On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the fenton reaction of the iron-ATP complex

Four flavonoids, baicilein, luteolin, naringenin, and quercetin were investigated for their ability to suppress the Fenton reaction characteristic of the iron-ATP complex. Absorption spectroscopy indicates that under the conditions of 18.75% aqueous methanol, 0.0625 mM HEPES pH 7.4 buffer and 1.5:1 quercetin/iron-ATP ratio a mix ligand complex formed. All four flavonoids were found to interfere with the voltammetric catalytic wave associated with the iron-ATP complex in the presence of H₂O₂. Quercetin and luteolin were able to completely suppress the catalytic wave of the iron-ATP/H₂O₂ system when a minimum ratio of 1.5:1 of the flavonoid to iron-ATP was reached. At this ratio, the ability of the studied series of flavonoids to suppress the Fenton reaction characteristic of iron-ATP follows as quercetin luteolin > naringenin baicilein. Both quercetin and luteolin contain catechol on the B ring, which may enhance the iron chelation of these species over baicilein and naringenin. The common structural feature of all of these flavonoids is the 4-keto, 5-hydroxy region, which may also contribute to the chelation of iron.     

Peroxidative metabolism of apigenin and naringenin versus luteolin and quercetin: glutathione oxidation and conjugation

GSH was readily depleted by a flavonoid, H(2)O(2), and peroxidase mixture but the products formed were dependent on the redox potential of the flavonoid. Catalytic amounts of apigenin and naringenin but not kaempferol (flavonoids that contain a phenol B ring) when oxidized by H(2)O(2) and peroxidase co-oxidized GSH to GSSG via a thiyl radical which could be trapped by 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) to form a DMPO-glutathionyl radical adduct detected by ESR spectroscopy. On the other hand, quercetin and luteolin (flavonoids that contain a catechol B ring) or kaempferol depleted GSH stoichiometrically without forming a thiyl radical or GSSG. Quercetin, luteolin, and kaempferol formed mono-GSH and bis-GSH conjugates, whereas apigenin and naringenin did not form GSH conjugates. MS/MS electrospray spectroscopy showed that mono-GSH conjugates for quercetin and luteolin had peaks at m/z 608 [M + H](+) and m/z 592 [M + H](+) in the positive-ion mode, respectively. (1)H NMR spectroscopy showed that the GSH was bound to the quercetin A ring. Spectral studies indicated that at a physiological pH the luteolin-SG conjugate was formed from a product with a UV maximum absorbance at 260 nm that was reducible by potassium borohydride. The quercetin-SG conjugate or kaempferol-SG conjugate on the other hand was formed from a product with a UV maximum absorbance at 335 nm that was not reducible by potassium borohydride. These results suggest that GSH was oxidized by apigenin/naringenin phenoxyl radicals, whereas GSH conjugate formation involved the o-quinone metabolite of luteolin or the quinoid (quinone methide) product of quercetin/kaempferol.     

Anaerobic Degradation of Flavonoids by Clostridium orbiscindens

An anaerobic, quercetin-degrading bacterium was isolated from human feces and identified as Clostridium orbiscindens by comparative 16S rRNA gene sequence analysis. The organism was tested for its ability to transform several flavonoids. The isolated C. orbiscindens strain converted quercetin and taxifolin to 3,4-dihydroxyphenylacetic acid; luteolin and eriodictyol to 3-(3,4-dihydroxyphenyl)propionic acid; and apigenin, naringenin, and phloretin to 3-(4-hydroxyphenyl)propionic acid, respectively. Genistein and daidzein were not utilized. The glycosidic bonds of luteolin-3-glucoside, luteolin-5-glucoside, naringenin-7-neohesperidoside (naringin), quercetin-3-glucoside, quercetin-3-rutinoside (rutin), and phloretin-2′-glucoside were not cleaved. Based on the intermediates and products detected, pathways for the degradation of the flavonol quercetin and the flavones apigenin and luteolin are proposed. To investigate the numerical importance of C. orbiscindens in the human intestinal tract, a species-specific oligonucleotide probe was designed and tested for its specificity. Application of the probe to fecal samples from 10 human subjects proved the presence of C. orbiscindens in 8 out of the 10 samples tested. The numbers ranged from 1.87 × 10⁸ to 2.50 × 10⁹ cells g of fecal dry mass⁻¹, corresponding to a mean count of 4.40 × 10⁸ cells g of dry feces⁻¹.     

Alfalfa Root Exudates and Compounds which Promote or Inhibit Induction of Rhizobium meliloti Nodulation Genes

Using a plate induction assay, we demonstrate that alfalfa exudes inducer of Rhizobium meliloti nodulation genes. The inducer is exuded from the infectible zone of the root, accumulates to at least 1 micromolar, and is not affected by 10 millimolar nitrate. No zones of inhibition are observed. A nodulation minus mutant line of alfalfa, MN-1008, exudes normal levels of inducer. R. meliloti grown in rich medium requires ten-fold higher concentrations of luteolin to achieve half-maximal induction as compared to cells grown in a minimal medium. Flavonoids other than luteolin are found to have activity in R. meliloti nodulation gene induction assays. The compounds apigenin and eriodictyol have activities two-fifths and one-seventh that of luteolin, respectively. Several of the flavonoids tested (morin = naringenin > kaempferol = chrysin > quercetin = fisetin = hesperitin) demonstrate antagonistic activity toward induction by luteolin. The most effective antagonist is the coumarin, umbelliferone.     

Anaerobic degradation of flavonoids by Eubacterium ramulus

Eubacterium ramulus, a quercetin-3-glucoside-degrading anaerobic microorganism that occurs at numbers of approximately 10⁸/g dry feces in humans, was tested for its ability to transform other flavonoids. The organism degraded luteolin-7-glucoside, rutin, quercetin, kaempferol, luteolin, eriodictyol, naringenin, taxifolin, and phloretin to phenolic acids. It hydrolyzed kaempferol-3-sorphoroside-7-glucoside to kaempferol-3-sorphoroside and transformed 3,4-dihydroxyphenylacetic acid, a product of anaerobic quercetin degradation, very slowly to non-aromatic fermentation products. Luteolin-5-glucoside, diosmetin-7-rutinoside, naringenin-7-neohesperidoside, (+)-catechin, and (–)-epicatechin were not degraded. Cell extracts of E. ramulus contained α- and β-d-glucosidase activities, but were devoid of α-l-rhamnosidase activity. Based on the degradation patterns of these substrates, a pathway for the degradation of flavonoids by E. ramulus is proposed. Received: 1 July 1999 / Accepted: 25 September 1999     

Chemotaxis of Rhizobium meliloti to the plant flavone luteolin requires functional nodulation genes.

Luteolin is a phenolic compound from plants that acts as a potent and specific inducer of nodABC gene expression in Rhizobium meliloti. We have found that R. meliloti RCR2011 exhibits positive chemotaxis towards luteolin. A maximum chemotactic response was observed at 10(-8) M. Two closely related flavonoids, naringenin and apigenin, were not chemoattractants. The presence of naringenin but not apigenin abolished chemotaxis of R. meliloti towards luteolin. A large deletion in the nif-nod region of the symbiotic megaplasmid eliminated all chemotactic response to luteolin but did not affect general chemotaxis, as indicated by swarm size on semisoft agar plates and chemotaxis towards proline in capillary tubes. Transposon Tn5 mutations in nodD, nodA, or nodC selectively abolished the chemotactic response of R. meliloti to luteolin. Agrobacterium tumefaciens GMI9050, a derivative of the C58 wild type lacking a Ti plasmid, responded chemotactically to 10(-8) M luteolin. The introduction of a 290-kilobase nif-nod-containing sequence of DNA from R. meliloti into A. tumefaciens GMI9050 enabled the recipient to respond to luteolin at concentrations peaking at 10(-6) M as well as at concentrations peaking at 10(-8) M. The response of A. tumefaciens GMI9050 to luteolin was also abolished by the presence of naringenin.     

Glycosylation of various flavonoids by recombinant oleandomycin glycosyltransferase from <Emphasis Type="Italic">Streptomyces antibioticus</Emphasis> in batch and repeated batch modes

An oleandomycin glycosyltransferase (OleD GT) gene from Streptomyces antibioticus was functionally expressed in Escherichia coli BL21 (DE3) with various molecular chaperones. The purified recombinant OleD GT catalyzed glycosylation of various flavonoids: apigenin, chrysin, daidzein, genistein, kaempferol, luteolin, 4-methylumbelliferone, naringenin, quercetin and resveratrol with UDP–glucose. 4.6 μg OleD GT was readily immobilized onto 1 mg hybrid nanoparticles of Fe₃O₄/silica/NiO on the basis of the affinity between His-tag and NiO nanoparticles with retention of 90% activity. In batch reaction, more than 90% naringenin (20 μM) was converted to its glycoside in 5 h. The immobilized OleD GT was efficiently reused for seven times whilst maintaining >60% of the residual activity in repeated glycosylation of naringenin.     

Structure-activity relationships of flavonoids for vascular relaxation in porcine coronary artery

Flavonoids are polyphenolic compounds that are widespread in the plant kingdom, and structure-activity relationships (SAR) for vascular relaxation effects were examined for 17 of them using porcine coronary arteries. Density functional theory was employed to calculate the chemical parameters of these compounds. The order of potency for vascular relaxation was as follows: flavones (apigenin and luteolin) >or= flavonols (kaempferol and quercetin)>isoflavones (genistein and daidzein)>flavanon(ol)es (naringenin)>chalcones (phloretin)>anthocyanidins (pelargonidin)>flavan(ol)es ((+)-catechin and (-)-epicatechin). SAR analysis revealed that for good relaxation activity, the 5-OH, 7-OH, 4'-OH, C2=C3 and C4=O functionalities were essential. Comparison of rutin with quercetin, genistin with genistein, and puerarin with daidzein demonstrated that the presence of a glycosylation group greatly reduced relaxation effect. Total energy and molecular volume were also predictive of their relaxation activities. Our findings indicated that the most effective relaxing agents are apigenin, luteolin, kaempferol and genistein. These flavonoids possess the key chemical structures demonstrated in our SAR analysis.     

Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids

In this study, we investigated the estrogenic activity of environmental estrogens by a competition binding assay using a human recombinant estrogens receptor (hERbeta) and by a proliferation assay using MCF-7 cells and a sulforhodamine-B assay. In the binding assay, pharmaceuticals had a stronger binding activity to hERbeta than that of some phytoestrogens (coumestrol, daidzein, genistein, luteolin, chrysin, flavone, and naringenin) or industrial chemicals, but phytoestrogens such as coumestrol had a binding activity as strong as pharmaceuticals such as 17alpha-ethynylestradiol (EE), tamoxifen (Tam), and mestranol. In the proliferation assay, pharmaceuticals such as diethylstilbestrol, EE, Tam, and clomiphene, and industrial chemicals such as 4-nonylphenol, bisphenol A, and 4-dihydroxybiphenyl had a proliferation-stimulating activity as strong as 17beta-estradiol (ES). In addition, we found that phytoestrogens such as coumestrol, daidzein, luteolin, and quercetin exerted a proliferation stimulating activity as strong as ES. Furthermore, we examined the suppression of proliferation-stimulating activity, induced by environmental estrogen, by flavonoids, such as daidzein, genistein, quercetin, and luteolin, and found that these flavonoids suppressed the induction of the proliferation-stimulating activity of environmental estrogens. The suppressive effect of flavonoids suggests that these compounds have anti-estrogenic and anti-cancer activities.     

Interference by luteolin,quercetin, and taxifolin with chloroplast-mediated electron transport and phosphorylation

Summary The effects of luteolin, quercetin, and taxifolin on light induced phosphorylation and electron transport in isolated, greenhouse-grown, spinach (Spinacia oleracea L.) thylakoids were investigated. Luteolin and quercetin interacted with components associated with both the ATP-generating pathway and the electron-transport pathway. However, the action of taxifolin involved only the phosphorylation pathway. Interference with the phosphorylation pathway was evidenced by the greater sensitivity of phosphorylation than oxygen uptake in coupled whole-chain electron transport, inhibition of the light-activated Mg²⁺-ATPase, and inhibition of the Ca²⁺-ATPase associated with CF₁. The following order of decreasing inhibitory effectiveness was exhibited: luteolin > quercetin >>> taxifolin. On the electron-transport pathway, luteolin and quercetin interfered with the activity of the Q_B-protein complex as evidenced by inhibition of the partial reaction with diphenylcarbazide as the electron donor and 2,6-dichlorophenolindophenol as electron acceptor; alteration of the chlorophyll fluorescence transients; and competitive displacement of radiolabeled atrazine [2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine].     

Chemotaxonomic consideration of flavonoids from the leaves of Chrysanthemum arcticum subsp. arcticum and yezoense,and related species

We examined the foliar flavonoids of Chrysanthemum arcticum subsp. arcticum and yezoense, and related Chrysanthemum species. Five flavonoid glycosides (luteolin 7-O-glucoside and 7-O-glucuronides of luteolin, apigenin, eriodictyol and naringenin) were isolated from these taxa. Luteolin 7-O-xylosylglucoside, luteolin, apigenin and quercetin 3-methyl ether were found in subsp. yezoense as very minor compounds that were not recognised by high-performance liquid chromatography/photodiode array (HPLC/PDA). The related species C. yezoense contained acacetin 7-O-rutinoside and some methoxylated flavone aglycones as major compounds. Thus, C. arcticum was distinguished from C. yezoense according to their flavonoid profiles.     

Effect of three flavonoids, 5,7,3',4'-tetrahydroxy-3-methoxy flavone, luteolin, and quercetin, on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophil

The effect of three flavonoids, 5,7,3',4'-tetrahydoxy-3-methoxy flavone (THMF), luteolin, and quercetin, on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils were investigated. When the cells were preincubated with these flavonoids, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was significantly suppressed, showing a dependence on amounts of the flavonoid. The suppressing effect of the flavonoid was THMF > luteolin > quercetin. These flavonoids also suppressed the superoxide generation induced by phorbol 12-myristate 13-acetate. In this case also, THMF was more effective than luteolin and quercetin. On the other hand, the superoxide generation induced by arachidonic acid was markedly suppressed by quercetin. The suppressing effect was quercetin > THMF > luteolin. THMF, luteolin, and quercetin significantly suppressed tyrosyl phosphorylation of 80.1-, 58.0-, and 45.0-kDa proteins in fMLP-treated human neutrophils. The suppression depended on the concentration of the flavonoids, and the inhibition of tyrosyl phosphorylation was in parallel to that of the fMLP-induced superoxide generation, respectively. While luteolin and quercetin showed a weak hemolytic activity at 2.5 mM, THMF showed almost no hemolytic activity even at 5 mM, suggesting an advantage of THMF for its clinical use.     

Anaerobic degradation of flavonoids by Clostridium orbiscindens

An anaerobic, quercetin-degrading bacterium was isolated from human feces and identified as Clostridium orbiscindens by comparative 16S rRNA gene sequence analysis. The organism was tested for its ability to transform several flavonoids. The isolated C. orbiscindens strain converted quercetin and taxifolin to 3,4-dihydroxyphenylacetic acid; luteolin and eriodictyol to 3-(3,4-dihydroxyphenyl)propionic acid; and apigenin, naringenin, and phloretin to 3-(4-hydroxyphenyl)propionic acid, respectively. Genistein and daidzein were not utilized. The glycosidic bonds of luteolin-3-glucoside, luteolin-5-glucoside, naringenin-7-neohesperidoside (naringin), quercetin-3-glucoside, quercetin-3-rutinoside (rutin), and phloretin-2'-glucoside were not cleaved. Based on the intermediates and products detected, pathways for the degradation of the flavonol quercetin and the flavones apigenin and luteolin are proposed. To investigate the numerical importance of C. orbiscindens in the human intestinal tract, a species-specific oligonucleotide probe was designed and tested for its specificity. Application of the probe to fecal samples from 10 human subjects proved the presence of C. orbiscindens in 8 out of the 10 samples tested. The numbers ranged from 1.87 x 10(8) to 2.50 x 10(9) cells g of fecal dry mass(-1), corresponding to a mean count of 4.40 x 10(8) cells g of dry feces(-1).     

Exploration of glycosylated flavonoids from metabolically engineered <Emphasis Type="Italic">E. coli</Emphasis>

Flavonoids glycosylated with UDP-glucuronic acid and UDP-xylose are spatially distributed in nature. To produce these glycosides, E. coli was engineered to overexpress biosynthetic gene clusters of UDP-sugars (galU from E. coli K12, UDP-glucose dehydrogenase (calS8), and UDP-glucuronic acid decarboxylase (calS9) from Micromonospora echinospora spp. calichensis). Flavonoids were glycosylated by overexpression of the glycosyltransferase gene (atGt-5) from Arabidopsis thaliana. Finally, metabolically engineered host E. coli (US89Gt-5) was generated. Production of flavonoid glycosides was observed in a biotransformation system consisting of flavonoids (naringenin and quercetin) exogenously fed to host cells. The glycosylated derivatives 7-O-glucuronyl naringenin (m/z⁺ 449), 7-O-xylosyl naringenin (m/z⁺ 405), and 7-O-glucuronyl quercetin (m/z⁺ 479) were detected and confirmed by ESI-MS/MS, ESI-MS/MS and LC/MS-MS analysis, respectively.     

Analysis of flavonoids and characterization of theOsFNS gene involved in flavone biosynthesis in Rice

The major flavonoids in rice leaves were analyzed via LC-MS/MS after their total flavonoid extracts were hydrolyzed. The most abundant flavones were apigenin, luteolin, and tricetin. Of these, tricetin was methylated at its 3′ and 5′-hydroxyl group to form tricin, which was probablyO-glycosylated. Both 3′-O-methylated luteolin and luteolin were found in theC-glycosylated form while apigenin wasC-glycosylated. We also cloned and characterizedOsFNS, which catalyzes the reaction from flavanone (naringenin) to flavone (apigenin). Analysis of the reaction product with recombinant OsFNS showed that it indeed converts naringenin to apigenin.     

Degradation of Quercetin and Luteolin by Eubacterium ramulus

The degradation of the flavonol quercetin and the flavone luteolin by Eubacterium ramulus, a strict anaerobe of the human intestinal tract, was studied. Resting cells converted these flavonoids to 3,4-dihydroxyphenylacetic acid and 3-(3,4-dihydroxyphenyl)propionic acid, respectively. The conversion of quercetin was accompanied by the transient formation of two intermediates, one of which was identified as taxifolin based on its specific retention time and UV and mass spectra. The structure of the second intermediate, alphitonin, was additionally elucidated by ¹H and ¹³C nuclear magnetic resonance analysis. In resting-cell experiments, taxifolin in turn was converted via alphitonin to 3,4-dihydroxyphenylacetic acid. Alphitonin, which was prepared by enzymatic conversion of taxifolin and subsequent purification, was also transformed to 3,4-dihydroxyphenylacetic acid. The coenzyme-independent isomerization of taxifolin to alphitonin was catalyzed by cell extract or a partially purified enzyme preparation of E. ramulus. The degradation of luteolin by resting cells of E. ramulus resulted in the formation of the intermediate eriodictyol, which was identified by high-performance liquid chromatography and mass spectrometry analysis. The observed intermediates of quercetin and luteolin conversion suggest that the degradation pathways in E. ramulus start with an analogous reduction step followed by different enzymatic reactions depending on the additional 3-hydroxyl group present in the flavonol structure.     

Four glucosyltransferases from rice: cDNA cloning, expression, and characterization

Four UDP-dependent glucosyltransferase (UGT) genes, UGT706C1, UGT706D1, UGT707A3, and UGT709A4 were cloned from rice, expressed in Escherichia coli, and purified to homogeneity. In order to find out whether these enzymes could use flavonoids as glucose acceptors, apigenin, daidzein, genistein, kaempferol, luteolin, naringenin, and quercetin were used as potential glucose acceptors. UGT706C1 and UGT707A3 could use kaempferol and quercetin as glucose acceptors and the major glycosylation position was the hydroxyl group of carbon 3 based on the comparison of HPLC retention times, UV spectra, and NMR spectra with those of corresponding authentic flavonoid 3-O-glucosides. On the other hand, UGT709A4 only used the isoflavonoids genistein and daidzein and transferred glucose onto 7-hydroxyl group. In addition, UGT706D1 used a broad range of flavonoids including flavone, flavanone, flavonol, and isoflavone, and produced at least two products with glycosylation at different hydroxyl groups. Based on their substrate preferences and the flavonoids present in rice, the in vivo function of UGT706C1, UGT706D1, and UGT707A3 is most likely the biosynthesis of kaempferol and quercetin glucosides.     

O-Methylation of flavonoid substrates by a partially purified enzyme from soybean cell suspension cultures.

A methyltransferase, which catalyzes the methylation of luteolin (K_m, 16 μM) using S-adenosyl-l-methionine as the methyl donor, has been purified about 38-fold from cell suspension cultures of soybean (Glycine max L., var. Mandarin). The following 3,4-dihydroxy phenolic compounds were also methylated: luteolin 7-O-glucoside (K_m, 28 μm), quercetin (K_m, 35 μm), eriodictyol (K_m, 75 μm), 5-hydroxyferulic acid (K_m, 227 μm), dihydroquercetin (K_m, 435 μm), and caffeic acid (K_m, 770 μm). Rutin and quercetin 3-O-glucoside were poor substrates. Methylation proceeded only in the meta position. The enzyme was unable to catalyze the methylation of p-coumaric acid, m-coumaric acid, ferulic acid, isoferulic acid, sinapic acid, apigenin, or naringenin. While the isoflavones biochanin A and daidzein did not serve as substrates, texasin (6,7-dihydroxy-3′-methoxyisoflavone) was methylated (K_m, 35 μm). The methylation of caffeic acid and quercetin showed a pH optimum of 8.6–8.9. The enzyme required Mg²⁺ ions for maximum activity (approximately 1 mm) and could be totally inhibited by EDTA (10 mm). The K_m for S-adenosyl-l-methionine was 11 μm. S-Adenosyl-l-homocysteine inhibited the methylation of luteolin by S-adenosyl-l-methionine.     

Distinct mechanisms of DNA damage in apoptosis induced by quercetin and luteolin

Quercetin has been reported to have carcinogenic effects. However, both quercetin and luteolin have anti-cancer activity. To clarify the mechanism underlying the carcinogenic effects of quercetin, we compared DNA damage occurring during apoptosis induced by quercetin with that occuring during apoptosis induced by luteolin. Both quercetin and luteolin similarly induced DNA cleavage with subsequent DNA ladder formation, characteristics of apoptosis, in HL-60 cells. In HP 100 cells, an H₂O₂-resistant clone of HL-60 cells, the extent of DNA cleavage and DNA ladder formation induced by quercetin was less than that in HL-60 cells, whereas differences between the two cell types were minimal after treatment with luteolin. In addition, quercetin increased the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), an indicator of oxidative DNA damage, in HL-60 cells but not in HP 100 cells. Luteolin did not increase 8-oxodG formation, but inhibited topoisomerase II (topo II) activity of nuclear extract more strongly than quercetin and cleaved DNA by forming a luteolin-topo II-DNA ternary complex. These results suggest that quercetin induces H₂O₂-mediated DNA damage, resulting in apoptosis or mutations, whereas luteolin induces apoptosis via topo II-mediated DNA cleavage. The H₂O₂-mediated DNA damage may be related to the carcinogenic effects of quercetin.     

Quercetin-iron chelates are transported via glucose transporters

Flavonoids are well-known antioxidants and free radical scavengers. Their metal-binding activity suggests that they could be effective protective agents in pathological conditions caused by both extracellular and intracellular oxidative stress linked to metal overload. Quercetin is both a permeant ligand via glucose transport proteins (GLUTs) and a high-affinity inhibitor of GLUT-mediated glucose transport. Chelatable “free iron” at micromolar concentrations in body fluids is a catalyst of hydroxyl radical (OH^?) production from hydrogen peroxide. A number of flavonoids, e.g., quercetin, luteolin, chrysin, and 3,6-dihydroxyflavone, have been demonstrated to chelate intracellular iron and suppress OH^? radical production in Madin Darby canine kidney cells. The most effective chelation comes from the flavonone B ring catechol found in both quercetin and luteolin. We show here that quercetin concentrations of < 1 μM can facilitate chelatable iron shuttling via GLUT1 in either direction across the cell membrane. These siderophoric effects are inhibited by raised quercetin concentrations (> 1 μM) or GLUT inhibitors, e.g., phloretin or cytochalasin B, and iron efflux is enhanced by impermeant extracellular iron chelators, either desferrioxamine or rutin. This iron shuttling property of quercetin might be usefully harnessed in chelotherapy of iron-overload conditions.