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PubMed2006

Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death.

PURPOSE: To determine whether specific dietary and synthetic flavonoids can protect human retinal pigment epithelial (RPE) cells from oxidative-stress-induced death. METHODS: The efficacy and potency were determined of a variety of dietary and synthetic flavonoids on the survival of human ARPE-19 cells and primary human RPE cells treated with either hydrogen peroxide (H2O2) or t-butyl hydroperoxide (t-BOOH). We determined the effective concentrations (EC50s) and the toxicities (LD50s) of the flavonoids after 24 hours, by using the MTT assay. The efficacy of vitamins E and C on RPE cell survival were compared under identical conditions. The ability of specific flavonoids to protect RPE cells from cell death was determined at various time intervals after the cells were exposed to oxidative stress. The ability of flavonoids to block the accumulation of intracellular reactive oxygen species was examined with dichlorofluorescein (DCF) fluorescence. Finally, the ability of flavonoids to induce phase-2 detoxifying enzymes was tested by immunoblot analysis for the transcription factor Nrf2 and the phase-2 gene product heme-oxygenase 1. RESULTS: Specific flavonoids protected human RPE cells from oxidative-stress-induced death with efficacies between 80% and 100% and potencies in the high-nanomolar and low-micromolar range. The toxicities of most of the effective flavonoids were low. The effective flavonoids included the dietary flavonoids fisetin, luteolin, quercetin, eriodictyol, baicalein, galangin and EGCG, and the synthetic flavonoids, 3,6-dihydroxy flavonol and 3,7 dihydroxy flavonol. Several flavonoids can protect RPE cells even when they are added after the cells have been exposed to oxidative stress. The flavonoids acted through an intracellular route to block the accumulation of reactive oxygen species. Many of these flavonoids induced the expression of Nrf2 and the phase-2 gene product heme-oxygenase 1 in human RPE cells. CONCLUSIONS: The results identify a select group of flavonoids that protect RPE cells from oxidative-stress-induced death with a high degree of potency and low toxicity. Many of these flavonoids also induce the expression of phase-2 detoxification proteins which could function to provide additional protection against oxidative stress. This select group of flavonoids and the foods that contain high levels of these compounds may have some clinical benefit for patients with retinal diseases associated with oxidative stress.

Blotting, Western↗
PubMed2004

Flavonoids in food and their health benefits.

There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids through epidemiological studies. As occurrence of flavonoids is directly associated with human daily dietary intake of antioxidants, it is important to evaluate flavonoid sources in food. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. However, there is still difficulty in accurately measuring the daily intake of flavonoids because of the complexity of existence of flavonoids from various food sources, the diversity of dietary culture, and the occurrence of a large amount of flavonoids itself in nature. Nevertheless, research on the health aspects of flavonoids for humans is expanding rapidly. Many flavonoids are shown to have antioxidative activity, free-radical scavenging capacity, coronary heart disease prevention, and anticancer activity, while some flavonoids exhibit potential for anti-human immunodeficiency virus functions. As such research progresses. further achievements will undoubtedly lead to a new era of flavonoids in either foods or pharmaceutical supplements. Accordingly, an appropriate model for a precise assessment of intake of flavonoids needs to be developed. Most recent research has focused on the health aspects of flavonoids from food sources for humans. This paper reviews the current advances in flavonoids in food, with emphasis on health aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.

Antioxidants↗
PubMed1999

Flavonoid transport by mammalian endothelial cells.

Despite the ever-growing body of literature reporting the effects of flavonoids on animals at both the cellular and systemic levels, one of the most basic questions-"Are the effects of flavonoids on animal cells initiated through their interaction with extracellular targets or intracellular targets?"-has yet to be addressed. Because many effects of flavonoids on cells can be detected within minutes of flavonoid application and because flavonoids diffuse across lipid membranes slowly or not at all, intracellular mechanisms would necessitate a flavonoid transport system for rapid flavonoid uptake. The specific aims of this investigation were (1) to determine if endothelial cells contain a mechanism that mediates rapid flavonoid uptake and (2) to provide evidence for or against the hypothesis that rapid flavonoid effects on endothelial cell synthesis of prostacyclin and endothelin are initiated through the interaction of flavonoids with intracellular targets. Data show that bovine and human aortic endothelial cells possess a transport system that mediates rapid uptake of the flavonoid morin and suggest that the flavonoid uptake system utilizes a variety of oxygenated phenolic compounds as substrates. Further investigation into flavonoid transport should expedite future investigation into the mechanisms of flavonoid actions, because it may allow research to focus on the cellular locations where flavonoids are concentrated. Although endothelial cells contain a mechanism for the rapid uptake of morin, data reported herein suggest that morin initiates its rapid effects on endothelial cell synthesis of prostacyclin and endothelin through an interaction with extracellular targets.

Journal Article↗
PubMed2004

Structural requirements for the flavonoid-mediated modulation of glutathione S-transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells.

The objective of this study was to investigate the structural requirements necessary for inhibition of glutathione S-transferase P1-1 (GSTP1-1) and GS-X pump (MRP1 and MRP2) activity by structurally related flavonoids, in GSTP1-1 transfected MCF7 cells (pMTG5). The results reveal that GSTP1-1 activity in MCF7 pMTG5 cells can be inhibited by some flavonoids. Especially galangin was able to inhibit almost all cellular GSTP1-1 activity upon exposure of the cells to a concentration of 25microM. Other flavonoids like kaempferol, eriodictyol and quercetin showed a moderate GSTP1-1 inhibitory potential. For GSTP1-1 inhibition, no specific structural requirements necessary for potent inhibition could be defined. Most flavonoids appeared to be potent GS-X transport inhibitors with IC(50) values ranging between 0.8 and 8microM. Luteolin and quercetin were the strongest inhibitors with IC(50) values of 0.8 and 1.3microM, respectively. Flavonoids without a C2-C3 double bond like eriodictyol, taxifolin and catechin did not inhibit GS-X pump activity. The results of this study demonstrate that the structural features necessary for high potency GS-X pump inhibition by flavonoids are (1) the presence of hydroxyl groups, especially two of them generating the 3',4'-catechol moiety; and (2) a planar molecule due to the presence of a C2-C3 double bond. Other factors, like lipophilicity and the total number of hydroxyl groups do not seem to be dominating the flavonoid-mediated GS-X pump inhibition. To identify the GS-X pump responsible for the DNP-SG efflux in MCF7 cells, the effects of three characteristic flavonoids quercetin, flavone and taxifolin on MRP1 and MRP2 activity were studied using transfected MDCKII cells. All three flavonoids as well as the typical MRP inhibitor (MK571) affected MRP1-mediated transport activity in a similar way as observed in the MCF7 cells. In addition, the most potent GS-X pump inhibitor in the MCF7 cells, quercetin, did not affect MRP2-mediated transport activity. These observations clearly indicate that the GS-X pump activity in the MCF7 cells is likely to be the result of flavonoid-mediated inhibition of MRP1 and not MRP2. Altogether, the present study reveals that a major site for flavonoid interaction with GSH-dependent toxicokinetics is the GS-X pump MRP1 rather than the conjugating GSTP1-1 activity itself. Of the flavonoids shown to be most active especially quercetin is frequently marketed in functional food supplements. Given the physiological levels expected to be reached upon supplement intake, the IC(50) values of the present study point at possible flavonoid-drug and/or flavonoid-xenobiotic interactions especially regarding transport processes involved in toxicokinetics.

Biological Transport↗
PubMed2005

Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.

Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo Biloba, Soy Isoflavones, and Milk Thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. Additionally, they are extremely safe and associated with low toxicity, making them excellent candidates for chemopreventive agents. The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. Importantly, the effects of flavonoids on enzymes are generally dependent on the concentrations of flavonoids present, and the different flavonoids ingested. Due to the low oral bioavailability of many flavonoids, the concentrations achieved in vivo following dietary administration tend to be low, and may not reflect the concentrations tested under in vitro conditions; however, this may not be true following the ingestion of herbal preparations when much higher plasma concentrations may be obtained. Effects will also vary with the tissue distribution of enzymes, and with the species used in testing since differences between species in enzyme activities also can be substantial. Additionally, in humans, marked interindividual variability in drug-metabolizing enzymes occurs as a result of genetic and environmental factors. This variability in xenobiotic metabolizing enzymes and the effect of flavonoid ingestion on enzyme expression and activity can contribute to the varying susceptibility different individuals have to diseases such as cancer. As well, flavonoids may also interact with chemotherapeutic drugs used in cancer treatment through the induction or inhibition of their metabolism.

Animals↗
PubMed2002

Flavonoids and gene expression in mammalian cells.

Flavonoids appear to regulate the expression of many genes. As expected, when multiple flavonoids were compared in one study, structure-specificity was always observed. Unfortunately, little information is available regarding the proportion of contribution of various structural elements. Also, we have very limited information on their molecular mechanisms of action. The affinity of flavonoids for ER could explain the stimulatory effect on genes with ERE but other modes of action apparently also exist and need to be further explored. Physiological relevance is always a concern when investigating the regulation of gene expression by environmental chemicals such as flavonoids. One factor of concern is the in vivo concentration of flavonoids. Besides intestinal cells, liver cells and skin cells, other tissues obtain flavonoids through blood circulation. Thus, plasma concentrations of flavonoids are normally discussed. Steady state plasma concentrations of flavonoids are usually not much higher than 1 microM even in populations that consume large amounts of plant material. This concentration is relatively low compared to the concentrations of flavonoids that were commonly used in cell culture systems to demonstrate their effectiveness. Nevertheless, we have evidence that some flavonoids may accumulate in the cell. The effect of quercetin on metallothionein expression in Caco-2 cells persisted for at least 24 hours after its removal from the culture medium (Kuo et al., 1998). Also, long-term treatment of cultured cells with quercetin at low concentrations led to a similar effect on metallothionein expression as one high concentration treatment (Kuo et al., 2001). If intracellular accumulation of certain flavonoids is a shared characteristic for various cell types, it implies that routine ingestion of flavonoids could lead to biological effects at the concentration lower than predicted from a single treatment. Experiments to address possible cell/tissue accumulation of flavonoids are greatly needed.

Animals↗
PubMed2002

Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450.

Flavonoids represent a group of phytochemicals exhibiting a wide range of biological activities arising mainly from their antioxidant properties and ability to modulate several enzymes or cell receptors. Flavonoids have been recognized to exert anti-bacterial and anti-viral activity, anti-inflammatory, anti-angionic, analgesic, anti-allergic effects, hepatoprotective, cytostatic, apoptotic, estrogenic and anti-estrogenic properties. However, not all flavonoids and their actions are necessarily beneficial. Some flavonoids have mutagenic and/or prooxidant effects and can also interfere with essential biochemical pathways. Among the proteins that interact with flavonoids, cytochromes P450 (CYPs), monooxygenases metabolizing xenobiotics (e.g. drugs, carcinogens) and endogenous substrates (e.g. steroids), play a prominent role. Flavonoid compounds influence these enzymes in several ways: flavonoids induce the expression of several CYPs and modulate (inhibit or stimulate) their metabolic activity. In addition, some CYPs participate in metabolism of flavonoids. Flavonoids enhance activation of carcinogens and/or influence the metabolism of drugs via induction of specific CYPs. On the other hand, inhibition of CYPs involved in carcinogen activation and scavenging reactive species formed from carcinogens by CYP-mediated reactions can be beneficial properties of various flavonoids. Flavonoids show an estrogenic or anti-estrogenic activity owing to the structural similarity with the estrogen skeleton. Mimicking natural estrogens, they bind to estrogen receptor and modulate its activity. They also block CYP19, a crucial enzyme involved in estrogen biosynthesis. Flavonoids in human diet may reduce the risk of various cancers, especially hormone-dependent breast and prostate cancers, as well preventing menopausal symptoms. For these reasons the structure-function relationship of flavonoids is extensively studied to provide an inspiration for a rational drug and/or chemopreventive agent design of future pharmaceuticals.

Animals↗
PubMed2001

Cytoplasmic accumulation of flavonoids in flower petals and its relevance to yellow flower colouration.

It is widely accepted that the mix of flavonoids in the cell vacuole is the source of flavonoid based petal colour, and that analysis of the petal extract reveals the nature and relative levels of vacuolar flavonoid pigments. However, it has recently been established with lisianthus flowers that some petal flavonoids can be excluded from the vacuolar mix through deposition in the cell wall or through complexation with proteins inside the vacuole, and that these flavonoids are not readily extractable. The present work demonstrates that flavonoids can also be compartmented within the cell cytoplasm. Using adaxial epidermal peels from the petals of lisianthus (Eustoma grandiflorum), Lathyrus chrysanthus and Dianthus caryophyllus, light and laser scanning confocal microscopy studies revealed a significant concentration of petal flavonoids in the cell cytoplasm of some tissues. With lisianthus, flavonoid analyses of isolated protoplasts and vacuoles were used to establish that ca 14% of petal flavonoids are located in the cytoplasm (cf. 30% in the cell wall and 56% in the vacuole). The cytoplasmic flavonoids are predominantly acylated glycosides (cf. non-acylated in the cell wall). Flavonoid aggregation on a cytoplasmic protein substrate provides a rational mechanism to account for how colourless flavonoid glycosides can produce yellow colouration in petals, and perhaps also in other plant parts. High vacuolar concentrations of such flavonoids are shown to be insufficient.

Chromatography, High Pressure Liquid↗
PubMed2002

Flavonoid concentrations in three grass species and a sedge grown in the field and under controlled environment conditions in response to enhanced UV-B radiation.

An investigation was carried out to find whether enhanced levels of UV-B radiation induce increased concentrations of flavonoids in the leaves of the grass species Deschampsia antarctica, Deschampsia borealis and Calamagrostis epigeios and the sedge Carex arenaria. Whether the enhanced levels of UV-B influenced the proportions of the various flavonoids in the leaves was also studied. Increased flavonoid concentrations would improve the UV-B shielding of UV-B susceptible tissues. Using HPLC analysis the flavonoids orientin and luteolin were identified in D. antarctica, orientin in D. borealis and tricin in C. arenaria. Neither flavonoid concentrations nor the proportion of the various flavonoids in climate room grown D. antarctica and D. borealis plants differed between individuals grown under 0, ambient or elevated UV-B levels. After 12 weeks of growth biomass production and shoot-to-root ratios of D. antarctica were not affected by elevated UV-B radiation. Greenhouse grown C. epigeios plants contained higher concentrations and different proportions of flavonoids grown under elevated levels of UV-B than when grown under ambient or 0 UV-B. In C. epigeios plants grown in their natural habitat in the field under ambient or elevated levels of UV-B, flavonoid concentrations and proportions were the same in plants from both treatments. In the leaves of the sedge C. arenaria grown in a greenhouse flavonoid concentrations and proportions were not affected by UV-B radiation. Leaves were harvested four times during the growing season from C. arenaria plants grown in their natural habitat in the field under ambient or elevated levels of UV-B. Leaves harvested in January contained higher concentrations of flavonoids when grown under elevated UV-B than when grown under ambient UV-B radiation. In leaves harvested in May, September and December flavonoid concentrations were the same in plants grown under ambient or elevated UV-B. The proportion of the different flavonoids was the same for both treatments in all months. These results indicate that constitutive levels of flavonoids in these grass and sedge species are adequately high to protect them against ambient and elevated levels of solar UV-B radiation.

Environment, Controlled↗
PubMed2006

Age-related variations in flavonoid intake and sources in the Australian population.

OBJECTIVE: To estimate flavonoid intake in the Australian population. DESIGN: Flavonoid consumption was estimated from 24-hour recall data and apparent consumption data using US Department of Agriculture flavonoid composition data. SUBJECTS: The National Nutrition Survey 1995 assessed dietary intake (24-hour recall) in a representative sample (n=13,858) of the Australian population aged 2 years and over. RESULTS: Analysis of the 24-hour recall data indicated an average adult intake (>18 years) of 454 mg day(-1) (92% being flavan-3-ols). Apple was the highest quercetin source until age 16-18 years, after which onion became an increasingly important prominent source. Variations in hesperetin consumption reflected orange intake. Apple, apricot and grapes were the major sources of epicatechin and catechin for children, but subsided as wine consumption increased in adulthood. Wine was the main source of malvidin. Naringenin intake remained static as a percentage of total flavonoid intake until age 19-24 years, corresponding to orange intake, and then increased with age from 19-24 years, corresponding to grapefruit intake. Apparent dietary flavonoid consumption was 351 mg person(-1) day(-1), of which 75% were flavan-3-ols. Black tea was the major flavonoid source (predominantly flavan-3-ols) representing 70% of total intake. Hesperetin and naringenin were the next most highly consumed flavonoids, reflecting orange intake. Both 24-hour recall and apparent consumption data indicated that apigenin intake was markedly higher in Australia than reported in either the USA or Denmark, presumably due to differences in consumption data for leaf and stalk vegetables and parsley. CONCLUSIONS: Tea was the major dietary flavonoid source in Australia. Flavonoid consumption profiles and flavonoid sources varied according to age. More consistent methodologies, survey tools validated for specific flavonoid intakes and enhanced local flavonoid content data for foods would facilitate better international comparisons of flavonoid intake.

Adolescent↗
PubMed2002

Measuring flavonoid intake: need for advanced tools.

OBJECTIVE: Flavonoids are phytochemicals with potentially beneficial biological effects that are poorly characterised in existing tables of food composition. DESIGN: To describe new techniques for analysis, absorption, informatics and dietary assessment that are important in measuring the flavonoid content in foods and in developing a flavonoid food composition database. SETTING: Data on chemical analyses of the major flavonoid compounds that exist in the food science literature are being located, collated and compiled into a preliminary flavonoid food composition database. RESULTS: The analytical process begins with preparation of the food for flavonoid analysis using techniques to disrupt the food matrix, alcoholic extraction, and enzymatic or acidic hydrolysis to remove sugars. Separation is usually accomplished using high-performance liquid chromatography. Flavonoids are identified by diode array spectrometry, mass spectrometry or nuclear magnetic resonance spectroscopy. Quantification usually employs comparison of the sample with standards, if available, using the area under the curve of the chromatogram to estimate quantity. Absorption studies are useful since flavonoids vary in their absorption. Finally, information management technologies (informatics) are used to translate flavonoid data information into food composition databases. This process involves identification of foods containing the compounds of interest, collection and organisation of sources of existing analytical data, assignment of quality scores or aggregation of acceptable data for each component and food, calculation of appropriate statistics, assignment of food codes and verification, and finalization. The resulting food flavonoid database can be used with state-of-the-art dietary assessment methods to develop estimates of flavonoid intakes in foods and to correlate these with estimates of disease risk. CONCLUSIONS: A provisional flavonoid database, including at least two components from each of six classes of flavonoids, should be completed in 2002.

Databases, Factual↗
PubMed2005

Synergistic effects of flavonoids and ascorbate on enhancement in DNA degradation induced by a bleomycin-Fe complex.

Flavonoids were examined for synergistic effects with ascorbate on enhancement of DNA degradation induced by a bleomycin(BLM)-Fe complex. The synergistic effects of flavonoids and ascorbate on DNA degradation induced by the BLM-Fe complex were observed to be greater with flavonoids such as isorhamnetin, kaempferol and morin, which accelerated oxidation more markedly in the presence, than in the absence of BLM. Conversely, myricetin and fisetin, which showed oxidation barely accelerated by the addition of BLM, inhibited DNA degradation promoted by ascorbate. Consequently, there was a good correlation between oxidation of flavonoids accelerated by BLM and the extent of DNA degradation promoted synergistically with ascorbate. Our previous studies indicated that oxidation of flavonoids accelerated by BLM and DNA degradation promoted by flavonoids were not correlated with Fe(III)-reducing activity of flavonoids. Those results suggest that Fe(III)-reducing activity of flavonoids is not the only factor determining DNA degradation-promoting activity induced by the BLM-Fe complex. On the other hand, in a Fenton reaction, degradation of 2-deoxy-d-ribose promoted by flavonoids was correlated to the Fe(III)-reducing activity of flavonoids. However, there was not a synergistic interaction between flavonoids and ascorbate in the degradation of 2-deoxy-d-ribose. Therefore, it is suggested that the synergistic DNA degradation caused by flavonoids and ascorbate in the BLM-Fe redox cycle arose from the difference in the reductive processes in which flavonoids and ascorbate mainly act.

Animals↗
PubMedDate not supplied

Modulation by plant flavonoids and related phenolics of microsome catalyzed adduct formation between benzo[a]pyrene and DNA.

Twenty-six flavonoids and related compounds were screened for their ability to modulate microsome mediated covalent adduct formation between [3H]benzo[a]pyrene ([3H]BP) and DNA in vitro. Some of these flavonoids, notably robinetin, quercetin, isorhamnetin and kaempferol were observed to inhibit the adduct formation significantly at very low levels. The unsubstituted flavone and some of the other flavonoids moderately inhibited this adduct formation, while some flavonoids were inactive, viz., most of the isoflavonoids and methylether derivatives of polyhydroxylated flavonoids. Structural features contributory towards the inhibitory activity of flavonoids appeared to be hydroxyl groups in 3 position of C ring, 5,7-positions of A ring and 3',4'- and 5'-positions of B ring. Methylation or glycosylation of hydroxyl group rendered the flavonoid less active or inactive. Flavanones, with saturated 2,3 double bond, were also inactive. Metabolic activation of BP to proximate carcinogen (+/-)-trans-7,8-dihydroxy-7,8-dihydro-BP (BP-7,8-dihydrodiol) was also measured in presence of some of these flavonoids. The extent of inhibition of metabolism by these flavonoids did not correlate with their ability to inhibit the adduct formation. Thus, suppression of metabolism did not appear to be a major contributory factor towards inhibition of adduct formation. The solvolysis in aqueous dioxane of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydro-BP (BPDE I), the ultimate carcinogen of BP, was accelerated in presence of selected flavonoids. Inactivation of BPDE I, therefore, appeared to be the major mechanism by which some of these flavonoids inhibited the adduct formation between BP and DNA, and this could be the basis for the anti-carcinogenic nature of these flavonoids.

Benzo(a)pyrene↗
PubMed2004

Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport.

PURPOSE: The purpose of this study was to determine the dynamic parameter (EC50) of flavonoids apigenin, biochanin A, chrysin, genistein, kaempferol, hesperetin, naringenin, and silymarin for breast cancer resistance protein (BCRP) inhibition when used alone, and to evaluate their potential interactions (additive, synergistic, or antagonistic) with regards to BCRP inhibition when used in multiple-flavonoid combinations. METHODS: The effects of flavonoids on BCRP-mediated transport were examined by evaluating their effects on mitoxantrone accumulation and cytotoxicity in MCF-7 MX100 cells overexpressing BCRP. The EC50 values of these flavonoids for increasing mitoxantrone accumulation were estimated using a Hill equation. The potential interactions among multiple flavonoids with regard to BCRP inhibition were assessed by isobologram and Berenbaum's interaction index methods. RESULTS: The EC50 values of these flavonoids for increasing mitoxantrone accumulation ranged from 0.39+/-0.13 microM to 33.7+/-2.78 microM. Quantitative analysis of the combined effects of multiple flavonoids on mitoxantrone accumulation indicated that these flavonoids act additively in inhibiting BCRP when given as 2-, 3-, 5-, or 8-flavonoid combinations with equimolar concentrations of all constituents. The results of the mitoxantrone cytotoxicity studies were consistent with these findings. CONCLUSIONS: The additive effects of multiple flavonoids for BCRP inhibition suggests that prediction of BCRP-mediated food (herbal product)-drug interactions should also take into consideration the presence of multiple flavonoids and provides a rationale for using "flavonoid cocktails" as a potential approach for multidrug resistance reversal in cancer treatment.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Clinical use of micronized purified flavonoid fraction for treatment of symptoms after hemorrhoidectomy: results of a randomized, controlled, clinical trial.

PURPOSE: The aim of this study was to evaluate if the combination of micronized purified flavonoid fraction with short-term routine antibiotic and anti-inflammatory therapy was better at reducing the intensity of postoperative symptoms and wound bleeding after a Milligan-Morgan's open hemorrhoidectomy than antibiotic and anti-inflammatory treatment alone. METHODS: Fifty patients were randomly assigned to receive routine antibiotic and anti-inflammatory treatment alone (control patients) or a combination of micronized purified flavonoid fraction with identical antibiotic and anti-inflammatory treatment (micronized purified flavonoid fraction patients). The evolution of symptoms (pain, tenesmus, pruritus, and bleeding) during the postoperative period was assessed by means of patients' self-questionnaires. Each symptom was scored on a graded severity scale from 0 to 3, daily during the first three days of the immediate postoperative period, then at regular intervals (about every 14 days) until postoperative day 60. A global score for evaluation of each postoperative symptom and bleeding was used. The global score for each symptom was the sum of scores for each patient over the study period. The global score for each symptom was compared between the two groups with the Mann-Whitney U test. RESULTS: No significant differences in age, gender distribution, and stage of disease between the two groups were noticed at baseline. Posthemorrhoidectomy symptoms were relieved more rapidly in the micronized purified flavonoid fraction group; during the first three postoperative days, the global score for each symptom was significantly more reduced in the micronized purified flavonoid fraction group. The global scores for each symptom are as follows: pain after 3 days, 6.16 (SD = 1.9) in the control group vs. 3.48 (SD = 1.8) in the micronized purified flavonoid fraction group (P < 0.0001); tenesmus, 5.36 (SD = 1.8) in the control group vs. 1.48 (SD = 1.5) in the micronized purified flavonoid fraction group (P < 0.0001); pruritus, 4.04 (SD = 1.9) in the control group vs. 1.84 (SD = 1.4) in the micronized purified flavonoid fraction group (P < 0.0001); bleeding, 4.4 (SD = 2.1) in the control group vs. 2.0 (SD = 1.3) in the micronized purified flavonoid fraction group (P < 0.0001). A significant difference (P < 0.0001) between groups was also shown in favor of micronized purified flavonoid fraction patients when global scores were calculated over the entire study period (60 days). CONCLUSION: Micronized purified flavonoid fraction used in combination with short-term antibiotic and anti-inflammatory treatment can reduce both the duration and extent of postoperative symptoms and wound bleeding following hemorrhoidectomy.

Adult↗
PubMed1992

Effects of flavonoids on immune and inflammatory cell functions.

No doubt can remain that the flavonoids have profound effects on the function of immune and inflammatory cells as determined by a large number and variety of in vitro and some in vivo observations. That these ubiquitous dietary chemicals may have significant in vivo effects on homeostasis within the immune system and on the behavior of secondary cell systems comprising the inflammatory response seems highly likely but more work is required to strengthen this hypothesis. Ample evidence indicates that selected flavonoids, depending on structure, can affect (usually inhibit) secretory processes, mitogenesis, and cell-cell interactions including possible effects on adhesion molecule expression and function. The possible action of flavonoids on the function of cytoskeletal elements is suggested by their effects on secretory processes. Moreover, evidence indicates that certain flavonoids may affect gene expression and the elaboration and effects of cytokines and cytokine receptors. How all of these effects are mediated is not yet clear but one important mechanism may be the capacity of flavonoids to stimulate or inhibit protein phosphorylation and thereby regulate cell function. Perhaps the counterbalancing effect of cellular protein tyrosine phosphatases will also be found to be affected by flavonoids. Some flavonoid effects can certainly be attributed to their recognized antioxidant and radical scavenging properties. A potential mechanism of action that requires scrutiny, particularly in relation to enzyme inhibition, is the redox activity of appropriately configured flavonoids. Finally, in a number of cell systems it seems that resting cells are not affected significantly by flavonoids but once a cell becomes activated by a physiological stimulus a flavonoid-sensitive substance is generated and interaction of flavonoids with that substance dramatically alters the outcome of the activation process.

Animals↗
PubMed2005

Structure activity relationships and quantitative structure activity relationships for the flavonoid-mediated inhibition of breast cancer resistance protein.

Breast cancer resistance protein (BCRP) is a newly identified ABC transporter, which plays an important role in drug disposition and represents an additional mechanism for the development of MDR. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be BCRP inhibitors. The objective of the present study was to elucidate the SAR and derive a QSAR model for flavonoid-BCRP interaction. The EC(50) values for increasing mitoxantrone accumulation in MCF-7 MX100 cells for 25 flavonoids, from five flavonoid subclasses, were determined in this study or obtained from our previous publication [Zhang S, Yang X, Morris ME. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res 2004;21(7):1263-73], and ranged from 0.07+/-0.02 microM to 183+/-21.7 microM. We found that the presence of a 2,3-double bond in ring C, ring B attached at position 2, hydroxylation at position 5, lack of hydroxylation at position 3 and hydrophobic substitution at positions 6, 7, 8 or 4', are important structural properties important for potent flavonoid-BCRP interaction. These structural requirements are similar but not identical to those for potent flavonoid-NBD2 (P-glycoprotein) interaction, indicating that inhibition of BCRP by flavonoids may involve, in part, the binding of flavonoids with the NBD of BCRP. In addition, a QSAR model consisting three structural descriptors was constructed, and both internally and externally validated, suggesting the model could be used to quantitatively predict BCRP inhibition activity of flavonoids. These findings should be useful for predicting BCRP inhibition activity of other untested flavonoids and for guiding the synthesis of potent BCRP inhibitors for potential clinical application.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1998

Taxonomic classification helps identify flavonoid-containing foods on a semiquantitative food frequency questionnaire.

We describe foods on the National Cancer Institute (NCI) semiquantitative food frequency questionnaire with respect to their botanical taxonomic classification and the likely presence of flavonoids. Foods listed in the NCI questionnaire were classified for potential flavonoid content using information from Linnaean taxonomic classification and processing techniques known to modify flavonoid content. The outcome measure was flavonoid presence in foods as evidenced in the food composition analytical literature. We then verified the presence of 6 classes of flavonoids in these foods by searching the chemical analytical literature (represented by Food Science and Technology Abstracts Service from January 1969 to June 1996). One hundred ninety foods were mentioned on the NCI questionnaire; after duplications were removed, 153 foods remained. Data obtained from literature searches indicated that 54 foods (35%) contained flavonoids. An additional 19 recipe foods (12%) had flavonoid-containing components or ingredients. Thirty-nine foods (25%) had flavonoids that had been reduced or removed during milling and other processing. Seven foods (5%) were stripped and judged to have no flavonoids. Thirty-four foods (22%), for example, dairy, meat, and sugar, were completely devoid of flavonoids. When food composition data are unavailable, botanical taxonomic classifications may be helpful in ascertaining the likely presence of flavonoids in foods. However, quantitative estimates are likely to be imprecise.

Databases, Factual↗