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PubMed2004

Effect of quercetin conjugates on vascular permeability and expression of adhesion molecules.

Quercetin and its glucosides exist in plant foods and are recovered in human plasma as glucuronide and sulfate conjugates. Quercetin and its conjugates show antioxidant activity in model experiments. It remains obscure, however, whether these conjugates retain these biological functions in vivo. We investigated the interaction of quercetin conjugates with lipid bilayers using liposome systems. Less quercetin conjugate was incorporated into liposomes than quercetin aglycone. We also studied the vascular permeability of quercetin-3-glucuronide using cell culture inserts. Incubation of human aortic endothelial cells (HAECs) with IL-1alpha resulted in increased permeability of quercetin-3-glucuronide. Furthermore, quercetin-3-glucuronide showed no suppressive effect on TNF-alpha-induced cell expression of intercellular adhesion molecule-1 (ICAM-1) on HAECs. These observations suggest that circulating conjugates of quercetin pass through the endothelium to reach vascular smooth muscle cells and exert their biological effects in the blood vessels during inflammation followed by deconjugation of the conjugates.

Aorta↗
PubMed2005

The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor.

Quercetin causes biphasic modulation of the proliferation of specific colon and mammary cancer cells. In this study, the possible involvement of the estrogen receptor (ER) in the stimulation of cell proliferation by quercetin was investigated. For this purpose, the effect of quercetin on cell proliferation was tested in ER-positive MCF-7 and T47D cells, and in ER-negative HCC-38 and MDA-MB231 cells. Quercetin stimulated proliferation of ER-positive cells only, suggesting this effect to be ER-dependent. In support of these results, quercetin induced ER-ERE-mediated gene expression in a reporter gene assay using U2-OS cells transfected with either ERalpha or ERbeta, with 10(5)-10(6) times lower affinity than 17beta-estradiol (E2) and 10(2)-10(3 )times lower affinity than genistein. Quercetin activated the ERbeta to a 4.5-fold higher level than E2, whereas the maximum induction level of ERalpha by quercetin was only 1.7 fold that of E2. These results point at the relatively high capacity of quercetin to stimulate supposed 'beneficial' ERbeta responses as compared to the stimulation of ERalpha, the receptor possibly involved in adverse cell proliferative effects. Altogether, the results of this study reveal that physiologically relevant concentrations of quercetin can exert phytoestrogen-like activity similar to that observed for the isoflavonoid genistein.

Breast Neoplasms↗
PubMed1994

Quercetin increases the severity of estradiol-induced tumorigenesis in hamster kidney.

Catechol estrogens have been postulated to mediate estradiol-induced kidney tumorigenesis in Syrian hamsters. As part of an examination of this postulate, we studied the influence of quercetin, a polyphenolic flavonoid, on the incidence and severity of estrogen-induced kidney tumors, on the metabolic activation of estradiol to catechol estrogens, and on the inactivation of catechol estrogens by catechol-O-methyltransferase-mediated O-methylation. None of the hamsters treated with 0.3 or 3% quercetin in the diet for 5.7 or 6.5 months, respectively, developed tumors, whereas all animals treated with estradiol developed kidney tumors. The coadministration of estradiol plus 3% quercetin significantly (p < 0.05) increased the mean number of large tumor nodules and the incidence of abdominal metastases over values obtained with hormone treatment alone. The coadministration of estradiol plus 0.3 or 3% quercetin for 16 days increased renal NADPH-dependent estradiol-4- but not estradiol-2-hydroxylase activities by 91 or 73%, respectively, over values obtained with hormone treatment alone. In vitro, quercetin and its structural analog, fisetin, strongly inhibited the catechol-O-methyltransferase-catalyzed O-methylation of 60 microM 4-hydroxyestradiol, with IC50 values of approximately 2-4 microM. Kinetic analyses of the enzyme inhibition by quercetin and fisetin revealed a mixed-type of inhibition (competitive plus non-competitive). Combined treatment of estradiol plus 3% quercetin decreased the rates of kidney catechol-O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by 34 and 22%, respectively, from values obtained with hormone treatment alone. Rates of hamster liver and kidney microsome-mediated estrogen quinone formation and quinone reduction (redox cycling) in estradiol plus 3% quercetin-treated hamsters were not markedly altered compared to values obtained in estradiol-treated animals. It is concluded that increased rates of formation of 4-hydroxyestradiol combined with an inhibition of the inactivation of this catechol estrogen by catechol-O-methyltransferase may result in elevated levels of this estrogen metabolite, specifically in the hamster kidney, where it may undergo metabolic redox cycling and generate potentially mutagenic free radicals. Thus, the potentiation by quercetin of estradiol-induced tumorigenesis in hamster kidney supports a role of 4-hydroxyestradiol in estrogen-induced carcinogenesis in this species.

Animals↗
PubMed2004

Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro.

BACKGROUND: Many different mechanisms are involved in nutrient-related prevention of colon cancer. In this study, a comprehensive assessment of the spectrum of possible biological actions of the bioactive compound quercetin is made using multiple gene expression analysis. Quercetin is a flavonoid that can inhibit proliferation of tumor cells and reduce the number of aberrant crypt foci, although increase of number of colon tumors was also reported. AIM OF THE STUDY: In order to elucidate possible mechanisms involved in its mode of action the effect of quercetin on expression of 4000 human genes in Caco-2 cells was studied and related to functional effects. METHODS: Caco-2 cells were exposed to 5 or 50 microM quercetin for 48 hours, differential expression of 4000 human genes was studied using microarrays and related to functional effects. Differentially expressed genes were categorized in seven functional groups: cell cycle and differentiation, apoptosis, tumor suppressor genes and oncogenes, cell adhesion and cell-cell interaction, transcription, signal transduction and energy metabolism. Also, cell proliferation and cell cycle distribution were measured. RESULTS: Quercetin (5 microM) downregulated expression of cell cycle genes (for example CDC6, CDK4 and cyclin D1), downregulated cell proliferation and induced cell cycle arrest in Caco-2 cells. After exposure to 50 microM quercetin cell proliferation decreased to 51.3% of control, and further decrease of the percentage of cells in the G1 phase coincided with an increase of the percentage of cells in the sub-G1 phase. Quercetin upregulated expression of several tumor suppressor genes. In addition, genes involved in signal transduction pathways like beta catenin/TCF signalling and MAPK signal transduction were influenced by quercetin. CONCLUSIONS: This study shows that large-scale gene expression analysis in combination with functional assays yields a considerable amount of information on (anti-)carcinogenic potential of food components like quercetin.

Antineoplastic Agents↗
PubMed2007

NAG-1 up-regulation mediated by EGR-1 and p53 is critical for quercetin-induced apoptosis in HCT116 colon carcinoma cells.

Quercetin, a flavonoid molecule ubiquitously present in nature, has multiple effects on cancer cells, including the inhibition of cell proliferation and migration. However, the responsible molecular mechanisms are not fully understood. We found that quercetin induces the expression of NAG-1 (Non-steroidal anti-inflammatory drug activated gene-1), a TGF-beta superfamily protein, during quercetin-induced apoptosis of HCT116 human colon carcinoma cells. Reporter assays using the luciferase constructs containing NAG-1 promoter region demonstrate that early growth response-1 (EGR-1) and p53 are required for quercetin-mediated activation of the NAG-1 promoter. Overexpression of NAG-1 enhanced the apoptotic effect of quercetin, but suppression of quercetin-induced NAG-1 expression by NAG-1 siRNA attenuated quercetin-induced apoptosis in HCT116 cells. Taken together, the present study demonstrates for the first time that quercetin induces apoptosis via NAG-1, providing a mechanistic basis for the apoptotic effect of quercetin in colon carcinoma cells.

Apoptosis↗
PubMed2005

Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease.

PURPOSE: Orally administered rutin reportedly ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of rats. We investigated the metabolic and pharmacological properties of rutin underlying the rutin-mediated amelioration of the rat colitis. METHODS: Apparent partition coefficients of rutin and its aglycone quercetin were compared. The biochemical/chemical stability of rutin was examined in the contents of various segments of gastrointestinal tracts of rats. Inflammatory indices were determined in the colitis rats after oral administration of rutin or rectal administration of quercetin. In human colon epithelial cells, the effect of quercetin on tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor kappa B (NFkappaB) activation was examined. RESULTS: The sugar residue in rutin greatly lowered the apparent partition coefficient and was rapidly deglycosylated to liberate quercetin in the cecal contents, whereas it was stable in the contents of the upper intestine. Not only oral administration of rutin but also rectal administration of quercetin remarkably ameliorated TNBS-induced colitis rats, indicating that quercetin liberated from rutin is therapeutically active. Furthermore, quercetin dose-dependently inhibited an inflammatory signal TNF-alpha-dependent NFkappaB activation. CONCLUSIONS: Our data suggest that rutin acted as a quercetin deliverer to the large intestine and its anti-inflammatory action in TNBS-induced colitis rats may be through quercetin-mediated inhibition of TNF-alpha-induced NFkappaB activation.

Animals↗
PubMed1987

Mutagenicity modulating effect of quercetin on aromatic amines and acetamides.

The effect of quercetin on the mutagenicity of 32 kinds of aromatic amines and their acetamides were investigated using Salmonella typhimurium TA98 with a mammalian metabolic activation system (S9 mix). Quercetin enhanced the mutagenicity of the tricyclic aromatic amines (aminofluorene, aminoanthracene and aminophenanthrene) and their acetamides by 1.2-5.9-fold. Whereas, quercetin depressed the mutagenicity of aniline derivatives, biphenyl derivatives, and bi- and tetra-cyclic amino derivatives. The modulation of mutagenicity of Trp-P-1, Trp-P-2, Glu-P-1 and Glu-P-2 (heterocyclic amines) by quercetin were liable to be affected by the content of S9 in the S9 mix. It seems that quercetin does not have the same effect as norharman, because quercetin did not enhance the mutagenicity of aniline. It is suggested that the modulation of the mutagenicity of aromatic amines and acetamides is caused by the modulation of the balance between the mutagenic activation and inactivation in the metabolism of these amines and acetamides in the presence of quercetin. In this modulation, quercetin may participate through its effects on the promotion of N-hydroxylation and the inhibition of arylhydroxylation and transacylation. The presence of tricyclic aromatic rings of amines and acetamides is a structural requirement for the mutagenicity enhancement by quercetin.

Amides↗
PubMed2004

Electrochemical study of quercetin-DNA interactions: part I. Analysis in incubated solutions.

The present study aims to investigate the quercetin-deoxyribonucleic acid (DNA) interaction occurring in bulk solution either electrochemically using differential pulse voltammetry or spectrophotometrically, in order to explain the possible DNA-damaging activity of quercetin. A very weak interaction between quercetin and DNA in solution was found to take place. However, since extensive quercetin-induced DNA damage via reaction with Cu(II) has been reported, an electrochemical study of the DNA-Cu(II)-quercetin system in solution was undertaken. The product of DNA interaction with quercetin-Cu(II) complex was observed. Damages to DNA were electrochemically recognized via the increasing of the anodic peaks corresponding to the oxidation of guanosine and adenosine bases and spectrophotometrically via increasing of the 260 nm adsorption band. It was also observed that dsDNA damage produced by the quercetin-Cu(II) complex occurred with time. Control experiments with different mixtures of Cu(II), quercetin, ssDNA, dsDNA or poly[A] were carried out in order to establish a possible mechanism of interaction between DNA and quercetin via Cu(II).

Cations, Divalent↗
PubMed2005

Quercetin arrests G2/M phase and induces caspase-dependent cell death in U937 cells.

Quercetin, a natural product derived from grapes, has been shown to prevent carcinogenesis in murine models. We report here that quercetin induces anti-proliferation and arrests G2/M phase in U937 cells. The G2/M phase accumulation was accompanied by an increase in the level of the cyclin B. In contrast, the level of the cyclin D, cyclin E, E2F1, and E2F2 was marked decreased in quercetin-treated U937 cells. Removal of quercetin from the culture medium stimulates U937 cells to synchronously re-enter the cell cycle, decrease expression level of cyclin B, and increased the expression level of cyclin D and cyclin E. These data demonstrate that quercetin causes reversible G2/M phase arrest, which was related with dramatic changes in the level of cyclin B, cyclin D, and cyclin E. Quercetin-induced down-regulation of cyclin D and cyclin E was associated with suppression of transcriptional levels but not protein stability. In addition, quercetin-treated U937 cells showed DNA fragmentation, increased sub-G1 population, and generated a 60kDa cleavage product of PLC-gamma1 in a dose-dependent manner, which were significantly inhibited by z-VAD-fmk. These data clearly indicate that quercetin-induced apoptosis is associated with caspase activation. In summary, the growth inhibition of the quercetin is highly related to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis in human promonocytic U937 cells.

Apoptosis↗
PubMed2005

Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia.

In the present study, experiments were performed to explore the action of quercetin, the most widely distributed flavonoids, and its major metabolite, quercetin-3'-sulfate, on lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-induced nitric oxide (NO) production in BV-2 microglia. Quercetin could suppress LPS- and IFN-gamma-induced NO production and inducible nitric oxide synthase (iNOS) gene transcription, while quercetin-3'-sulfate had no effect. LPS-induced IkappaB kinase (IKK), nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation, and IFN-gamma-induced NF-kappaB, signal transducer and activator of transcription-1 (STAT1) and interferon regulatory factor-1 (IRF-1) activation were reduced by quercetin. Moreover quercetin was able to induce heme oxygenase-1 expression. To address the involvement of heme oxygenase-1 induction in iNOS inhibition, heme oxygenase-1 antisense oligodeoxynucleotide was used. Quercetin-mediated inhibition of NO production and iNOS protein expression were partially reversed by heme oxygenase-1 antisense oligodeoxynucleotide, but was mimicked by hemin, a heme oxygenase-1 inducer. The involvement of signal pathways in quercetin-induced heme oxygenase-1 gene expression was associated with tyrosine kinase and mitogen-activated protein kinases activation. All these results suggest quercetin should provide therapeutic benefits for suppression of inflammatory-related neuronal injury in neurodegenerative diseases.

Amides↗
PubMed2006

In vitro evaluation of quercetin cutaneous absorption from topical formulations and its functional stability by antioxidant activity.

Recently, it was demonstrated that two different formulations containing quercetin inhibit the UVB-induced cutaneous oxidative stress and inflammation. Therefore, in the present study it was evaluated the functional stability of those formulations by the antioxidant activity, the release of quercetin from the formulations, and its skin retention using modified Franz diffusion cells. Both formulations tested ((1) non-ionic emulsion with high lipid content and (2) anionic emulsion with low lipid content) remained functionally (hydrogen-donating ability) stable during 180 days. Furthermore, quercetin was released from both formulations as determined using nitrocellulose membrane. In vitro antioxidant activity of retained quercetin into the skin was observed for both formulations as detected by the inhibition of malondialdehyde formation. The effect of quercetin retention was time-dependent for formulation 1. Concluding, this study demonstrates that quercetin remains functionally stable in formulations, and measuring the antioxidant activity is an efficient approach to evaluate quercetin skin retention with minimal interference of the tissue products. Furthermore, the present results on skin retention explain the previous study on quercetin in vivo activities, and together, these data suggest that formulations containing quercetin may be used as topical active products to control UVB-mediated oxidative damage of the skin.

Administration, Cutaneous↗
PubMed2004

Lethal quercetin-digoxin interaction in pigs.

Digoxin is a popular cardiac glycoside with very narrow therapeutic range. Quercetin is an ubiquitous antioxidant flavonoid. Digoxin is a substrate of P-glycoprotein (P-gp), a multi-drug efflux transporter, and quercetin was reported to be a modulator of P-gp. The aim of this study was to investigate the effect of quercetin on the absorption and disposition of digoxin in pigs. Pigs were orally given digoxin (0.02 mg/kg) with and without quercetin in crossover designs. The blood was collected via jugular vein and fluorescence polarization immunoassay was used to determine the serum concentration of digoxin. The pharmacokinetic parameters were calculated using WINNONLIN. The paired Student's t-test was used for statistical comparison. The coadministration of 50 mg/kg quercetin unexpectedly resulted in sudden death of two among three pigs within 30 min after digoxin administration. The coadministration of 40 mg/kg quercetin significantly elevated the Cmax of digoxin by 413% and increased the AUC0-t by 170%. The results indicated that a very serious pharmacokinetic interaction occurred between quercetin and digoxin. The concomitant administration of digoxin and quercetin or quercetin-containing herbs and dietary supplement should be avoided.

Animals↗
PubMed2002

The interaction of quercetin with human serum albumin: a fluorescence spectroscopic study.

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 538 nm. 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 Förster 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 microM) 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=1.9 x 10(5)M(-1)) and Gibbs free energy change (deltaG(0)=-30.12 kJ/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.

Anisotropy↗
PubMed2003

Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9.

The French paradox has been attributed to the antioxidant properties of flavonoids present in the red wine. Quercetin, a bioflanoid present in the human diet, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. However, it is not known whether quercetin exerts similar cardioprotective effects in cells treated with TNF-alpha. In this study, we investigated whether quercetin exerts the multiple suppressive effects on cytokine TNF-alpha-induced human aortic smooth muscle cells (HASMC). Treatment of quercetin showed potent inhibitory effects on the DNA synthesis of cultured HASMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK)1/2 activity and G1 cell-cycle arrest. Treatment of quercetin, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by quercetin was not observed. Because anti-atherogenic effects need not be limited to antiproliferation, we decided to examine whether quercetin exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF-alpha-induced HASMC. Quercetin inhibited TNF-alpha-induced MMP-9 secretion on HASMC in a dose-dependent manner. This inhibition was characterized by down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB site and activation protein-1 (AP-1) site in the MMP-9 promoter. These findings indicate the efficacy of quercetin in inhibiting cell proliferation, G1- to S-phase cell-cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 on TNF-alpha-induced HASMC.

Cell Cycle↗
PubMed1997

Studies on the inhibitory effects of quercetin on the growth of HL-60 leukemia cells.

Quercetin, a naturally occurring flavonoid, has been shown to exert multiple pharmacological effects and to be an anticancer agent or a supplementary anticancer agent. In this report, the human HL-60 promyelocytic leukemia cell line was used to study the effects of quercetin on the growth, cell cycle, activities of cytosolic and membrane protein kinase C (PKC) and tyrosine protein kinase (TPK), and phosphoinositide production of the tumor cells. The results showed that quercetin inhibited the growth of HL-60 cells in a concentration-dependent manner, with an IC50 value of about 7.7 microM after 96 hr of treatment; when the concentration of quercetin was 10 microM, the percent inhibition on the growth of HL-60 cells was 17.1, 27.3, 40.1, and 52.7% after 24, 48, 72, and 96 hr of treatment, respectively. Flow cytometric analyses showed that quercetin caused an increase in cells in the G2/M phase and a decrease in cells in the G0/G1 phase of the cell cycle in a concentration-dependent manner; these effects were reversed when quercetin was removed from the culture medium. Quercetin strongly inhibited the activities of cytosolic PKC and membrane TPK from HL-60 cells in vitro, with IC50 values of about 30.9 and 20.1 microM, respectively, but did not affect membrane PKC or cytosolic TPK activity from HL-60 cells in vitro. Quercetin markedly inhibited in a concentration-dependent manner the production of phosphoinositides in intact HL-60 cells. The results provide evidence that the inhibitory effect of quercetin on the growth of HL-60 cells may be related to its inhibitory effects on PKC and/or TPK in vitro and/or on the production of phosphoinositides.

Antineoplastic Agents↗
PubMed2002

Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats.

Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of quercetin on the absorption and disposition of cyclosporin in pigs and rats. Cyclosporin (Sandimmune, 10 mg/kg) was orally administered with and without a concomitant dose of quercetin (50 mg/kg) to pigs and rats. Cyclosporin concentrations in blood samples were determined by a specific monoclonal fluorescence polarization immunoassay. The pharmacokinetic parameters were calculated by noncompartmental analysis using WINNONLIN. A paired Student's t-test was conducted for statistical comparison. A study using the everted intestinal sac was carried out to evaluate the effect of quercetin on the function of intestinal Pgp. The coadministration of quercetin significantly decreased cyclosporin AUC(0-3) (area under the concentration-time curve from time zero to 3 h) by 56% and AUC(0-t) (area under the concentration-time curve from time zero to the last point) by 43% in pigs and rats, respectively, indicating that the coadministration of quercetin significantly decreased cyclosporin oral bioavailability. However, the inverted sac study showed that quercetin significantly inhibited the function of intestinal Pgp. It is suggested that concurrent use of quercetin or quercetin-containing dietary supplement or herbs with cyclosporin or other medications whose absorption and metabolism are mediated by Pgp and/or CYP3A4 should require close monitoring.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Quercetin modifies reactive oxygen levels but exerts only partial protection against oxidative stress within HL-60 cells.

Quercetin may contribute to the protection afforded by fruit- and vegetable-rich diets against diseases for which excess production of reactive oxygen species (ROS) has been implicated as a causal or contributory factor. We examine the effect of short term (90 min) quercetin (1-100 microM) exposure on the progress of menadione induced oxidative stress within HL-60 cells. 2',7'-dichlorofluorescein and rhodamine-123 fluorescence, resulting from oxidation of the ROS-sensitive dyes dichlorodihydrofluorescein and dihydrorhodamine-123 respectively, were utilised as indicators of general ROS levels. Ethidium fluorescence, resulting from oxidation of dihydroethidium, was used as a potentially more specific indicator of O(2)(-). Exposure to quercetin alone induced a decrease in DCF and rhodamine fluorescence. Conversely, ethidium fluorescence was enhanced by treatment with >or=40 microM quercetin. Incubation with 1-100 microM quercetin reduced the extent of menadione-induced increase in DCF and rhodamine fluorescence but the menadione-induced increase in ethidium fluorescence was further elevated for cells treated with >or=25 microM quercetin. Exposure to >or=10 microM quercetin abrogated menadione-induced DNA single-strand breaks but, paradoxically, quercetin exacerbated membrane damage and failed to enhance the viability of menadione-challenged cells. In conclusion, quercetin exerts only site-specific protection against oxidative stress.

Cell Membrane Permeability↗
PubMed2003

'In vitro' antioxidant and photoprotective properties and interaction with model membranes of three new quercetin esters.

Quercetin is well known to possess the strongest protective effect against UV light-induced lipoperoxidation. However, the absolute water insolubility of quercetin is a key step that may limit its bioavailability and, thus, its 'in vivo' employment as a photoprotective agent. The aim of the present paper was to evaluate 'in vitro' the antioxidant and photoprotective properties and the interaction with model membranes of three new semisynthetic quercetin derivatives, quercetin-3-O-acetate (Q-ac), quercetin-3-O-propionate (Q-pr) and quercetin-3-O-palmitate (Q-pal), obtained by esterification of the C-3 OH function with an aliphatic side-chain of different length. The antioxidant activity of quercetin and of its three esters was assessed in two 'in vitro' experimental models: (a) the bleaching of the stable 1,1-diphenyl-2-picrylhydrazyl radical; (b) UV radiation-induced peroxidation in multilamellar vesicles (MLVs). Differential scanning calorimetry on dimyristoylphosphatidylcholine MLVs and unilamellar vesicles was employed to investigate the interaction of the drugs tested with model membranes. Finally, the stability following UV light exposure and the lipophilicity and water solubility of quercetin and its three esters were examined. The findings obtained demonstrated that the esterification with an opportune aliphatic side chain of the OH function located at the C-3 position allows the production of new quercetin derivatives, which may be good candidates as photoprotective agents. In particular, one could speculate that the esterification with a short side-chain (such as in Q-ac and Q-prop) provides the suitable chemico-physical features not only to maintain the antioxidant and photoprotective effectiveness of the parent drug, but also to be able to migrate through the aqueous environment and to interact with and cross phospholipid membranes.

Antioxidants↗