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PubMed2002

Perturbation of microtubule polymerization by quercetin through tubulin binding: a novel mechanism of its antiproliferative activity.

The dietary flavonoid quercetin has a broad range of biological activities, including potent antitumor activity against several types of tumors. Recently, it has been shown that quercetin inhibits cancer cells proliferation by depleting cellular microtubules and perturbing cellular microtubule functions. However, the direct interactions of quercetin with tubulin and microtubules have not been examined so far. Here, we found that quercetin inhibited polymerization of microtubules and depolymerized microtubules made from purified tubulin in vitro. The binding of quercetin with tubulin was studied using quercetin fluorescence and intrinsic tryptophan fluorescence of tubulin. Quercetin bound to tubulin at a single site with a dissociation constant of 5-7 microM, and it specifically inhibited colchicine binding to tubulin but did not bind at the vinblastine site. In addition, quercetin perturbed the secondary structure of tubulin, and the binding of quercetin stimulated the intrinsic GTPase activity of soluble tubulin. Further, quercetin stabilized tubulin against decay and protected two cysteine residues of tubulin toward chemical modification by 5,5'-dithiobis-2-nitrobenzoic acid. Our data demonstrated that the binding of quercetin to tubulin induces conformational changes in tubulin and a mechanism through which quercetin could perturb microtubule polymerization dynamics has been proposed. The data suggest that quercetin inhibits cancer cells proliferation at least in part by perturbing microtubule functions through tubulin binding.

Anilino Naphthalenesulfonates↗

PubMed2004

Nitric oxide (NO) scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle.

The flavonoid quercetin reduces blood pressure and endothelial dysfunction in animal models of hypertension. However, the results concerning the relationship between quercetin and NO present a complex picture. We have analyzed the mechanisms involved in the NO scavenging effects of quercetin and its repercussion on NO bioactivity in vascular smooth muscle. Quercetin scavenged NO with apparent zero-order kinetics with respect to NO. This effect was strongly dependent on the O(2) concentrations, so that NO decay at pH 7.4 could be fitted to the equation -d[NO]/dt = k x [O(2)] x [quercetin], where k was 0.15 M(-1) s(-1). The NO scavenger effects were prevented by superoxide dismutase (SOD), reduced by lowering pH, accompanied by O(2)(.) production and correlated with decreased NO bioactivity in rat aortic rings. However, under conditions of increased O(2)(.) concentrations, quercetin was a better scavenger of O(2)(.) than of NO. When NO scavenging by quercetin was prevented by addition of SOD, NO bioactivity was increased. Quercetin also prevented the inhibitory effects of the SOD inhibitor diethyldithiocarbamic acid (DETCA) on NO bioactivity. In the presence of DETCA, quercetin reduced tissue O(2)(.) as measured by nitro blue tetrazolium staining. In conclusion, quercetin exerts dual effects on O(2)(.) and NO. At physiological conditions of pH, O(2) concentrations and NO, quercetin effectively scavenged NO in the low micromolar range, and the rate-limiting step was the autooxidation of quercetin and the formation of O(2)(.). When the extracellular NO scavenging effect was prevented, quercetin increased the biological activity of NO, an effect related to its O(2)(.) scavenger properties and/or its inhibitory effect on tissue O(2)(.) generation.

Animals↗

PubMed2002

Quercetin 3,7-dimethyl ether: a vasorelaxant flavonoid isolated from Croton schiedeanus Schlecht.

The vasorelaxant profile of quercetin 3,7-dimethyl ether, a flavonoid isolated from Croton schiedeanus Schlecht (Euphorbiaceae), was assessed in aortic rings isolated from Wistar rats. To gain insight into its structure-activity relationship, we compared this substance with quercetin 3,4',7-trimethyl ether (ayanin), another flavonoid isolated from this plant, quercetin 3,3',4',7-tetramethyl ether, a flavonoid synthesized by us, and quercetin. In addition we examined the interaction of quercetin 3,7-dimethyl ether with the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. According to their pEC50 values (concentration producing a 50% inhibition of the maximal contractile response) to phenylephrine-induced precontraction in rat isolated aorta, the potency order was quercetin 3,7-dimethyl ether > quercetin > quercetin 3,4',7-trimethyl ether > quercetin 3,3',4',7-tetramethyl ether (4.70+/-0.18; 3.96+/-0.07; 3.64+/-0.02; 3.11+/-0.16). The relaxant effect of quercetin 3,7-dimethyl ether was significantly decreased by the removal of endothelium as well as by methylene blue, an inhibitor of guanylyl cyclase, and by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an NO-synthase inhibitor. Therefore, quercetin 3,7-dimethyl ether has a NO/cGMP pathway-related profile, with increased vasorelaxant activity due to hydroxylation at positions 3 and 4 of the B ring. In addition, methylation at positions 3 and 7 with respect to quercetin of the C and A rings, respectively, seems to further enhance the vasorelaxant activity of quercetin 3,7-dimethyl ether.

Animals↗

PubMedDate not supplied

Quercetin-induced apoptosis in the monoblastoid cell line U937 in vitro and the regulation of heat shock proteins expression.

Quercetin, a widely distributed plant flavonoid, inhibits the growth of tumor cells and the expression of heat shock proteins. In this study, we examined quercetin-induced apoptosis of U937 cells in vitro and the regulation of heat shock proteins expression. The quercetin-induced apoptosis was demonstrated to be dose- and time-dependent. Flow cytometry analysis revealed that sub-G1 peak appeared at 12 hours, 24 hours and 48 hours respectively when treated with 50 mM of quercetin and at 6 hours, 12 hours, 24 hours and 48 hours with 100 mM of quercetin. Agarose gel electrophoresis demonstrated a typical ladder-like pattern of DNA fragments in the same time intervals with 50 mM of quercetin and at 6 hours only with 100 mM of quercetin. The distribution of DNA contents showed that U937 cells were accumulated mainly at G2/M phase when incubated with 50 mM of quercetin for 24 hours and 48 hours. There was no specific effect on cell cycle distribution at 100 mM of quercetin. On exposure to 100 mM of quercetin, the inhibition of hsp27 and hsp70 expression was observed from 12 hours to 48 hours and 6 hours to 48 hours respectively. The inhibition of hsp90 expression was not found eiyher at 50 mM or 100 mM of quercetin exposure. When incubated with 50 mM of quercetin, there was no inhibitory effect on hsp27, hsp70 and hsp90 expression by the Western blot analysis. These results suggested that it is dependent on the dose and exposure time of quercetin to induce apoptosis of U937 cells in vitro, to affect the cell cycle distribution and to regulate the expression of hsp27 and hsp70.

Apoptosis↗

PubMed2003

Differential effects of quercetin, a natural polyphenolic flavonoid, on L-type calcium current in pituitary tumor (GH3) cells and neuronal NG108-15 cells.

The effects of quercetin, a natural polyphenolic compound, on voltage-dependent L-type Ca(2+) current (I(Ca,L)) in rat pituitary GH(3) cells were investigated with the aid of the whole-cell voltage-camp technique. Quercetin (0.5-200 microM) stimulated I(Ca,L) in a concentration-dependent manner. The current-voltage (I-V) relationship of I(Ca,L) was slightly shifted to more negative potentials in the presence of quercetin. The EC(50) value of the quercetin-induced stimulation of I(Ca,L) was about 7 microM. The presence of quercetin (5 microM) shifted the steady state inactivation curve of I(Ca,L) to a more negative potential by approximately -10 mV. Although quercetin might increase intracellular cyclic AMP, sp-cAMPS did not affect I(Ca,L). In addition, neither flavone nor wortmannin had any effect on the amplitude of I(Ca,L), while epicatechin and genistein slightly suppressed it. Quercetin (50 microM) decreased the amplitude of tetrodotoxin-sensitive Na(+) current in GH(3) cells. Under current-clamp configuration, quercetin could increase the firing frequency of actions potentials. Conversely, in NG108-15 neuronal cells, quercetin suppressed the amplitude of I(Ca,L). The quercetin-induced inhibition of I(Ca,L) was abolished in NG108-15 cells preincubated with t-butyl hydroperoxide (1 mM). Quercetin-mediated stimulation of I(Ca,L) in GH(3) cells was presumably not associated with the level of intracellular cyclic AMP, or with the activity of tyrosine or phosphoinositide 3-kinases. Therefore, the effects of quercetin on ion currents may, at least in part, contribute to the underlying mechanisms through which it affects neuronal or neuroendocrine function.

Action Potentials↗

PubMed1999

Inhibitory effect of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation in human low-density lipoprotein.

To determine the antioxidant activity of dietary quercetin (3,3',4', 5,7-pentahydroxyflavone) in the blood circulation, we measured the inhibitory effect of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation of human low-density lipoprotein (LDL). Conjugated quercetin metabolites were prepared from the plasma of rat 1 h after oral administration of quercetin aglycone (40 micromol/rat). The rate of cholesteryl ester hydroperoxide (CE-OOH) accumulation and the rate of alpha-tocopherol consumption in mixtures of LDL solution (0.4 mg/ml) with equal volumes of this preparation were slower than the rates in mixtures of LDL with preparations from control rats. The concentrations of CE-OOH after 2 h oxidation in the mixtures of LDL with preparations of conjugated quercetin metabolites were significantly lower than those in the control preparation. It is therefore confirmed that conjugated quercetin metabolites have an inhibitory effect on copper ion-induced lipid peroxidation in human LDL. Quercetin 7-O-beta-glucopyranoside (Q7G) and rhamnetin (3,3',4', 5-tetrahydroxy-7-methoxyflavone) exerted strong inhibition and their effect continued even after complete consumption, similarly to quercetin aglycone. The effect of quercetin 3-O-beta-glucopyranoside (Q3G) did not continue after its complete consumption, indicating that the antioxidant mechanism of quercetin conjugates lacking a free hydroxyl group at the 3-position is different from that of the other quercetin conjugates. The result that 4'-O-beta-glucopyranoside (Q4'G) and isorhamnetin (3,4',5, 7-tetrahydroxy-3'-methoxyflavone) showed little inhibition implies that introduction of a conjugate group to the position of the dihydroxyl group in the B ring markedly decreases the inhibitory effect. The results of azo radical-induced lipid peroxidation of LDL and the measurement of free radical scavenging capacity using stable free radical, 1,1,-diphenyl-2-picrylhydrazyl, demonstrated that the o-dihydroxyl structure in the B ring is required to exert maximum free radical scavenging activity. It is therefore likely that conjugation occurs at least partly in positions other than the B ring during the process of metabolic conversion so that the inhibitory effect of dietary quercetin is retained in blood plasma after absorption.

Amidines↗

PubMed2006

Quercetin downregulates matrix metalloproteinases 2 and 9 proteins expression in prostate cancer cells (PC-3).

BACKGROUND: Cancer metastasis, involving multiple processes and various cytophysiological changes, is a primary cause of cancer death and may complicate the clinical management, even lead to death. Quercetin is a flavonoid and widely used as an antioxidant and recent studies have revealed its pleiotropic anticancer and antiproliferative capabilities. Gelatinases A and B (matrixmetalloproteinases 2 and 9) are enzymes known to involve in tumor invasion and metastases. In this study, we observed the precise involvement of quercetin role on these proteinases expression and activity. DESIGN AND METHODS: PC-3 cells were treated with quercetin at various concentrations (50 and 100 microM), for 24 h period and then subjected to western blot analysis to investigate the impact of quercetin on matrix metalloproteinase-2 (MMP-2) and 9 (MMP-9) expressions. Conditioned medium and cell lysate of quercetin-treated PC-3 cells were subjected to western blot analysis for proteins expression of MMP-2 and MMP-9. Gelatin zymography was also performed in quercetin treated PC-3 cells. RESULTS: The results showed that quercetin treatment decreased the expressions of MMP-2 and MMP-9 in dose-dependent manner. The level of pro-MMP-9 was found to be high in the 100 microM quercetin-treated cell lysate of PC-3 cells, suggesting inhibitory role of quercetin on pro-MMP-9 activation. Gelatin zymography study also showed the decreased activities of MMP-2 and MMP-9 in quercetin treated cells. CONCLUSION: Hence, we speculated that inhibition of metastasis-specific MMPs in cancer cells may be one of the targets for anticancer function of quercetin, and thus provides the molecular basis for the development of quercetin as a novel chemopreventive agent for metastatic prostate cancer.

Blotting, Western↗

PubMed2005

Pharmacokinetics and modeling of quercetin and metabolites.

PURPOSE: To determine the pharmacokinetics of quercetin and its glucuronide/sulfate conjugates and to develop a pharmacokinetic model to simultaneously describe their disposition after intravenous and oral administration in rats. METHODS: After oral, intraportal, and intravenous administration of quercetin, serial plasma, urine, and fecal concentrations of quercetin and its conjugates were determined by an HPLC method. Enterohepatic recirculation was evaluated in a linked-rat model as well as after oral administration of bile containing quercetin and its metabolites. Based on the experimental data, a specific compartmental model was developed and validated to describe and predict the plasma concentration-time profiles of quercetin and its conjugates after oral and intravenous administration. RESULTS: Only 5.3% of unchanged quercetin was bioavailable, although the total quercetin absorbed was as high as 59.1%. After oral administration, about 93.3% of quercetin was metabolized in the gut, with only 3.1% metabolized in the liver. No significant enterohepatic recirculation was observed for both quercetin and its conjugated metabolites. The pharmacokinetic model fitted well the observed data of quercetin and its conjugates. CONCLUSIONS: Our study clarifies the relative importance of the gut, liver, and bile in the metabolism and excretion of quercetin and its conjugates. The pharmacokinetic model appears to be suitable for describing the absorption and disposition of the quercetin and its conjugates and may be applicable to other flavonoids that undergo similar pharmacokinetic pathways.

Administration, Oral↗

PubMed1991

Inhibition of photooxidation of alpha-tocopherol by quercetin in human blood cell membranes in the presence of hematoporphyrin as a photosensitizer.

Photooxidation of alpha-tocopherol (alpha-TH) and photoperoxidation of lipids in blood cell membranes in the presence of hematoporphyrin (HP) as a photosensitizer were inhibited by quercetin. Half maximal inhibition for the photooxidation of alpha-TH was obtained at about 0.3 mM quercetin and that for the lipid photoperoxidation at about 1.5 microM quercetin. The difference of the half maximal inhibition may be due to the difference of mechanism of the inhibition between the two reactions. O2- and H2O2 hardly participated in the photooxidation of alpha-TH and 1O2 participated in the photooxidation only partially (about 5%). The electron transfer reaction from alpha-TH to excited HP was indicated by measuring ferricyanide photoreduction in the suspensions of alpha-TH in PBS solution in the presence of HP. The photooxidation of alpha-TH in PBS solution was inhibited by quercetin and vice versa. In the presence of linoleic acid in PBS solution, quercetin inhibited the photooxidation of alpha-TH and alpha-TH stimulated the photooxidation of quercetin. Based on the above data, as possible mechanisms of the inhibition of photooxidation of alpha-TH in blood cell membranes by quercetin, competition of quercetin with alpha-TH for excited HP and for radicals generated during lipid peroxidation and reduction of oxidized alpha-TH by quercetin are proposed. The antioxidative function of quercetin was enhanced by ascorbate even under conditions in which ascorbate functioned as a prooxidant when it was added alone. The enhancement is attributed to the functions of ascorbate to reduce the oxidized quercetin and of quercetin to inhibit ascorbate photooxidation.

Ascorbic Acid↗

PubMed2004

Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin.

The aim of this study was to investigate the effect of quercetin on the bioavailability of paclitaxel after the oral administration of paclitaxel or a prodrug to rats pretreated with quercetin. Paclitaxel (40 mg/kg) and prodrug (280 mg/kg, 40 mg/kg as the paclitaxel) were administered orally to rats pretreated with quercetin (2, 10, 20 mg/kg). The plasma concentrations of paclitaxel pretreated with quercetin were increased significantly (P < 0.01 for paclitaxel; P < 0.05 for prodrug) compared to the control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of paclitaxel pretreated with quercetin were significantly higher (P < 0.01) than the control. The half-life (t(1/2)) and mean residence times were significantly (P < 0.05) longer compared to the control. The absolute bioavailability (AB%) of paclitaxel pretreated with quercetin was significantly higher (P < 0.01) than the control. The AUC of paclitaxel after administration of the prodrug to rats pretreated with quercetin was significantly (P < 0.05) higher than the prodrug control. The relative bioavailability of paclitaxel after administration of the prodrug to rats pretreated with quercetin was 1.25- to 2.02-fold higher than the prodrug control. The AB% of paclitaxel was increased significantly (P < 0.05) by quercetin from 8.0 to 10.1 and 16.2%. The bioavailability of paclitaxel administered as a prodrug with or without pretreatment of quercetin was remarkably higher than the control. AUC, AB% and Cmax of paclitaxel after administration of the paclitaxel or prodrug pretreated with quercetin for 3 days were much higher than those administered after 20 min. It might have resulted from the physicochemical properties of the prodrug, which is a water-soluble compound and passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. It seems that the development of oral paclitaxel preparations as a prodrug or with quercetin is feasible, which is more convenient than the i.v. dosage forms.

Administration, Oral↗

PubMed2006

Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats.

Orally administered tamoxifen undergoes a first-pass metabolism and substrates for multidrug resistance (MDR) transporters efflux in the liver and intestines, which obstructs its systemic exposure. This study investigated the effect of quercetin, a dual inhibitor of CYP3A4 and P-gp, on the bioavailability and pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen in plasma were determined after orally administering tamoxifen (10 mg/kg) with or without quercetin (2.5, 7.5 and 15 mg/kg). The coadministration of quercetin (2.5 and 7.5 mg/kg) significantly (p < 0.05) increased the absorption rate constant (K(a)), peak concentration (C(max)) and the areas under the plasma concentration-time curve (AUC) of tamoxifen. The absolute bioavailability (AB%) of tamoxifen with 2.5 and 7.5 mg/kg quercetin ranged from 18.0% to 24.1%, which was significantly higher than the control group, 15.0% (p < 0.05). The relative bioavailability (RB%) of tamoxifen coadministered with quercetin was 1.20-1.61 times higher than the control group. The coadministration of quercetin caused no significant changes in the terminal half-life (t(1/2)) and the time to reach the peak concentration (T(max)) of tamoxifen. Compared with the control group, the coadministration of 7.5 mg/kg quercetin significantly (p < 0.05) increased the AUC of 4-hydroxytamoxifen. However, the metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower (p < 0.05). This suggests that quercetin inhibits the both MDR transporters efflux and first-pass metabolism of tamoxifen. The enhanced bioavailability of tamoxifen as a result of its coadministration with quercetin might be due to the effect of quercetin promoting the intestinal absorption and reducing the first-pass metabolism of tamoxifen. If the results are further confirmed in the clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with quercetin or quercetin-containing dietary supplements in order to avoid potential drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Identification of glutathione-related quercetin metabolites in humans.

The glutathionylation of quercetin was investigated in murine hepatic suspensions, in the absence of chemically or enzymatically induced oxidative stress, and in human urine after the consumption of 200 g of cooked onions ( approximately 74 mg of quercetin). In murine hepatic suspensions, 22 metabolites, including glucuronide, sulfate, and glutathione conjugates of quercetin, were identified by LC/ESI-MS/MS. In total, eight glutathione conjugates were identified in these suspension, including three isomeric forms of monoglutathionyl quercetin, two isomers of monoglutathionyl quercetin glucuronide, and three isomers of glutathionyl methyl quercetin. Quinone forms of glutathionyl quercetin and glutathionyl methyl quercetin were also apparent in mass spectra. In humans, several glutathione-related metabolites of quercetin were identified in urine as mercapturic acids of common hydroxyphenylacetic acids generated by the microbial degredation of quercetin in the gut. These include mercaptic acids of dihydroxytoluene, dihydroxybenzaldehyde, dihydroxyphenylacetic acid, dihydroxycinnamic acid, and dihydroxyphenylpropionic acid. Our results suggest that glutathionylation of quercetin occurs in both murine hepatic suspensions and humans and indicate that under certain conditions, quercetin intermediates require inactivation through conjugation with glutathione.

Acetylcysteine↗

PubMed2004

Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells.

Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells. However, the regulation of survivin and p53 on the quercetin-induced cell growth inhibition and apoptosis in cancer cells remains unclear. In this study, we investigated the roles of survivin and p53 in the quercetin-treated human lung carcinoma cells. Quercetin (20-80 mum for 24 h) induced the cytotoxicity and apoptosis in both A549 and H1299 lung carcinoma cells in a concentration-dependent manner. Additionally, quercetin inhibited the cell growth, increased the fractions of G(2)/M phase, and raised the levels of cyclin B1 and phospho-cdc2 (threonine 161) proteins. Moreover, quercetin induced abnormal chromosome segregation in H1299 cells. The survivin proteins were highly expressed in mitotic phase and were located on the midbody of cytokinesis; however, the survivin proteins were increased and concentrated on the nuclei following quercetin treatment in the lung carcinoma cells. Transfection of a survivin antisense oligodeoxynucleotide enhanced the quercetin-induced cell growth inhibition and cytotoxicity. Subsequently, quercetin increased the levels of total p53 (DO-1), phospho-p53 (serine 15), and p21 proteins, which were translocated to the nuclei in A549 cells. Treatment with a specific p53 inhibitor, pifithrin-alpha, or transfection of a p53 antisense oligodeoxynucleotide enhanced the cytotoxicity of the quercetin-treated cells. Furthermore, transfection of a small interfering RNA of p21 enhanced the quercetin-induced cell death in A549 cells. Together, our results suggest that survivin can reduce the cell growth inhibition and apoptosis, and p53 elevates the p21 level, which may attenuate the cell death in the quercetin-treated human lung carcinoma cells.

Apoptosis↗

PubMed2005

Ellagic acid potentiates the effect of quercetin on p21waf1/cip1, p53, and MAP-kinases without affecting intracellular generation of reactive oxygen species in vitro.

Anticarcinogenic effects attributed to polyphenols in fruits may be based on synergistic, additive, or antagonistic interactions of many compounds. In a previous study, it was demonstrated that quercetin and ellagic acid interacted synergistically in the induction of apoptosis in the human leukemia cell line, MOLT-4. To investigate possible cellular mechanisms, this study evaluated whether synergistic effects might be detectable within proapoptotic or antiproliferative signal transduction pathways. We found that quercetin and combinations of quercetin and ellagic acid nonsynergistically increased p53 protein levels. In contrast, ellagic acid potentiated the effects of quercetin for p21(cip1/waf1) protein levels and p53 phosphorylation at serine 15, possibly explaining the synergistic effect observed in apoptosis induction. Phosphorylation of the mitogen-activated protein (MAP) kinases, c-jun N-terminal (JNK)1,2 and p38, was also increased by the combination of ellagic acid and quercetin, whereas quercetin alone induced only p38. We further evaluated whether the generation of reactive oxygen species (ROS) and/or quercetin stability were influenced by interactions of ellagic acid with quercetin. Quercetin increased the generation of ROS, which was neither potentiated nor inhibited by ellagic acid. The stability of intracellular and extracellular quercetin was not influenced by the presence of ellagic acid. In summary, quercetin and ellagic acid combined increase the activation of p53 and p21(cip1/waf1) and the MAP kinases, JNK1,2 and p38, in a more than additive manner, suggesting a mechanism by which quercetin and ellagic acid synergistically induce apoptosis in cancer cells.

Cell Cycle Proteins↗

PubMed2004

Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans.

BACKGROUND: Quercetin, a flavonoid present in the human diet, which is found in high levels in onions, apples, tea and wine, has been shown previously to inhibit platelet aggregation and signaling in vitro. Consequently, it has been proposed that quercetin may contribute to the protective effects against cardiovascular disease of a diet rich in fruit and vegetables. OBJECTIVES: A pilot human dietary intervention study was designed to investigate the relationship between the ingestion of dietary quercetin and platelet function. METHODS: Human subjects ingested either 150 mg or 300 mg quercetin-4'-O-beta-D-glucoside supplement to determine the systemic availability of quercetin. Platelets were isolated from subjects to analyse collagen-stimulated cell signaling and aggregation. RESULTS: Plasma quercetin concentrations peaked at 4.66 microm (+/- 0.77) and 9.72 microm (+/- 1.38) 30 min after ingestion of 150-mg and 300-mg doses of quercetin-4'-O-beta-D-glucoside, respectively, demonstrating that quercetin was bioavailable, with plasma concentrations attained in the range known to affect platelet function in vitro. Platelet aggregation was inhibited 30 and 120 min after ingestion of both doses of quercetin-4'-O-beta-D-glucoside. Correspondingly, collagen-stimulated tyrosine phosphorylation of total platelet proteins was inhibited. This was accompanied by reduced tyrosine phosphorylation of the tyrosine kinase Syk and phospholipase Cgamma2, components of the platelet glycoprotein VI collagen receptor signaling pathway. CONCLUSIONS: This study provides new evidence of the relatively high systemic availability of quercetin in the form of quercetin-4'-O-beta-D-glucoside by supplementation, and implicates quercetin as a dietary inhibitor of platelet cell signaling and thrombus formation.

Blood Platelets↗

PubMed2004

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits.

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg(-1)) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg(-1)). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the C(max) and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg(-1) quercetin. There was no significant change in T(max) and terminal plasma half-life (t(1/2)) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P < 0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.

Animals↗

PubMed2003

[Effects of quercetin on the proliferation and apoptosis in transplantation tumor of breast cancer in nude mice].

OBJECTIVE: To investigate the effects of quercetin on tumour growth, cell proliferation and apoptosis in transplantation tumor of breast cancer cell line MCF-7 in nude mice. METHODS: MCF-7 cells were inoculated into the mammary fatty pad of nude mice to establish breast cancer model, then twenty-four BALB/c nude mice with xenograft tumor were randomized into four groups: Control group, Quercetin group, 5-Fu group and Quercetin + 5-Fu group. After 15 days treatment, samples of tumor were collected. The sections of tumor were observed under light microscope and electron microscope. Cell apoptosis in situ was examined by a Tunel assay, and the expressions of ki67 antigen and B-cell lymphoma/leukemia-2 (Bcl-2) were detected by immunohistochemistry. RESULTS: 1. The tumor weight of Control group was significantly higher than those of Quercetin group, 5-Fu group and Quercetin + 5-Fu group (P < 0.05). 2. Immunohistochemical staining of ki67 showed that the ki67 label index (ki67-LI) displayed significant difference between Control group and Quercetin group, 5-Fu group, Quercetin + 5-Fu group, and so did the staining of Bcl-2. 3. Detection of apoptosis in situ showed that apoptosis index (AI) was significantly higher in Quercetin group, 5-Fu group and Quercetin + 5-Fu group than in control group (P < 0.01), and higher AI was observed in Quercetin + 5-Fu group as compared with the AI in Quercetin group and 5-Fu group (P < 0.05). CONCLUSION: Quercetin can inhibit the growth of transplantation tumor of breast cancer cell line MCF-7 in nude mice.

Animals↗

PubMed1983

Metabolic fate of [14C] quercetin in the ACI rat.

To explain why quercetin, a mutagenic flavonoid distributed widely in edible plants, showed no carcinogenicity in experimental animals, overall metabolic fate of the drug was pursued using radiolabeled compound. [4-(14)C]Quercetin was administered orally or intraperitoneally to male ACI rats and its distribution, metabolism and excretion were studied by autoradiography and/or quantitation of radioactivity, and chemical analysis. [14C]Quercetin was also administered intravenously, intraperitoneally or orally to bile duct-cannulated rats and radioactivities in CO2 expired, bile, urine and feces were measured. To elucidate chemical structure of radiolabeled flavonoids in the bile and urine, urinary flavonoids derived from the rats given non-labeled quercetin diet was analyzed chemically. When [14C]-quercetin was administered orally, around 20% of the administered [14C]quercetin was absorbed from the digestive tract, more than 30% was decomposed to yield 14CO2 and around 30% was excreted unchanged in the feces. The absorbed [14C]quercetin was rapidly excreted into the bile and urine within 48 hours as the glucuronide and sulfate conjugates of [14C]quercetin, 3'-O-monomethyl [14C]quercetin and 4'-O-monomethyl [14C]quercetin. The present data indicate that the lack of carcinogenicity of quercetin in the rat is attributable to neither its poor absorption from the digestive tract nor its microbial degradation in the tract. Efficient metabolism and elimination of quercetin may be one reason of the lack of carcinogenicity.

Animals↗