostatitis (non bacterial Cornell University in New York, a potent chronic prostatitis and prostodynia). Thirty men antioxidant (quercetin) in apples and in with this disorder received either placebo or 500 vegetables appear to protect brain cells against mg of quercetin twice daily for one month. oxidative stress, a tissue damaging process Significant improvement was achieved in treated associated with Alzheimer and other group, as measured by the National Institute of neurodegenerative disorders111. Quercetin seems Health Chronic Prostatitis score118. In a follow to protect the brain functions by inhibiting the up unblind open study, additional men received formation if fibrillated amyloid–beta, the senile the same amount of quercetin for one month, but plaque found in Alzheimer’s brain106. An this time quercetin was combined with bromelain experiment was performed to demonstrate the and papain, which may enhance its absorption. In possible effects of quercetin on cognitive this study 82% achieved a minimum 25% performance of young and aged, improvement score. intoxicated mice (animal model), where chronic quercetin treatment had shown the reversal of Viral infections: cognitive deficits112. Even though quercetin is The antiviral effect of Flavonoid was shown in a relatively stable during cooking, fresh apples are study conducted by Wang et al119. Some of the

31 Internet Journal of Medical Update, Vol. 2, No. 2, Jul-Dec 2007 Clinical Knowledge viruses reported to be affected by Flavonoids are literature over the past 10 years and a variety of herpes simplex virus, respiratory syncitial virus potential beneficial effects have been elucidated. and adenovirus. Quercetin was reported to However, most of the studies have been exhibit both anti-infective and antireplicative conducted in vitro studies; therefore, it is difficult abilities. By far most of the studies were to draw definite conclusion about the usefulness performed in vitro and little is known about the of flavonoids in the diet. Furthermore, antiviral effect of flavonoids in vivo. There is insufficient methods are available to measure some evidence that flavonoids in their glycon oxidative damage in vivo and the measurement form seem to be more inhibitory effect on of objective endpoints remains difficult. rotavirus infectivity than flavonoids in their Although recently some studies124,125,126 have aglycon form120. Because of the worldwide been conducted on absorption and excretion of spread of HIV, since 1980s, the investigations of flavonols including quercetin but there is a need the antiviral activity of flavonoids have mainly to improve analytic techniques to allow focused on HIV. The discovery and the collection of more data in this aspect. Data on development of flavonoids as anti-HIV agents the long-term consequences of chronic quercetin have expanded in the past two decades. Most of ingestion are especially scarce. To conclude, in- the studies focused on the inhibitory activity of vivo studies could be performed to give a hopeful reverse transcriptase or RNA directed DNA picture for the future. Currently, the intake of polymerase but antiintegrase and antiprotease fruit, vegetables, and beverages (e.g., tea and activities were also reported. Flavonoids have moderate amounts of red wine) containing mainly been studied in vitro experiments; quercetin is recommended, although it is too therefore no clear contribution of flavonoids to early to make recommendations on daily the treatment of HIV infected patients has yet quercetin intakes. been shown121, 122. REFERENCES: PREPARATION AND DOSAGES: 1. Middleton EJ. Effect of plant flavonoids on The average diet can supply 15 to 40mg of immune and inflammatory cell functions. quercetin per day from fruit and vegetable Adv Exp Med Biol 1998;439:175-182. consumption. Increasing quercetin intake for 2. De Groot H, Rauen U. Tissue injury by general health reasons can be accomplished by reactive oxygen species and the protective simply eating more vegetables and fruit. effects of flavonoids. Fundam Clin However, as most people are confronted with the Pharmacol 1998;12:249-55. reality of not being able to maintain an adequate 3. Narayana K Raj, Reddy M Sripal, Chaluvadi intake of bioflavonoid from food sources, extra MR, Krishna DR. Bioflavonoids quercetin can be obtained from dietary classification, pharmacological, Biochemical supplements. For therapeutic purposes such as effects and therapeutic potential. Indian allergy management, anti-inflammatory Journal of pharmacology 2001;33:2-16. treatment, and disease treatment, higher dosages 4. Molecular structures of major classes of of quercetin are usually prescribed. Therapeutic flavonoids retrieved from dosages can range from 250 to 500mg three http://www.emolecules.com/cgi-bin/search times per day. Quercetin is available in the form 5. Havsteen B. Flavonoids: A class of natural of capsules (250 mg, 300 mg, and 500mg) and products of high pharmacological potency. tablets (50 mg, 250 mg, and 500mg). Biochem Pharmacol 1983;32:1141-8. Recommended adult dosages of quercetin vary 6. Middleton E. The Flavonoids. Trends depending on the health condition being treated. Pharmacol Sci 1984;5:335-8. For allergic conditions, 250-600 mg per day in 7. Murphy Karen J, Chronopoulos Andriana K, divided doses and for chronic hives, 200-400 mg Singh I, el al. Dietary flavanols and thrice daily quercetin is recommended123. procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function. FUTURE IMPLICATIONS: American Journal of Clinical Nutrition Various cohort studies indicated an inverse 2003;77(6):1466-73. association between Flavonoids intake 8. Moskuag JO, Carlson H, Myhrstad M, et al. (Quercetin) and coronary heart disease mortality. Molecular Imaging of the biological effects These studies are promising and indicate that of Quercetin and Quercetin-rich foods. flavonoids may be useful food compounds. Mechanism of Ageing and Development Flavonoids have received much attention in the 2004;125:315-24.

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