tamarixetin and 3-methylquercetin

To investigate the plasma kinetics of quercetin derived from hard capsules filled with onion skin extract powder or quercetin dihydrate in humans.. In a randomized, single-blind, diet-controlled crossover study, 12 healthy subjects (six men and six women) aged 21-33 years were administered a single oral supra-nutritional dose of approximately 163 mg quercetin derived from onion skin extract powder (containing 95.3 % of total flavonoids as quercetin aglycone) or quercetin dihydrate (134 mg quercetin aglycone equivalent). Blood samples were collected before and during a 24-h period after quercetin administration. The concentrations of quercetin and its two monomethylated derivatives, isorhamnetin (3'-O-methyl quercetin), and tamarixetin (4'-O-methyl quercetin), were measured using HPLC with fluorescence detection after plasma enzymatic treatment.. The systemic availability, determined by comparing the plasma concentration-time curves of quercetin, was 4.8 times higher, and the maximum plasma concentration (C. Quercetin aglycone derived from onion skin extract powder is significantly more bioavailable than that from quercetin dihydrate powder filled hard capsules.

Topics: Administration, Oral; Adult; Biological Availability; Cross-Over Studies; Disaccharides; Dose-Response Relationship, Drug; Female; Humans; Male; Onions; Plant Extracts; Powders; Quercetin; Single-Blind Method; Young Adult

Chronic ingestion of apple pectin has been shown to increase the absorption of quercetin in rats. The present study was designed to elucidate whether the simultaneous ingestion of quercetin with apple pectin could enhance the absorption of quercetin in humans, and the effects of dose dependency and degree of pectin methylation on quercetin absorption were also investigated. Healthy volunteers (n 19) received 200 ml of 0.5 mg/ml of quercetin drinks with or without 10 mg/ml of pectin each in a randomised cross-over design study with over 1-week intervals; urine samples from all the subjects were collected within 24 h after ingestion of the test drinks, and urinary deconjugated quercetin and its metabolites were determined using HPLC. The sum of urinary quercetin and its metabolites excreted was increased by 2.5-fold by the simultaneous ingestion of pectin. The metabolism of methylated quercetin (isorhamnetin and tamarixetin) was not affected by pectin ingestion. In six volunteers, who received quercetin drinks containing 0, 3 and 10 mg/ml of pectin, the sum of urinary quercetin and its metabolites excreted also increased in a pectin dose-dependent manner. Furthermore, the simultaneous ingestion of quercetin with low-methoxy and high-methoxy pectin, respectively, increased the sum of urinary excretion of quercetin and its metabolites by 1.69-fold and significantly by 2.13-fold compared with the ingestion of quercetin without pectin. These results elucidated that apple pectin immediately enhanced quercetin absorption in human subjects, and that its enhancing effect was dependent on the dose and degree of pectin methylation. The results also suggested that the viscosity of pectin may play a role in the enhancement of quercetin absorption.

Topics: Adult; Antioxidants; Beverages; Cross-Over Studies; Dietary Supplements; Disaccharides; Fruit; Gastrointestinal Agents; Humans; Hydrolysis; Intestinal Absorption; Male; Malus; Methylation; Pectins; Quercetin; Renal Elimination; Up-Regulation; Viscosity

Epidemiologic evidence supports that dietary quercetin reduces cardiovascular disease (CVD) risk, but its oral bioavailability is paradoxically low. The aim of this study was to determine whether dietary fat would improve quercetin bioavailability in adults at high risk for CVD and to assess lipid-mediated micellarization of quercetin in vitro.. In a randomized, cross-over study, overweight/obese men and postmenopausal women (n = 4 M/5 F; 55.9 ± 2.1 years; 30.8 ± 1.4 kg/m(2) ) ingested 1095 mg of quercetin aglycone with a standardized breakfast that was fat-free (<0.5 g), low-fat (4.0 g), or high-fat (15.4 g). Plasma was obtained at timed intervals for 24 h to measure quercetin and its methylated metabolites isorhamnetin and tamarixetin. Compared to the fat-free trial, plasma quercetin maximum concentration (Cmax ), and area under curve (AUC0-24 h ) increased (p < 0.05) by 45 and 32%, respectively, during the high-fat trial. During the high-fat trial, isorhamnetin Cmax and AUC0-24 h also increased by 40 and 19%, respectively, whereas Cmax and AUC0-24 h of tamarixetin increased by 46 and 43%, respectively. Dietary fat dose-dependently increased micellarization efficiency of quercetin aglycone in vitro.. Dietary fat improves quercetin bioavailability by increasing its absorption, likely by enhancing its micellarization at the small intestine.

Topics: Area Under Curve; Biological Availability; Biomarkers; Body Mass Index; Chromatography, High Pressure Liquid; Cross-Over Studies; Dietary Fats; Disaccharides; Female; Humans; Inflammation; Linear Models; Male; Middle Aged; Overweight; Oxidative Stress; Quercetin

The flavonol quercetin, is one of the major flavonoids found in edible plants. The bioavailability of quercetin in humans may be influenced by the food matrix in which it is consumed as well as by its chemical and physical form. The objective of the present study was to investigate the biokinetics of quercetin from quercetin-enriched cereal bars and quercetin powder-filled hard capsules. In a randomised, single-blinded, diet-controlled cross-over study, six healthy women aged 22-28 years took a single oral dose of approximately 130 mg quercetin equivalents from either quercetin-enriched cereal bars (containing 93·3 % quercetin aglycone plus 6·7 % quercetin-4'-glucoside) or quercetin powder-filled hard capsules (100 % quercetin aglycone). Blood samples were drawn before and after quercetin administration over a 24 h period. The concentrations of quercetin and its monomethylated derivatives, isorhamnetin (3'-O-methyl quercetin) and tamarixetin (4'-O-methyl quercetin), were measured by HPLC with fluorescence detection after plasma enzymatic treatment. The systemic availability as determined by comparing the plasma concentration-time curves of quercetin was found to be five times and the cmax values six times higher after ingestion of 130 mg quercetin by quercetin-enriched cereal bars than after ingestion by quercetin capsules. In contrast, tmax did not differ significantly between the two treatments. The cmax values for isorhamnetin and tamarixetin were four and nine times higher after ingestion of quercetin by quercetin-enriched cereal bars than after ingestion by quercetin capsules. In conclusion, quercetin from quercetin-enriched cereal bars is significantly more bioavailable than from quercetin powder-filled hard capsules.

Topics: Adult; Antihypertensive Agents; Antioxidants; Capsules; Cross-Over Studies; Dietary Supplements; Disaccharides; Edible Grain; Fast Foods; Female; Food, Fortified; Humans; Kinetics; Nutritive Value; Pilot Projects; Powders; Quercetin; Single-Blind Method; Young Adult

Although the flavonol quercetin is intensively investigated, our knowledge about its bioavailability and possible target organs is far from being complete. The aim of this study was to check the potential of quercetin to accumulate in various tissues after long-term dietary treatment compared with a single treatment with flavonol. Pigs ingested either a single dose of quercetin aglycone (25 mg/kg body weight; Expt. 1) or received the flavonol twice a day at the same dose mixed into their regular meals (i.e 50 mg.kg(-1).d(-1)) for 4 wk (Expt. 2). In both experiments, we took plasma and tissue samples 90 min after the final meal and analyzed them using HPLC. Additionally, the specific activity of the enzyme beta-glucuronidase was measured in selected tissues. Higher flavonol concentrations than in plasma were found in only the liver (Expt. 1) or the intestinal wall and kidneys (Expt. 2). All tissues except blood plasma contained a variable amount of deconjugated quercetin in the range of 30-100% of total flavonols. However, the specific beta-glucuronidase activity was not correlated with the proportions of deconjugated flavonols in the various tissues. Long-term dietary intake of the flavonol did not lead to a greater accumulation in any tissue compared with the single treatment. Flavonol concentrations only exceeded the plasma concentration within organs involved in its metabolism and excretion, including liver, small intestine, and kidneys.

Topics: Adipose Tissue, White; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Brain; Brain Chemistry; Diet; Dietary Supplements; Disaccharides; Drug Administration Schedule; Flavonols; Intestinal Mucosa; Intestines; Kidney; Liver; Lung; Male; Mesentery; Models, Animal; Muscle, Skeletal; Quercetin; Swine; Tissue Distribution

Our aim was to investigate the effects of an oral supplementation of quercetin at 3 different doses on plasma concentrations of quercetin, parameters of oxidant/antioxidant status, inflammation, and metabolism. To this end, 35 healthy volunteers were randomly assigned to take 50, 100, or 150 mg/d (group Q50-Q150) quercetin for 2 wk. Fasting blood samples were collected at the beginning and end of the supplementation period. Compared with baseline, quercetin supplementation significantly increased plasma concentrations of quercetin by 178% (Q50), 359% (Q100), and 570% (Q150; P < 0.01 for all). High interindividual variation was found for plasma quercetin concentrations (36-57%). Quercetin did not affect concentrations of serum uric acid or plasma alpha- and gamma-tocopherols, oxidized LDL, and tumor necrosis factor-alpha, or plasma antioxidative capacity as assessed by the ferric-reducing antioxidant potential and oxygen radical absorbance capacity assays. In addition, serum lipids and lipoproteins, body composition, and resting energy expenditure did not significantly change during quercetin supplementation. Pharmacokinetics of quercetin were investigated in a subgroup of 15 volunteers. The areas under the plasma concentration-time curves ranged from 76.1 mumol.min.L(-1) to 305.8 mumol.min.L(-1) (50- and 150-mg dosages, respectively). Median maximum plasma concentrations of quercetin (431 nmol/L) were observed 360 min after intake of 150 mg quercetin. In conclusion, daily supplementation of healthy humans with graded concentrations of quercetin for 2 wk dose-dependently increased plasma quercetin concentrations but did not affect antioxidant status, oxidized LDL, inflammation, or metabolism.

Topics: Administration, Oral; Adult; Antioxidants; Dietary Supplements; Disaccharides; Dose-Response Relationship, Drug; Double-Blind Method; Energy Metabolism; Female; Flavonols; Humans; Inflammation; Male; Nutritional Physiological Phenomena; Oxidative Stress; Quercetin

Epidemiological data suggest that those who consume a diet rich in quercetin-containing foods may have a reduced risk of CVD. Furthermore, in vitro and ex vivo studies have observed the inhibition of collagen-induced platelet activation by quercetin. The aim of the present study was to investigate the possible inhibitory effects of quercetin ingestion from a dietary source on collagen-stimulated platelet aggregation and signalling. A double-blind randomised cross-over pilot study was undertaken. Subjects ingested a soup containing either a high or a low amount of quercetin. Plasma quercetin concentrations and platelet aggregation and signalling were assessed after soup ingestion. The high-quercetin soup contained 69 mg total quercetin compared with the low-quercetin soup containing 5 mg total quercetin. Plasma quercetin concentrations were significantly higher after high-quercetin soup ingestion than after low-quercetin soup ingestion and peaked at 2.59 (sem 0.42) mumol/l. Collagen-stimulated (0.5 mug/ml) platelet aggregation was inhibited after ingestion of the high-quercetin soup in a time-dependent manner. Collagen-stimulated tyrosine phosphorylation of a key component of the collagen-signalling pathway via glycoprotein VI, Syk, was significantly inhibited by ingestion of the high-quercetin soup. The inhibition of Syk tyrosine phosphorylation was correlated with the area under the curve for the high-quercetin plasma profile. In conclusion, the ingestion of quercetin from a dietary source of onion soup could inhibit some aspects of collagen-stimulated platelet aggregation and signalling ex vivo. This further substantiates the epidemiological data suggesting that those who preferentially consume high amounts of quercetin-containing foods have a reduced risk of thrombosis and potential CVD risk.

Topics: Adult; Collagen; Cross-Over Studies; Diet; Disaccharides; Double-Blind Method; Eating; Female; Fibrinolytic Agents; Flavonoids; Flavonols; Humans; Male; Onions; Pilot Projects; Platelet Activation; Platelet Aggregation; Quercetin; Signal Transduction

Quercetin, a common flavonoid from human diet, is extensively metabolized. Its two metabolites with the preserved flavonoid core were tested in detail for their interactions with transition metals, iron and copper. Both compounds chelated both metals; however, there were some significant differences between them notwithstanding that the major chelation site (3-hydroxy-4-keto) was the same. The complex stoichiometries were also determined under different pH conditions and in both oxidation states. Mostly, complexes 2:1, flavonoid to metal, were observed. Both compounds reduced iron and copper in a bell-shaped manner with tamarixetin being less potent in general. Both metabolites potentiated the Fenton reaction triggered by iron, while they were able to decrease the copper-based Fenton reaction under acidic conditions. In cellular experiments, both metabolites attenuated the copper-triggered hemolysis with isorhamnetin being more potent. In conclusion, there are differences between methylated metabolites of quercetin in relation to their interactions with biologically relevant transition metals.

Topics: Copper; Disaccharides; Humans; Iron; Quercetin

Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Chromatography, High Pressure Liquid; Disaccharides; Lysosomal Membrane Proteins; Lysosomes; Macrophages; Mechanistic Target of Rapamycin Complex 1; Mice; Plasmids; Proteolysis; Quercetin; RAW 264.7 Cells; Signal Transduction; Tandem Mass Spectrometry; Transfection

Alzheimer's disease (AD) is marked by the presence of amyloid plaques, neurofibrillary tangles, oxidatively damaged neuronal macromolecules and redox sensitive ions. Reduction of amyloid plaques and oxidative stress emerge as a convincing treatment strategy. Plaque reduction is achieved by inhibition of BACE1, the rate limiting enzyme generating the prime constituent of plaques, Aβ, through proteolysis of the amyloid precursor protein. Here, we report a QSAR model with five descriptors, developed to screen natural compounds as potent BACE1 inhibitors. Seven compounds out of which five flavonols namely isorhamnetin, syringetin, galangin, tamarixetin, rhamnetin and two flavanonols namely dihydromyricetin, taxifolin were screened. The ability of these compounds were validated using the BACE1 activity assay. The antioxidant property were estimated by the DPPH and ABTS assay. Although inhibition assay implied syringetin to be a promising BACE1 inhibitor, its poor antioxidant activity leaves it less effective as a multitarget ligand. Exhibiting moderate dual ability, isorhamnetin and taxifolin qualified as multi-target scaffolds for AD therapeutics. Our study reveals the importance of 4'-OH in the B ring of flavonols and the lack of any effect of 5'-OH in flavanonols for BACE1 inhibition. In case of antioxidant activity favourable association of 3'-O-methylation derivatives was observed in flavonols.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Disaccharides; Flavonoids; Flavonols; Humans; Molecular Docking Simulation; Neurons; Oxidative Stress; Plaque, Amyloid; Protein Conformation; Quantitative Structure-Activity Relationship; Quercetin

Quercetin (Q) has rapid metabolism, which may make it worthwhile to focus on the potential activity of its metabolites. Our aim was to evaluate the triglyceride-lowering effects of Q metabolites in mature and pre-adipocytes, and to compare them to those induced by Q. 3T3-L1 mature and pre-adipocytes were treated with 0.1, 1 and 10 µM of Q, tamarixetin (TAM), isorhamnetin (ISO), quercetin-3-

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Differentiation; Disaccharides; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Gene Expression Profiling; Gene Expression Regulation; Glycerol; Lipid Metabolism; Mice; Quercetin; Triglycerides

Isorhamnetin (1) is a naturally occurring flavonoid having anticancer and anti-inflammatory properties. The present study demonstrated that 1 had antimycobacterial effects on Mycobacterium tuberculosis H37Rv, multi-drug- and extensively drug-resistant clinical isolates with minimum inhibitory concentrations of 158 and 316 μM, respectively. Mycobacteria mainly affect the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis. We investigated the effects of 1 on interferon (IFN)-γ-stimulated human lung fibroblast MRC-5 cells. Isorhamnetin suppressed the release of tumor necrosis factor (TNF)-α and interleukin (IL)-12. A nontoxic dose of 1 reduced mRNA expression of TNF-α, IL-1β, IL-6, IL-12, and matrix metalloproteinase-1 in IFN-γ-stimulated cells. Isorhamnetin inhibited IFN-γ-mediated stimulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase and showed high-affinity binding to these kinases (binding constants: 4.46 × 10(6) M(-1) and 7.6 × 10(6) M(-1), respectively). The 4'-hydroxy group and the 3'-methoxy group of the B-ring and the 5-hydroxy group of the A-ring of 1 play key roles in these binding interactions. A mouse in vivo study of lipopolysaccharide-induced lung inflammation revealed that a nontoxic dose of 1 reduced the levels of IL-1β, IL-6, IL-12, and INF-γ in lung tissue. These data provide the first evidence that 1 could be developed as a potent antituberculosis drug.

Topics: Animals; Anti-Inflammatory Agents; Antitubercular Agents; Female; Flavonoids; Humans; Interferon-gamma; Lipopolysaccharides; Matrix Metalloproteinase 1; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 3; Molecular Structure; Mycobacterium tuberculosis; p38 Mitogen-Activated Protein Kinases; Quercetin; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

It has been reported that quercetin is an activator of rat vitamin D receptor (rVDR). However, the conclusion was based on experiments performed without all the appropriate control groups, raising the possibility of a false-positive finding. Furthermore, distinct differences exist in the chemical structures of quercetin and 1α,25-dihydroxyvitamin D3, which is a prototypic agonist of VDR. Therefore, we investigated systematically whether quercetin and other flavonols are agonists of rVDR, mouse VDR (mVDR), or human VDR (hVDR). Quercetin, 3-hydroxyflavone, galangin, datiscetin, kaempferol, morin, isorhamnetin, tamarixetin, myricetin, and syringetin did not activate rVDR, mVDR, or hVDR in HEK-293 and HepG2 cells transfected with the corresponding receptor expression plasmid and either the secreted phosphoprotein 1 (Spp1) or cytochrome P450 24A1 (CYP24A1) reporter plasmid, when compared to the respective empty vector control group transfected with one or the other reporter plasmid and treated with one of the flavonols. Control analysis indicated that lithocholic acid and 1α,25-dihydroxyvitamin D3, but not rifampicin, activated rVDR, mVDR, and hVDR. As shown in transfected HEK293 and HepG2 cells, the flavonols did not influence hVDR ligand binding domain transactivation, steroid receptor coactivator-1 recruitment, or hVDR target gene expression (transient receptor potential cation channel 6 and CYP24A1) in hVDR-expressing Caco-2 or LS180 cells. The cumulative data from the cell-based experiments were corroborated by results obtained from molecular docking analysis. In conclusion, quercetin, 3-hydroxyflavone, galangin, datiscetin, kaempferol, morin, isorhamnetin, tamarixetin, myricetin, and syringetin are not agonists of rVDR, mVDR, or hVDR, as judged by cell-based and in silico evidence.

Topics: Animals; Caco-2 Cells; Calcitriol; Disaccharides; Flavonoids; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Humans; Kaempferols; Mice; Molecular Docking Simulation; Osteopontin; Quercetin; Receptors, Calcitriol; Structure-Activity Relationship; Transgenes; Vitamin D3 24-Hydroxylase

Polyphenols, such as flavonoids, are secondary plant metabolites with potentially health-promoting properties. In newborn calves flavonoids may improve health status, but little is known about the systemically availability of flavonoids in calves to exert biological effects. The aim of this study was to investigate the oral bioavailability of the flavonol quercetin, applied either as quercetin aglycone (QA) or as its glucorhamnoside rutin (RU), in newborn dairy calves. Twenty-one male newborn German Holstein calves were fed equal amounts of colostrum and milk replacer according to body weight. On d 2 and 29 of life, 9 mg of quercetin equivalents/kg of body weight, either fed as QA or as RU, or no quercetin (control group) were fed together with the morning meal. Blood samples were taken before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24, and 48 h after feed intake. Quercetin and quercetin metabolites with an intact flavonol structure (isorhamnetin, tamarixetin, and kaempferol) were analyzed in blood plasma after treatment with glucuronidase or sulfatase by HPLC with fluorescence detection. Maximum individual plasma concentration was depicted from the concentration-time-curve on d 2 and 29, respectively. Additional blood samples were taken to measure basal plasma concentrations of total protein, albumin, urea, and lactate as well as pre- and postprandial plasma concentrations of glucose, nonesterified fatty acids, insulin, and cortisol. Plasma concentrations of quercetin and its metabolites were significantly higher on d 2 than on d 29 of life, and administration of QA resulted in higher plasma concentrations of quercetin and its metabolites than RU. The relative bioavailability of total flavonols (sum of quercetin and its metabolites isorhamnetin, tamarixetin, and kaempferol) from RU was 72.5% on d 2 and 49.6% on d 29 when compared with QA (100%). Calves fed QA reached maximum plasma concentrations of total flavonols much earlier than did RU-fed calves. Plasma metabolites and hormones were barely affected by QA and RU feeding in this experiment. Taken together, orally administrated QA resulted in a greater bioavailability of quercetin than RU on d 2 and 29, respectively, and quercetin bioavailability of quercetin and its metabolites differed markedly between calves aged 2 and 29 d.

Topics: Administration, Oral; Animals; Animals, Newborn; Biological Availability; Blood Glucose; Body Weight; Cattle; Disaccharides; Fatty Acids, Nonesterified; Female; Flavonoids; Flavonols; Insulin; Kaempferols; Male; Pregnancy; Quercetin; Rutin

Because of their health-promoting properties, flavonoids are used in feed supplements for ruminants, although scientific evidence for their efficacy in vivo is limited. It has been shown recently that bioavailability of quercetin is low after ruminal administration in cows because of degradation by the ruminal microbiota. It is unknown whether quercetin could be absorbed from the small intestine in ruminants if degradation is prevented; therefore, we investigated the bioavailability of quercetin after duodenal administration in 6 German Holstein cows. On 88 ± 3 d in milk, each cow received equivalent doses of quercetin [9, 18, or 27 mg of quercetin equivalents (QE)/kg of body weight] either as quercetin aglycone (QA) or as its glucorhamnoside rutin (RU). In addition, 2 control studies with duodenal administration of NaCl solution (0.9%) were conducted per cow to examine concentrations of flavonoids in plasma during regular feeding. Blood samples were collected at defined time intervals over a period of 24h before and after administration of the test compounds. A washout period of 2d was applied between the runs to avoid possible carryover effects. Concentrations of plasma quercetin aglycone and its metabolites isorhamnetin, tamarixetin, and kaempferol were measured after treatment with glucuronidase/sulfatase by HPLC with fluorescence detection. After administration of RU, levels of plasma quercetin did not increase above baseline, irrespective of dose administered. After duodenal administration of QA, the plasma concentration of QA and its methylated metabolites clearly increased above baseline. The maximal plasma concentrations of total flavonols (about 2h after application) increased in a dose-dependent manner but showed high interindividual variability (range 368.8 to 983.3 nmol/L at 27 mg of QE/kg of body weight) but peak time did not differ. Preadministration baseline values of total flavonols were reached again 3 to 4h after QA administration. The bioavailability of quercetin and its metabolites, as measured by the area under the concentration-time curve, was affected by the quercetin source applied, whereby quercetin from RU was unavailable. Taken together, duodenal administration enhanced bioavailability of QA almost to values previously reported in pigs after oral administration of QA. In contrast to findings in monogastrics or after oral administration in cows, quercetin from RU seems to be unavailable when administered duodenally.

Topics: Animals; Biological Availability; Blood Glucose; Cattle; Chromatography, High Pressure Liquid; Disaccharides; Duodenum; Fatty Acids, Nonesterified; Female; Intestinal Absorption; Kaempferols; Lactation; Quercetin; Rumen; Rutin

Quercetin is a major flavonoid in the human diet and the most commonly used in studies of biological activity. Most of the knowledge about its biological effects has originated from in vitro studies while in vivo data are scarce. Quercetin mostly occurs in foodstuffs as glycosides that are deglycosylated during absorption and further submitted to different conjugation reactions. Methylation to isorhamnetin (quercetin 3'-O-methylether) or tamarixetin (quercetin 4'-O-methylether) seems to be an important conjugation process in quercetin metabolism. In this work, the effects of quercetin and its 3'- and 4'-O-methylated metabolites on the phenotypic characteristics, stress oxidative resistance, thermotolerance and lifespan of the model organism Caenorhabditis elegans have been assessed. The three assayed flavonols significantly prolonged the lifespan of this nematode with an increase from 11% to 16% in the mean lifespan with respect to controls. However, only quercetin significantly increased the reproductive capacity of the worm and enlarged the body size. Exposure to the assayed flavonols also increased significantly the resistance against thermal and juglone-induced oxidative stress, although differences were found depending on the stage of development of the worm. Thus, quercetin offered greater protection when thermal stress was applied in the 1st day of adulthood, whereas tamarixetin was more efficient in worms submitted to stress in the 6th day of adulthood. Similarly, significantly greater protection was provided by quercetin than by its methylated derivatives at the 1st day of adulthood, whilst quercetin and isorhamnetin were equally efficient when the oxidative stress was induced in the 6th of day of adulthood. Further evidence of antioxidant protection was obtained checking the oxidation status of proteins by the OxyBlot™ detection kit. Analyses by HPLC-DAD-ESI/MS confirmed that the three flavonols were taken up by C. elegans leading to the formation of some glycosylated, sulfated and methylated metabolites, and that demethylation of these latter to quercetin was also produced. Quantification of the levels of quercetin, isorhamnetin and tamarixetin, as well as their detected metabolites indicated a greater uptake of quercetin than its methylated derivatives by the nematode.

Topics: Animals; Body Temperature Regulation; Caenorhabditis elegans; Disaccharides; Flavonols; Longevity; Methylation; Oxidative Stress; Quercetin

Over the last few years many data have been published suggesting a participation of quercetin flavonoids in the antidepressive effect of St. John's wort (SJW) extract. To elucidate these data more deeply we performed two animal behavioural studies examining the antidepressant effects of SJW extract, rutin and, in addition, the quercetin metabolite isorhamnetin. The substances were in all cases compared to imipramine using Porsolt's forced swimming test (FST) after oral gavage of the substances over a 9 day period. All three compounds were found to be effective, with isorhamnetin exhibiting the strongest effect. In addition to this pharmacological study, we carried out two pharmacokinetic studies to examine the CNS level time-curve of the quercetin flavonoids after a single oral dose of SJW extract (1600 mg/kg) and isoquercitrin (100 mg/kg), respectively, and to observe the cumulative effects after daily repeated oral doses of SJW extract over 8 days. After a single dose the maximal CNS levels for quercetin (340 ng/g) and isorhamnetin/tamarixetin (50 ng/g) were found at 4 h. With repeated doses the maximal cumulation for quercetin (367 ng/g) occurred after 5 days whilst isorhamnetin/tamarixetin (640 ng/g) did not reach its maximal cumulation level within the 8 day test period.

Topics: Administration, Oral; Animals; Antidepressive Agents; Biological Availability; Brain; Disaccharides; Flavonoids; Flavonols; Hypericum; Male; Plant Extracts; Quercetin; Rats; Rats, Sprague-Dawley

Moderate consumption of red wine has been associated with beneficial effects on human health, and this has been attributed to the flavonoid content. Factors that influence the bioavailability of this group of polyphenolic compounds are therefore important. Using the rat cannulated everted jejunal sac technique, we have investigated the effect of alcohol on the intestinal absorption of quercetin and its 3-O-glucoside from red wine. Tissue preparations were incubated in whole or dealcoholised red wine, diluted 1 : 1 with Krebs buffer for 20 min at 37 degrees C, after which the mucosa was removed and processed for HPLC analysis. Tissues exposed to red wine had significantly higher amounts of both quercetin (x 3; P < 0.001) and quercetin-3-O-glucoside (x 1.5; P < 0.01) associated with them, compared with sacs incubated in the dealcoholised equivalent. In addition, both tamarixetin (T) and isorhamnetin (I), in the mucosal tissue from sacs exposed to the whole wine, were significantly elevated approximately two fold (P < 0.05; P < 0.01, respectively). Similar results were obtained when sacs were incubated in Krebs buffer containing a mixture of pure quercetin and quercetin-3-O-glucoside with or without alcohol, and, although effects on the apparent absorption of Q and Q-3-G were not so marked, concentrations of the metabolites quercetin-3-O-glucuronide and I were significantly increased by the presence of alcohol (P < 0.01 and P < 0.001, respectively). It is therefore plausible that the moderate alcohol content of red wine contributes to its beneficial health effects in humans by both increasing the absorption of quercetin and quercetin-3-O-glucoside and by channelling their metabolism towards O-methylation to yield compounds (T and I), which have potential protective effects against cancer and cardiovascular diseases.

Topics: Animals; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Disaccharides; Ethanol; Flavonols; Hydrogen-Ion Concentration; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Intestines; Jejunum; Male; Phenols; Quercetin; Rats; Rats, Wistar; Sulfur Dioxide; Wine