Quercitin

Brand Names:

Clinical Names: Quercitin; 3,3',4',5-7-pentahydroxyflavone

Summary

Quercitin

chemical name: 3,3',4',5-7-pentahydroxyflavone. Quercitrin is a flavonoid converted to quercitin by intestinal bacteria.

overview of interactions:
• nutrient affecting drug performance: Corticosteroids, including Prednisone

• nutrient affecting drug performance and toxicity: Cisplatin

chemistry/function: Quercitin is a flavonoid that functions as part of the structure of many other flavonoids, including the citrus flavonoids hesperidin, quercitrin and rutin, each varying according to the sugar molecules attached to the quercitin backbone. Quercitin is the most active of the various flavonoids according to most experimental research.

dietary sources: Quercitin is found in a wide variety of foods and medicinal plants.

deficiency: Flavonoids have sometimes been designated as "semi-essential." Flavonoid deficiencies were first noted in the 1930's when Albert Szent-Gyorgyi discovered that a crude form of vitamin C which contained a flavonoid fraction worked better for treating bleeding gums than did a more refined form of vitamin C.

known or potential therapeutic uses: Atherosclerosis, asthma, capillary fragility, cataracts, diabetes, edema, herpes, high cholesterol, peptic ulcer, rheumatoid arthritis, seasonal allergies (hay fever), SLE (lupus).

mechanism: Quercitin has anti-inflammatory, anti-allergic, anticarcinogenic, antioxidant, and antiviral properties. Flavonoids have generally been called "biological response modifiers" due to their ability to modify the body's reactions to various stressors such as allergens, carcinogens and viruses. Quercitin's strong anti-inflammatory action derives from its direct inhibition of the manufacture and release of histamine and other allergy/inflammatory mediators. Its antioxidant activity is significant. Quercitin is a potent inhibitor of aldose reductase, the enzyme responsible for converting glucose to sorbitol, a substance strongly associated with the development of cataracts, neuropathy, retinopathy and other diabetic complications. Quercitin also plays a special role in protecting vitamin C.

maintenance dose: Supplemental sources are usually not necessary for individuals eating a healthy, well-balanced diet. Optimal levels of intake have not been established.

therapeutic dose: Quercitin is often used in doses of 400 mg, three times daily.
Citrus bioflavonoids improve the absorption of vitamin C, while all bioflavonoids exert a protective action upon vitamin C.

side effects: Quercitin is considered safe, and no side effects have been reported. While some initial in vitro animal research provoked concern that quercitin might induce certain forms of cancer, subsequent research has vindicated quercitin and found that they are well-tolerated in large doses for extended periods of time. Quercitin and other flavonoids, in fact, have been found to exert a distinct protective effect against cancer and many are considered to have a potential therapeutic role in the treatment of some forms of cancer. While experimental research involving animal and in vitro studies shows promise for significant antitumor activity by quercitin against a wide range of cancers, there have been, as of yet, no studies supporting efficacy in humans.

toxicity: No toxicities have been reported or suspected as being associated with quercetin.

contraindications: None known to date.



Interactions

nutrient affecting drug performance: Corticosteroids, including Prednisone

• interactions: Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. Inhibition of cytochrome P-450 activity in the blood contributes to sustaining blood levels of corticosteroids. Moderate amounts of flavonoids, such as quercetin, can also be found in apples, onions and tea, with smaller amounts available in leafy green vegetables and beans.
(Schubert W, et al. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-224.)

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its absence or inhibition increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. This mineralocorticoid action of cortisol causes a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, which can lead to water retention, weight gain, and an increased risk of hypertension. Dietary flavonoids, such as found in grapefruit juice, can inhibit this enzyme and at high doses may cause an apparent mineralocorticoid effect.
(Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71.)

nutrient affecting drug performance and toxicity: Cisplatin

• research: Several studies indicate that quercetin exerts cisplatin sensitizing properties in cancer cells. Subsequently Kuhlmann et al conducted research to investigate whether quercitin could reduce cisplatin toxicity in cultured renal tubular cells. In their in vitro experiments they found that pretreatment of cells with quercetin for three hours significantly reduced the extent of cell damage due to cisplatin and that this protective activity was concentration dependent. They proposed that this activity most likely derived from quercetin's scavenging of free oxygen radicals. In contrast, they also noted that other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations. However, they also cautioned that, at least under these experimental circumstances, quercetin itself showed some intrinsic cytotoxicity at very high concentrations. (Scambia G, et al. Anticancer Drugs. 1990 Oct;1(1):45-48; Cross HJ, et al. Int J Cancer. 1996 May 3;66(3):404-408; Kuhlmann MK, et al. Arch Toxicol 1998 Jul-Aug;72(8):536-540.)

• nutritional support: As with other antioxidants, individuals being treated with cisplatin should consult with their prescribing physician and/or a healthcare professional trained in nutritional therapies before initiating use of quercitin. Quercitin is commonly used at dosage levels of 400-500 mg, two to three times per day. Bioflanoids such as quercitin are often taken with Vitamin C, which they potentiate and protect.

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Do not rely solely on the information in this article.

References

Aeschbacher H-U, Meier H, Ruch E. Nonmutagenicity in vivo of the food flavonol quercetin. Nutr Cancer 1982;2:90.

Amella M, Bronner C, Briancon F, Haag M, Anton R, Landry Y. Inhibition of mast cell histamine release by flavonoids and biflavonoids. Planta Med. 1985 Feb;(1):16-20.

Busse WW, Kopp DE, Middleton E Jr. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol. 1984 Jun;73(6):801-809.

Chaudhry PS, Cabrera J, Juliani HR, Varma SD. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol. 1983 Jul 1;32(13):1995-1998.

Cross HJ, Tilby M, Chipman JK, Ferry DR, Gescher A. Effect of quercetin on the genotoxic potential of cisplatin. Int J Cancer. 1996 May 3;66(3):404-408.
Abstract: The natural product flavonoid quercetin has been shown to sensitise cells to the cytotoxic potential of cisplatin. Both cisplatin and quercetin are genotoxicants. As quercetin is currently in clinical trial as a cytotoxicant-sensitising agent, we wanted to elucidate whether it affects the genotoxicity associated with cisplatin. The genotoxic potential of both agents alone and in combination was studied in Salmonella typhimurium strains TA 98, TA 100 and TA 102 and by assessment of unscheduled DNA synthesis (UDS) in rat hepatocytes. Furthermore, effects of quercetin on levels of cisplatin-DNA adducts were studied in hepatocytes by ELISA. Cisplatin was mutagenic in all 3 bacterial strains and quercetin in strain TA 98. The number of revertant Salmonella colonies observed with the combination did not differ significantly from that caused by the drugs on their own. In the UDS assay, cisplatin was genotoxic but quercetin was not. In combination, quercetin decreased the nuclear grain count caused by cisplatin, but quercetin did not alter the level of cisplatin-DNA adduct formation in hepatocytes. Our results suggest that the mutagenic potential of the combination cisplatin-quercetin, as judged by the bacterial short-term test, does not exceed that associated with the individual components. However, in hepatocytes, quercetin appears to inhibit repair of cisplatin-induced DNA damage. Therefore, in patients who are to be treated with a combination of cisplatin and quercetin, the risk of genotoxicity in normal tissues will have to be taken into consideration.

de Vries JH, Janssen PL, Hollman PC, van Staveren WA, Katan MB. Consumption of quercetin and kaempferol in free-living subjects eating a variety of diets. Cancer Lett. 1997 Mar 19;114(1-2):141-144.
Abstract: Quercetin and related flavonoids are anticarcinogenic in rats, but little is known about human intakes. The intake of five major flavonols and flavones was calculated using 1-day dietary records of 17 volunteers from 14 countries, and using both 3-day records and a food frequency questionnaire of eight Dutch adults. Total consumption (+/- SD) was 27.6 +/- 19.5 mg/day in the international subjects, 34.1 +/- 31.2 mg/day in the Dutch adults according to 3-day records, and 41.9 +/- 23.7 mg/day according to questionnaires. Quercetin contributed 68-73%, and kaempferol 22-29%, the major sources being tea and onions. A brief food frequency questionnaire may be a suitable method for ranking individuals by flavonol intake.

Ferrandiz ML, Alcaraz MJ. Anti-inflammatory activity and inhibition of arachidonic acid metabolism by flavonoids. Agents Actions. 1991 Mar;32(3-4):283-288.

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Hertog MG, Hollman PC. Potential health effects of the dietary flavonol quercetin. Eur J Clin Nutr. 1996 Feb;50(2):63-71. (Review)

Hirono I, Ueno I, Hosaka S, Takanashi H, et al. Carcinogenicity examination of quercetin and rutin in ACI rats. Cancer Lett 1981;13:15-21.

Hollman PC, Katan MB. Absorption, metabolism and health effects of dietary flavonoids in man. Biomed Pharmacother. 1997;51(8):305-310.
Abstract: Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Over 4,000 different flavonoids have been described, and they are categorized into flavonols, flavones, catechins, flavanones, anthocyanidins and isoflavonoids. Flavonoids have a variety of biological effects in numerous mammalian cell systems, in vitro as well in vivo. Recently, much attention has been paid to their antioxidant properties and to their inhibitory role in various stages of tumour development in animal studies. Quercetin, the major representative of the flavonol subclass, is a strong antioxidant, and prevents oxidation of low density lipoproteins in vitro. Oxidized low density lipoproteins are atherogenic, and are considered to be a crucial intermediate in the formation of atherosclerotic plaques. This agrees with observations in epidemiological studies that the intake of flavonols and flavones was inversely associated with subsequent coronary heart disease. However, no effects of flavonols on cancer were found in these studies. The extent of absorption of flavonoids is an important unsolved problem in judging their many alleged health effects. Flavonoids present in foods were considered non-absorbable because they are bound to sugars as beta-glycosides. Only free flavonoids without a sugar molecule, the so-called aglycones, were thought to be able to pass through the gut wall. Hydrolysis only occurs in the colon by microorganisms, which at the same time degrade flavonoids. We performed a study to quantify absorption of various dietary forms of quercetin. To our surprise, the quercetin glycosides from onions were absorbed far better than the pure aglycone. Subsequent pharmacokinetic studies with dietary quercetin glycosides showed marked differences in absorption rate and bioavailability. Absorbed quercetin was eliminated only slowly from the blood. The metabolism of flavonoids has been studied frequently in various animals, but very few data in humans are available. Two major sites of flavonoid metabolism are the liver and the colonic flora. There is evidence for O-methylation, sulphation and glucuronidation of hydroxyl groups in the liver. Bacterial ring fission of flavonoids occurs in the colon. The subsequent degradation products, phenolic acids, can be absorbed and are found in urine of animals. Quantitative data on metabolism are scarce.

Hollman PC, Hertog MG, Katan MB. Role of dietary flavonoids in protection against cancer and coronary heart disease. Biochem Soc Trans. 1996 Aug;24(3):785-789. (Review)

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Kaul TN, Middleton E Jr, Ogra PL. Antiviral effect of flavonoids on human viruses. J Med Virol. 1985 Jan;15(1):71-79.
Abstract: The effect of several naturally occurring dietary flavonoids including quercetin, naringin, hesperetin, and catechin on the infectivity and replication of herpes simplex virus type 1 (HSV-1), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in medium containing quercetin. Preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers. Hesperetin had no effect on infectivity but it reduced intracellular replication of each of the viruses. Catechin inhibited the infectivity but not the replication of RSV and HSV-1 and had negligible effects on the other viruses. Naringin had no effect on either the infectivity or the replication of any of the viruses studied. Thus, naturally occurring flavonoids possess a variable spectrum of antiviral activity against certain RNA (RSV, Pf-3, polio) and DNA (HSV-1) viruses acting to inhibit infectivity and/or replication.

Kuhlmann MK, Horsch E, Burkhardt G, Wagner M, Kohler H. Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin. Arch Toxicol 1998 Jul-Aug;72(8):536-540.
Abstract: Quercetin (QC), a polyphenolic compound widely distributed in fruits and vegetables has recently gained interest due to its cisplatin (CP) sensitizing properties in cancer cells. It is currently unknown, whether quercetin also increases the susceptibility of the kidneys to cisplatin toxicity. We studied the effects of various bioflavonoids on CP toxicity in an in vitro model of cultured tubular epithelial cells (LLC-PK1). Viability of LLC-PK1 cells, as assessed by lactate dehydrogenase (LDH) release and MTT-test, was affected by CP (100-400 microM) in a time and dose dependent fashion. Pretreatment of cells with QC for 3 h significantly reduced the extent of cell damage. The protective activity of QC was concentration dependent, starting at 10-25 microM and reaching a plateau between 50 and 100 microM. Other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations (100-500 microM). Quercetin itself showed some intrinsic cytotoxicity at concentrations exceeding 75 microM. Our data indicate that quercetin reduces cisplatin toxicity in cultured tubular epithelial cells. The exact mechanism of protection is unclear, though scavenging of free oxygen radicals may play an important role.

Larocca LM, Giustacchini M, Maggiano N, Ranelletti FO, Piantelli M, Alcini E, Capelli A. Growth-inhibitory effect of quercetin and presence of type II estrogen binding sites in primary human transitional cell carcinomas. J Urol. 1994 Sep;152(3):1029-1033.
Abstract: Eight cases of transitional cell carcinoma (TCC) of the bladder were investigated for the presence of estrogen receptors (ER) and Type II estrogen binding sites (Type II EBS). All these tumors specifically expressed type II EBS, while only 3 of 8 cases contained low amounts of ER. All the cases assayed for the presence of both nuclear and cytoplasmic type II EBS revealed the presence of these binding sites in the two compartments. Both cytoplasmic and nuclear receptors were similar to type II EBS described in other tissues relative to their binding specificity for estrogens and quercetin and their sensitivity to reducing agents. Quercetin, 10 microM., was effective in inhibiting in vitro bromodeoxyuridine (BrdUdR) incorporation by TCC cells. Rutin, which bound little if any to type II EBS, did not show any inhibitory effect on in vitro BrdUdR incorporation by tumor cells, suggesting a type II EBS mediated effect of flavonoids. Although the mechanism of the antiproliferative activity of quercetin remains to be fully clarified, the possible therapeutic potential of quercetin and related flavonoids should be considered.

Lee YS, Lorenzo BJ, Koufis T, Reidenberg MM. Grapefruit juice and its flavonoids inhibit 11 beta-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996 Jan;59(1):62-71.
Abstract: INTRODUCTION: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its congenital absence or inhibition by licorice increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. We tested the hypothesis that flavonoids found in grapefruit juice inhibit this enzyme in vitro and that grapefruit juice itself inhibits it in vivo. METHODS: Microsomes from guinea pig kidney cortex were incubated with cortisol and nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) and different flavonoids and the oxidation to cortisone measured with use of HPLC analysis. In addition, healthy human volunteers drank grapefruit juice, and the ratio of cortisone to cortisol in their urine was measured by HPLC and used as an index of endogenous enzyme activity. RESULTS: Both forms of 11 beta-OHSD requiring either NAD or NADP were inhibited in a concentration-dependent manner by the flavonoids in grapefruit juice. Normal men who drank grapefruit juice had a fall in their urinary cortisone/cortisol ratio, suggesting in vivo inhibition of the enzyme. CONCLUSION: Dietary flavonoids can inhibit this enzyme and, at high doses, may cause an apparent mineralocorticoid effect.

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Scambia G, Ranelletti FO, Benedetti Panici P, Bonanno G, De Vincenzo R, Piantelli M, Mancuso S. Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth. Anticancer Drugs. 1990 Oct;1(1):45-48.
Abstract: It has been demonstrated that the flavonoid quercetin (3,3',4',5-7-pentahydroxyflavone) (Q) inhibits the growth of several cancer cell lines and that the antiproliferative activity of this substance is mediated by a so-called type II estrogen binding site (type II EBS). We investigated the effects of quercetin and cisplatin (CDDP) alone and in combination on the proliferation of the ovarian cancer cell line OVCA 433. Both drugs exhibited a dose-related growth inhibition in a range of concentrations between 0.01 and 2.5 microM and 0.01 and 2.5 micrograms/ml for Q and CDDP respectively. The combination of the two drugs resulted in a synergistic antiproliferative activity. 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 CDDP. Since both rutin and hesperidin do not bind to type II EBS it can be hypothesized that Q synergizes with CDDP by acting through an interaction with these binding sites.

Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur J Drug Metab Pharmacokinet 1995 Jul-Sep;20(3):219-224.
Abstract: Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. The influence of these flavonoids on the metabolism of 17 beta-estradiol was investigated in a microsome preparation from human liver. The flavonoids were added in concentrations of 10, 50, 100, 250 and 500 mumol/l to the microsome preparation. The metabolism of 17 beta-estradiol was concentration dependently inhibited by all the flavonoids tested. Addition of the flavonoids to the microsome preparation did not influence estrone formation, while a potent inhibition of estriol formation was observed. At the highest concentrations tested of the respective flavonoid, there was approximately 75-85% inhibition of estriol formation. However, naringenin was a less potent inhibitor of 17 beta-estradiol metabolism as compared to quercetin and kaempferol. The most likely mechanism of action of the flavonoids on 17 beta-estradiol metabolism is inhibition of the cytochrome P-450 IIIA4 enzyme, which catalyzes the reversible hydroxylation of 17 beta-estradiol into estrone and further into estriol. These hydroxylation processes represent the predominant steps of the hepatic metabolic conversion of endogenous as well as exogenous 17 beta-estradiol. This interaction would be expected to inhibit the first-pass metabolism of 17 beta-estradiol, and this has recently been demonstrated after oral administration of 17 beta-estradiol to women.

Shen F, Weber G. Synergistic action of quercetin and genistein in human ovarian carcinoma cells. Oncol Res. 1997;9(11-12):597-602.
Abstract: Ovarian carcinoma is the fourth most common cause of cancer death in women and there has been a steady increase in the age-adjusted cancer death rates in the past 25 years in the US. However, patients who become cisplatin resistant respond poorly to available cytotoxic agents; therefore, discovering novel targets for ovarian carcinoma is vital. Quercetin, an anticancer agent, arrests the cell cycle at G1 and S phase boundary. Genistein, a plant flavonoid, attacks the cell cycle at G2 and/or early M phases in most carcinoma cells. Quercetin and genistein block the phosphatidylinositol conversion to IP3 signal transduction pathway mainly by inhibiting 1-phosphatidylinositol 4-kinase (PI kinase, EC 2.7.1.67) and 1-phosphatidylinositol 4-phosphate 5-kinase (PIP kinase, EC 2.7.1.68), respectively. Because each drug attacks a different phase of the cell cycle and reduces IP3 concentration by attacking different signal transduction enzymes, we tested the hypothesis that the two drugs might be synergistic in human carcinoma cells. In human ovarian carcinoma OVCAR-5 cells in growth inhibition assay, the IC50S for quercetin and genistein were (mean +/- SE) 66 +/- 3.0 and 32 +/- 2.5 microM; in clonogenic assays they were 15 +/- 1.2 and 5 +/- 0.5 microM, respectively. When quercetin was added to the cultures of OVCAR-5 cells followed 8 h later by genistein, synergism was observed in growth inhibition and clonogenic assays. The synergistic action of quercetin and genistein may be of interest in clinical treatment of human ovarian carcinoma.

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