Quercetin Research:
Quercetin Against Cancer:
According to Dr. Terrance Leighton, Ph.D., professor of biochemistry and molecular biology at the University of California at Berkeley, quercetin is one of the most potent anticancer agents ever discovered." It inactivates several cancer-causing agents, prevents damage to cell DNA and inhibits enzymes known to spur cancer growth. Much of the recent research on quercetin has shown it to be an anticarcinogen to numerous cancer cell types, including breast, leukemia, colon, ovary, squamous cell, endometrial, gastric, and non-small-cell lung.
Quercetin Against Coronary Heart Disease and Stroke:
Quercetin provides several health benefits for protecting cardiovascular health through its antioxidant and anti-inflammatory activity, its ability to inhibit platelet aggregation and its other anti-thrombotic effects to block the formation of blood clots. One study, called The Zutphen Elderly Study, investigated dietary flavonoid intake and risk of coronary heart disease. The risk of heart disease mortality decreased significantly as flavonoid intake increased. Individuals in the upper 25 percent of flavonoid intake had a relative risk of 0.42 compared to the lowest 25 percent in this 5-year follow-up study of men ages 65-84. Interestingly, the flavonoid-containing foods most commonly eaten in this study contain a high amount of quercetin (tea, onions, apples). In a cohort of the same study, dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence.
Quercetin Against Ulcers:
Animal studies have shown quercetin to protect against the formation of gastric ulcers caused by ethanol, probably by inhibiting lipid peroxidation of gastric cells and/or by inhibition of gastric acid secretion. Quercetin has also been shown to inhibit growth of Helicobacter pylori in a dose-dependent manner in vitro.
Quercetin Against Inflammation and Allergies:
Quercetin supports the immune system and reduces allergic reactions by inhibiting histamine release and appears to help combat hay fever, other allergies and asthma. Interestingly, quercetin is chemically similar to cromolyn, an anti-allergy drug that is known to inhibit histamine release. Quercetin's anti-histamine activity, combined with its anti-inflammatory effects, may explain much of the therapeutic activity of onions against asthma and allergies.
Quercetin as a Component of 'Vitamin P':
Citrus bioflavonoids were first identified by Albert Szent-Gyorgyi in 1936, winner of The Nobel Prize for the discovery of vitamin C. He reported that citrus bioflavonoids strengthened blood vessel walls and prevented capillary permeability in ways that vitamin C did not. Indeed, he called these bioflavonoids 'vitamin P' after the Permeability factor because they prevented the permeability of capillaries. It was in the course of isolating vitamin C that he came across the bioflavonoids. Certain vitamin C deficiency symptoms (i.e. easy bruising, bleeding gums) were found in early studies to be relieved by crude vitamin C extract but not by purified vitamin C. Szent-Gyorgyi had a friend with bleeding gums and thought this condition might have something to do with a vitamin C deficiency. He gave the man some raw, impure vitamin C, and sure enough the bleeding gums cleared up. Later on, confronted by a recurrence of bleeding gums, he decided to try again; this time with pure vitamin C. He expected to observe an even more dramatic result but it did not occur. The man's gums went right on bleeding. Szent-Gyorgyi re-examined his earlier preparation and decided that the effective impurity was bioflavonoids. He then tried these by themselves, and reported that they worked. He named these substances "vitamin P." Bioflavonoids thus first came into use as protectors of capillaries, the tiniest blood vessels in the body. Later studies disputed his findings because a deficiency state could not be identified and so these compounds (including quercetin) never actually attained full vitamin status. This is because there are over 4,000 different flavonoids with different properties and biological activities. Later studies done by Dr. Jacques Masquelier of France found that certain bioflavonoids called oligomeric proanthocyanidins (concentrated in grape seeds, grape skins, red wine, pine bark and many tree leaves) are the most effective components of the 'vitamin P' mixture that Szent-Gyorgyi spoke of. Studies now confirm that quercetin also has significant 'vitamin P' activity.
Kiesewetter H, Koscielny J, Kalus U, Vix JM, Peil H, Petrini O, van Toor BS, de Mey C. 2000. Efficacy of orally administered extract of red vine leaf AS 195 (folia vitis viniferae) in chronic venous insufficiency (stages I-II). A randomized, double-blind, placebo-controlled trial. Arzneimittelforschung 2000 Feb; 50(2): 109-17.
Institut fur Transfusionsmedizin und Immunhaematologie, Universitatsklinikum Charite, Berlin, Germany.
Red vine leaf extract (RVLE) is a herbal medicine containing several flavonoids, with quercetin-3-O-beta-glucuronide and isoquercitrin (quercetin-3-O-beta-glycoside) as the main components.
OBJECTIVE: To assess the efficacy and safety of once-daily doses of 360 and 720 mg RVLE (pharmaceutical extract code AS 195; Antistax Venenkapseln) compared to placebo in patients with stage I and incipient stage II chronic venous insufficiency (CVI).
DESIGN: A 12-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study.
PATIENTS: Male and female outpatients aged 25 to 75 years with stage I to stage II CVI (i.e. without extensive trophic changes), not having any other significant medical conditions and not treated with compression stockings, diuretics or other drugs affecting fluid balance.
INTERVENTION: Patients were randomly assigned to a double-blind treatment with placebo, 360 mg AS 195 or 720 mg AS 195 once daily for 12 weeks, preceded and followed by a single-blind 2-week placebo treatment for baseline run-in and end-of-trial washout, respectively. Study criteria were evaluated at baseline, after 6 and 12 weeks of treatment and 2 weeks after discontinuation of treatment.
RESULTS: Of the 260 patients enrolled and randomized, 219 completed the study in accordance with the protocol. In the intention-to-treat analysis (N = 257), the mean (+/- SD) lower leg volume (measured by water displacement plethysmography) of the patients treated with placebo (N = 87) increased by 15.2 +/- 90.1 g (displaced water mass) and by 33.7 +/- 96.1 g after 6 and 12 weeks compared to baseline. In contrast, for patients treated with AS 195, lower leg volume decreased, and after 12 weeks of treatment, the difference in mean lower leg volume between the active treatment groups and the placebo group was -75.9 g (95% CI: -106.1 to -45.8 g) and -99.9 g (95% CI: -130.3 to -69.6 g) for the group treated with 360-mg AS 195 (N = 86) and 720-mg AS 195 (N = 84), respectively. The changes in calf circumference showed a similar pattern: in patients treated with AS 195, both the higher dose (720 mg) and, albeit to a lesser extent, the lower dose (360 mg) resulted in a clear reduction in circumference over time, whereas, circumference remained largely unchanged in patients treated with the placebo (95% CI of the estimated treatment effects vs. placebo after 12 weeks: -1.40 to -0.56 cm and -1.73 to -0.88 cm for 360 and 720 mg AS 195, respectively). These differences were statistically significant (p < 0.001). The reductions in ankle circumference were qualitatively similar but quantitatively less marked. Subjectively, there was an improvement in key CVI symptoms (VAS) at 6 weeks with all treatments, but a further improvement at week 12 was seen only in the active treatment groups; at 12 weeks, the changes compared to baseline were significantly greater (p < 0.001) in both active treatment groups than in the placebo group. The treatments were well tolerated; Adverse events were rare and usually mild. Two adverse events (AEs) during treatment with the placebo led to hospitalization and were hence labeled as 'serious'. Three further patients were withdrawn because of AEs which occurred during treatment with the placebo.
CONCLUSION: Once-daily doses of 360 and 720 mg AS 195 were confirmed to be safe and effective in the treatment of mild CVI, reducing significantly lower leg edema and circumference whilst improving key CVI-related symptoms to a clinically relevant extent. The edema reduction is at least equivalent to that reported for compression stockings and/or other edema-reducing agents. The higher dose was as well tolerated as the lower dose but resulted in a slightly greater and more sustained improvement.
McAnlis GT, McEneny J, Pearce J, Young IS. 1999. Absorption and antioxidant effects of quercetin from onions, in man. Eur J Clin Nutr 1999 Feb; 53(2): 92-6.
Department of Food Science, Queen's University of Belfast, Northern Ireland.
OBJECTIVE: To investigate the in vivo effects of quercetin following the ingestion of fried onions.
DESIGN: Five healthy volunteers, three males and two females aged between 25 and 39 y, ingested 225 g of fried onions after an overnight fast and peripheral venous blood was collected 0, 2, 4, 24 and 48 h after consumption. Quercetin in the plasma, total antioxidant capacity and susceptibility of low density lipoproteins (LDL) to oxidation were measured.
RESULTS: Following the onion meal, quercetin levels increased from baseline values (28.4 +/- 1.9 ng/ml) to peak after 2 h (248.4 +/- 103.9 ng/ml), decreasing to baseline again after 24 h (P > 0.05). This was accompanied by an increase in the total antioxidant activity of the plasma from baseline (1.70 +/- 0.04 mmol/l trolox equivalents) to 1.75 +/- 0.10 mmol/l trolox equivalents after 2 h and 1.76 +/- 0.08 mmol/l trolox equivalents after 4 h. There was no significant change in the susceptibility of the plasma or the isolated LDL to oxidation over the 48 h period after consumption of the fried onions. In view of these negative findings, we isolated LDL and other lipoproteins from plasma at each time point. Quercetin was not detected in either LDL or VLDL, but was present in the HDL fraction, although this fraction also contains other proteins including albumin.
CONCLUSIONS: Quercetin can be absorbed in humans from dietary sources to high enough concentrations to increase the overall antioxidant activity of the plasma. Quercetin, however, has a strong affinity for protein and provides no direct protective effect during LDL oxidation.
Kienzler JL, Sallin D, Schifflers MH, Ghika A. 2002. Pharmacokinetics of mono-3'- and mono-4'-0-(beta-hydroxyethyl)-rutoside derivatives, after single doses of Venoruton powder in healthy volunteers. : Eur J Clin Pharmacol 2002 Sep; 58(6): 395-402.
BACKGROUND: Venoruton is a standardised mixture of O-(beta-hydroxyethyl) rutosides (HR) used for the relief of oedema and related symptoms in patients with chronic venous insufficiency.
OBJECTIVES. The primary objective was to evaluate the pharmacokinetic parameters, in particular the rate and extent of absorption (bioavailability) of two markers of Venoruton: mono-3'-HR and mono-4'-HR derivatives [glucuroconjugated forms (HG)], analysed in their deconjugated form as O-(beta-hydroxyethyl)-quercetin (HQ): mono-3'-HQ and mono-4'-HQ, and to investigate dose proportionality. A secondary objective was to evaluate the general safety of the different dosages.
METHODS: In this open, single-dose, randomised, four-way, crossover study, 16 healthy volunteers received four different oral doses of Venoruton powder (0.5, 1, 2 or 4 g). Eighteen blood samples were obtained between 10 min pre-dose and 120 h post-dose.
RESULTS: Peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) of mono-3'-HQ were or tended to be proportional to the dose between 1 g and 4 g. The dose proportionality could be extended to the 0.5-g dose, although C(max) and AUC were not always estimable at that dose level (due to the low number of data points above the limit of quantification). For mono-4'-HQ, the increase of C(max) and AUC was also or tended to be proportional to the dose over the whole tested range (0.5-4 g). Time to peak concentration of both Venoruton derivatives remained unaffected by the administered dose. The elimination half-life of both molecules was very similar with the three highest doses. It was shorter with the 0.5-g dose but was not accurately estimated (or even not estimable in some subjects) due to the low number of points above the limit of quantification.
CONCLUSIONS: The bioavailability of both Venoruton derivatives (mono-3'-HQ and mono-4'-HQ) tended to be proportional to the dose. The rate of appearance and the elimination half-life of both molecules were not modified with the administered dose. The different doses of the study medication were safe and well tolerated. Mono-3'-HQ and mono-4'-HQ are therefore new bioanalytic and pharmacokinetic markers for Venoruton.
Sengupta B, Sengupta PK. 2002. The interaction of quercetin with human serum albumin: a fluorescence spectroscopic study. Biochem Biophys Res Commun 2002 Dec 6; 299(3): 400-403.
Quercetin (3,3('),4('),5,7-pentahydroxyflavone), a ubiquitous, bioactive plant flavonoid, is known to possess anti-cancer, anti-tumor, and other important therapeutic activities of significant potency and low systemic toxicity. In this communication, we report for the first time a study on the interactions of quercetin with the plasma protein human serum albumin (HSA), exploiting the intrinsic fluorescence emission properties of quercetin as a probe. Quercetin is weakly fluorescent in aqueous buffer medium, with an emission maximum at approximately 538nm. Binding of quercetin with HSA leads to dramatic enhancement in the fluorescence emission intensity and anisotropy (r), along with significant changes in the fluorescence excitation and emission profiles. The excitation spectrum suggests occurrence of efficient Forster type resonance energy transfer (FRET) from the single tryptophan-214 residue of HSA to the protein bound quercetin. The emission, excitation, and anisotropy (r=0.18 at [HSA]=30&mgr;M) data (using the native protein) along with emission studies of quercetin using partially denatured HSA (by 8M urea) indicate that the quercetin molecules bind at a motionally restricted site near tryptophan-214 in the interdomain cleft region of HSA. Furthermore, the binding constant (K=1.9x10(5)M(-1)) and Gibbs free energy change (DeltaG(0)=-30.12kJ/mol)) for quercetin-HSA interaction have been calculated from the relevant anisotropy data. Implications of these results are examined, particularly in relation to prospective applications in biomedical research.
[No Authors Listed] 2002. [In Process Citation – on Quercetin and Activated Carbon Anthracite for Skin Healing]. Lik Sprava. 2002 Jul-Sep; (5-6): 74-8. [Article in Ukrainian].
The studies made suggest several leads for further study of healing of skin wounds with making use of the activated carbon anthracite (ACA) type carbon sorbent and quercetin-bound ACA type carbon sorbent. The results obtained suggest to us a shorter course and earlier beginning of the connective tissue regeneration after infliction of an incised wound to the skin in test animals under conditions of use of a carbon sorbent, the quercetin-bound one included.
Inal M, Altinisik M, Bilgin MD. 2002. The effect of quercetin on renal ischemia and reperfusion injury in the rat. Cell Biochem Funct 2002 Dec; 20(4): 291-6.
Renal ischemia-reperfusion injury occurs in many clinical conditions such as hypovolemic shock, thromboembolism, injury and after renal transplantation. Under these conditions, ROS are considered to be the reason for cellular damage. Bioflavonoids have antioxidant and renoprotective properties. We studied the effect of quercetin, a bioflavonoid, on ischemia and reperfusion in rats. The rats (n = 28) were separated into three groups. Group I was the control group. Animals in groups II (IR) and III (IR + Q) underwent 30 min ischemia and 45 min reperfusion, respectively. Rats, in group III, also received 50 mg kg(-1) quercetin before 45 min of reperfusion. The activities of SOD, CAT, GPx, and concentrations of GSH and GSSGR were determined in renal cortex and erythrocytes. Also, the levels of MDA in renal cortex and plasma, and XO in renal cortex were measured in these groups. The renal cortex XO levels in the IR group were higher than that of the control and IR+Q groups (p<0.001). The renal cortex and plasma MDA levels in the IR group were also found to be higher than the control and IR+Q groups (p<0.01, and p<0.001, respectively). However, a decrease in MAD level of the IR+Q group was found in renal cortex and erythrocytes. In addition, SOD, CAT, and GPx activities in renal cortex and erythrocytes of quercetin-treated animals were enhanced compared to animals of the IR group. Furthermore, there were no significant differences in the SOD, CAT, and GPx activities of the control and IR+Q group. A reduction of GSH and GSSGR levels in IR and IR+Q groups was detected but no significant differences were found between these groups. This study stresses that high concentration of ROS leads to renal ischemia and reperfusion, and quercetin reduces the renal injury by preventing the oxidative stress dependent on ischemia and reperfusion. Quercetin may be used in renal transplantation as an antioxidant drug. Copyright 2002 John Wiley & Sons, Ltd.
Jakubowicz-Gil J, Rzymowska J, Gawron A. 2002. Quercetin, apoptosis, heat shock. Biochem Pharmacol 2002 Dec 1; 64(11): 1591-5.
The present study was designed to investigate the correlation between the expression level of Hsp27 and Hsp72 and induction of apoptosis in HeLa cells in response to quercetin treatment. Treatment of HeLa cells with quercetin or with 1hr period of hyperthermia (42 degrees ) increased the number of apoptotic cells. Inhibition of the expression of Hsp72 and Hsp27 in tumour cells by anti-sense oligonucleotides, enhanced the induction of apoptosis by quercetin. Heat shock itself had little effect on apoptotic cell death in these cells, but when combined with quercetin treatment, caused a significant increase in the number of apoptotic cells. These results suggest that the reduction of Hsps expression in the HeLa cell line promotes the induction of apoptosis by quercetin.
Couladis M, Baziou P, Verykokidou E, Loukis A. 2002. Antioxidant activity of polyphenols from Hypericum triquetrifolium Turra. Phytother Res 2002 Dec; 16(8): 769-70.
From the aerial parts of Hypericum triquetrifolium Turra (Guttiferae) 3-8"-biapigenin, quercetin, rutin and chlorogenic acid were isolated. Their structures were elucidated by spectral techniques. Furthermore, the phenolic compounds were tested for antioxidant activity, using an in vitro method based on sodium arachidonoate, bleomycin and thiobarbituric acid with alpha-tocopherol as the reference solution. Copyright 2002 John Wiley & Sons, Ltd.
Chan MM, Fong D, Soprano KJ, Holmes WF, Heverling H. 2003. Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents. J Cell Physiol 2003 Jan; 194(1): 63-70.
The polyphenolic compounds curcumin and quercetin increased sensitivity of ovarian cancer cells (CAOV3 and SKOV3) to cisplatin. The effect was obtained when the compounds were added simultaneously with cisplatin, as well as when they were added 24 h before. High serum levels of certain cytokines, for example interleukin-6 (IL-6), have been associated with poor prognosis and cisplatin resistance in various forms of cancer. Furthermore, it has been hypothesized that cytokines may increase proliferation, metastasis, and stimulate production of detoxification enzymes and multi-drug resistant proteins. Curcumin inhibits the production of many cytokines. The two ovarian cell lines differ significantly in IL-6 production, and correspondingly the high producer, CAOV3, was less susceptible to cisplatin. Curcumin inhibited the production of IL-6 in this cell suggesting that one of the mechanisms for synergy between cisplatin and curcumin was by reducing the autologous production of IL-6. However, the synergy was also observed in the low IL-6 producer, SKOV3, indicating that the action was most probably a result of multiple targeting. In sum, this study suggests that the compounds, curcumin and quercetin, potentially may be useful for enhancing drug sensitivity in certain cancer. J. Cell. Physiol. 194: 63-70, 2002. Copyright 2002 Wiley-Liss, Inc.
Jaber R. 2002. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim Care 2002 Jun; 29(2): 231-61.
Patients with asthma and allergic rhinitis may benefit from hydration and a diet low in sodium, omega-6 fatty acids, and transfatty acids, but high in omega-3 fatty acids (i.e., fish, almonds, walnuts, pumpkin, and flax seeds), onions, and fruits and vegetables (at least five servings a day). Physicians may need to be more cautious when prescribing antibiotics to children in their first year of life when they are born to families with a history of atopy. More research is needed to establish whether supplementation with probiotics (lactobacillus and bifidobacterium) during the first year of life or after antibiotic use decreases the risk of developing asthma and allergic rhinitis. Despite a theoretic basis for the use of vitamin C supplements in asthmatic patients, the evidence is still equivocal, and long-term studies are needed. The evidence is stronger for exercise-induced asthma, in which the use of vitamin C supplementation at a dosage of 1 to 2 g per day may be helpful. It is also possible that fish oil supplements, administered in a dosage of 1 to 1.2 g of EPA and DHA per day, also may be helpful to some patients with asthma. Long-term studies of fish oil and vitamin C are needed for more definite answers. For the patient interested in incorporating nutritional approaches, vitamin C and fish oils have a safe profile. However, aspirin-sensitive individuals should avoid fish oils, and red blood cell magnesium levels may help in making the decision whether to use additional magnesium supplements. Combination herbal formulas should be used in the treatment of asthma with medical supervision and in collaboration with an experienced herbalist or practitioner of TCM. Safe herbs, such as Boswellia and gingko, may be used singly as adjuncts to a comprehensive plan of care if the patient and practitioner have an interest in trying them while staying alert for drug-herb interactions. No data on the long-term use of these single herbs in asthma exist. For the motivated patient, mind-body interventions such as yoga, hypnosis, and biofeedback-assisted relaxation and breathing exercises are beneficial for stress reduction in general and may be helpful in further controlling asthma. Encouraging parents to learn how to massage their asthmatic children may appeal to some parents and provide benefits for parents and children alike. Acupuncture and chiropractic treatment cannot be recommended at this time, although some patients may derive benefit because of the placebo effect. For patients with allergic rhinitis, there are no good clinical research data on the use of quercetin and vitamin C. Similarly, freeze-dried stinging nettle leaves may be tried, but the applicable research evidence also is poor. Further studies are needed to assess the efficacy of these supplements and herbs. Homeopathic remedies based on extreme dilutions of the allergen may be beneficial in allergic rhinitis but require collaboration with an experienced homeopath. There are no research data on constitutional homeopathic approaches to asthma and allergic rhinitis. Patients with COPD are helped by exercise, pulmonary rehabilitation, and increased caloric protein and fat intake. Vitamin C and n-3 supplements are safe and reasonable; however, studies are needed to establish their efficacy in COPD. On the other hand, there are convincing data in favor of N-acetyl-cysteine supplementation for the patient with COPD at doses ranging between 400 and 1200 mg daily. Red blood cell magnesium levels may guide the use of magnesium replacement. The use of L-carnitine and coenzyme Q10 in patients with COPD needs further study. The addition of essential oils to the dietary regimen of patients with chronic bronchitis is worth exploring. Patients with upper respiratory tract infections can expect a shorter duration of symptoms by taking high doses of vitamin C (2 g) with zinc supplements, preferably the nasal zinc gel, at the onset of their symptoms. Adding an herb such as echinacea or Andrographis shortens the duration of the common cold. The one study on Elderberry's use for the flu was encouraging, and the data on the homeopathic remedy Oscillococcinum interesting, but more studies should be performed. Saline washes may be helpful to patients with allergic rhinitis and chronic sinusitis. Patients also may try the German combination (available in the United States) of elderberry, vervain, gentian, primrose, and sorrel that has been tested in randomized clinical trials. Bromelain is safe to try; the trials of bromelain supplementation were promising but were never repeated. The preceding suggestions need to be grounded in a program based on optimal medical management. Patients need to be well educated in the proper medical management of their disease and skilled at monitoring disease stability and progress. Asthmatic patients need to monitor their bronchodilator usage and peak flow meter measurements to step up their medical treatment in a timely manner, if needed. Patients welcome physician guidance when exploring the breadth of treatments available today. A true patient-physician partnership is always empowering to patients who are serious about regaining their function and health.
