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At least 109 records · Page 6Linked to original sources
PubMed2005

Induction of phase-1 metabolizing enzymes by oltipraz, flavone and indole-3-carbinol enhance the formation and transport of benzo[a]pyrene sulfate conjugates in intestinal Caco-2 cells.

The small intestine is well equipped with various phase-1 and phase-2 xenobiotic metabolizing enzymes (XME), which contribute to the detoxification process of the body. Many XME are regulated via aryl hydrocarbon receptor (AhR)-dependent pathways, and numerous naturally occurring AhR agonists (e.g. flavonoids, dietary indoles) have been identified to date. In the present study we show that pretreatment of Caco-2 cells with food-associated compounds (flavone and indole-3-carbinol) and with the anticancer chemopreventive agent oltipraz enhances the formation of the major metabolites of the procarcinogen benzo[a]pyrene (BP) formed by intestinal Caco-2 cells, namely BP-1-sulfate and BP-3-sulfate, and their transport to the apical compartment of a Transwell chamber. Oltipraz treatment was most effective in this regard followed by flavone and indole-3-carbinol. The effect observed here after pretreatment with oltipraz, flavone and I3C was the result of the induction of both CYP1A1 and CYP1B1, as was confirmed by analysis of CYP1A1 (protein and mRNA) and CYP1B1 (mRNA) expression. In summary, our study shows that the induction of both CYP1A1 and CYP1B1 resulted in an accelerated metabolism and an enhanced clearance of the potent procarcinogen BP, indicating that flavone, indole-3-carbinol and oltipraz have an impact on the biochemical barrier against BP in intestinal cells.

Anticarcinogenic Agents↗
PubMed2005

Effects of natural prenylated flavones in the phenotypical ER (+) MCF-7 and ER (-) MDA-MB-231 human breast cancer cells.

The effect of seven natural prenylated flavones in DNA synthesis of two human breast cancer cell lines, the estrogen-dependent ER (+) MCF-7 and the estrogen-independent ER (-) MDA-MB-231 cells, was evaluated. Flavones with an isopentenyl group at C-8 and a ring linking C-3 and C-2' presented a biphasic effect in DNA synthesis of ER (+) MCF-7 and displayed a stimulation at low concentrations (0.02-0.78 microM) whilst at higher concentrations (> 3.12 microM) inhibition was observed. No stimulation was observed in ER (-) MDA-MB-231. In contrast, all the flavones exhibited an antiproliferative effect in both ER (-) and ER (+). Curiously, the inhibition of DNA synthesis was accompanied by a high capacity of these cells to reduce MTT, which was concurrent with the appearance of an intense intracytoplasmic vacuolization. The accumulation of the formazan product in these vacuoles could justify the enhancements of MTT reduction. The characterization of these vacuoles with the autophagic marker monodansylcadaverine (MDC) is consistent with autophagic vacuoles, which led to the suggestion that these flavones could induce autophagy in both ER (+) and ER (-) breast cancer cell lines.

Breast Neoplasms↗
PubMed1998

Transepithelial transport and accumulation of flavone in human intestinal Caco-2 cells.

Flavonoids are found in many food items of plant origin. Intake of flavonoids has been linked to the prevention of human diseases including cancer. However, little is known about the intestinal absorption of flavonoids in the cellular level. This study was designed to study the absorption of dietary flavonoids using cultured human intestinal epithelial cell monolayer as a model system and 14C-flavone as a model compound. 14C-flavone at 10 microM was found to move across the cell monolayer rapidly both from the luminal to basolateral direction and from the basolateral to luminal direction. The rate of transport from the luminal to basolateral direction was 5 times of the rate for phenylalanine, an aromatic amino acid. Flavone also accumulated substantially in the cells. Replacing sodium in the transport buffer with potassium did not affect the transport but reducing the incubation temperature significantly decreased the initial rate of transport. The presence of protein in the transport buffer reduced the initial rate of transport to half. Other flavonoids and hydrophobic chemicals at 100 microM had no effects on the transport. Together with the evidence from microscopic observation (Cancer Letts. 110: 41-48, 1996), this study supports that rapid diffusional transport may be the main route for flavonoid absorption. The ability of intestinal cells to accumulate flavone is consistent with the role of flavonoids in colon cancer prevention.

Biological Transport↗
PubMed2005

Flavones suppress the expression of the high-affinity IgE receptor FcepsilonRI in human basophilic KU812 cells.

We examined the effect of flavones on the expression of the high-affinity IgE receptor FcepsilonRI, which plays a central role in the IgE-mediated allergic response. Flow cytometric analysis showed that the flavones chrysin and apigenin were able to reduce the cell surface expression of FcepsilonRI in human basophilic KU812 cells. Immunoblot analysis revealed that the total cellular expression of the FcepsilonRI alpha and gamma chains decreased upon treatment with chrysin and apigenin. Moreover, the level of mRNA expression of the FcepsilonRI alpha and gamma chains also decreased when the cells were cultured with the two flavones. Previously, we demonstrated that the reduction of extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation was involved in the downregulation of FcepsilonRI expression. The two flavones were shown to reduce the level of ERK1/2 phosphorylation. These results suggested that chrysin and apigenin have the ability to downregulate FcepsilonRI expression and this suppressive effect may be due to the reduction of ERK1/2 phosphorylation.

Apigenin↗
PubMed2004

[Study on Enrichment process of total flavones from Semen cuscutae with macroporous resin].

OBJECTIVE: To study the optimal conditions and parameters for the enrichment process of total flavones in Semen cuscutae with macroporous resin. METHODS: With the enrichment degree of total flavones in Semen cuscutae as an index, the optimal conditions of the enrichment process were investigated. RESULTS: The aqueous extract from Semen cuscutae was taken into the macroporous resin column, then the resin was washed by distilled water to get rid of impurity and 30% and 70% ethannol to elute total flavones. The above conditions were optimal. CONCLUSIONS: The process is feasible to enrich effective ingredient flavones from Semen cuscutae.

Adsorption↗
PubMed2001

Purification and antigenicity of flavone synthase I from irradiated parsley cells.

Flavone synthase I, a soluble 2-oxoglutarate-dependent dioxygenase catalyzing the oxidation of flavanones to flavones in several Apiaceae species, was induced in parsley cell cultures by continuous irradiation with ultraviolet/blue light for 20 h. The enzyme was extracted from these cells and purified by a revised purification protocol including the fractionation on hydroxyapatite, Fractogel EMD DEAE, and Mono Q anion exchangers, which resulted in an apparently homogeneous flavone synthase at approximately 10-fold higher yield as compared to the previous report. The homogeneous enzyme was employed to raise an antiserum in rabbit for partial immunological characterization. The specificity of the polyclonal antibodies was demonstrated by immunotitration and Western blotting of the crude ammonium sulfate-fractionated enzyme as well as of the enzyme at various stages of the purification. High titer cross-reactivity was observed toward flavone synthase I, showing two bands in the crude extract corresponding to molecular weights of 44 and 41 kDa, respectively, while only the 41 kDa was detected on further purification. The polyclonal antiserum did not cross-react with recombinantly expressed flavanone 3beta-hydroxylase from Petunia hybrida or flavonol synthase from Citrus unshiu, two related 2-oxoglutarate-dependent dioxygenases involved in the flavonoid pathway.

Antibody Specificity↗
PubMed1995

A comparison of active site binding of 4-quinolones and novel flavone gyrase inhibitors to DNA gyrase.

The activity of 4-quinolone antibacterials at the enzyme target level is based on the well known and reported observations that 4-quinolone antibacterials target the Gyr A subunit of the DNA gyrase holoenzyme, inhibiting supercoiling while facilitating the "cleavable complex". Such inhibition can be observed by running the in vitro DNA gyrase supercoiling inhibition assay or the "cleavable complex" DNA gyrase assay. Although potency of the gyrase inhibitor is dependent on many factors including permeability and pharmacokinetics, the inherent potency of a gyrase inhibitor lies in its activity against the target enzyme. We have examined the binding activity of novel flavones [Bioorganic & Med. Chem. Letters 3:225-230, 1993] to Escherichia coli DNA gyrase and have found differences in binding consistent with inhibition of DNA gyrase supercoiling and ability to facilitate the cleavable complex, but of different rank order. [3H]norfloxacin was used in vitro competition studies with test compounds, pBR322 and E. coli DNA gyrase. Binding affinity results indicate the rank order of greatest to weakest binding (ability to compete with [3H]norfloxacin) of test compounds: Levofloxacin = ciprofloxacin > ofloxacin > norfloxacin > flavone compounds (including ellagic acid, quercetin, and compounds 5a through 5n [Bioorganic & Med. Chem. Letters 3:225-230, 1993]). Such differences in binding ability of the 4-quinolones and flavones to the ternary complex of DNA.DNA gyrase.drug, as compared to the catalytic inhibition and "cleavable complex" data, suggests a more complex binding of flavones than the previously hypothesized models for 4-quinolone binding.

Anti-Infective Agents↗
PubMed1995

Inhibition of nitric oxide (NO.) production in murine macrophages by flavones.

The effect of flavone (2-phenylbenzopyran-4-one) and three amino-substituted flavones on the production of nitrite by murine activated peritoneal macrophages was studied in vitro. Activated peritoneal macrophages obtained from mice pre-treated with concanavalin A (Con A) (in vivo), after exposure in vitro to lipopolysaccharide (LPS) at a concentration of 100 ng/ml, produced nitrite (20.3 +/- 2.5 nmol/10(6) cells), as measured after 24 hr by the Griess reaction. Stimulation of production of nitrite was inhibited by NG-monomethyl-L-arginine, suggesting that nitrite was formed via nitric oxide (NO.) as a product of metabolism of arginine. Stimulation was inhibited by flavone and the aminoflavones (20-100 microM). 3'-amino-4'-hydroxyflavone was the most potent inhibitor of nitrite production. Genistein (5,7-dihydroxy- 3-(4-hydroxy-phenyl)-4H-1-benzopyran-4-one) also inhibited production of nitrite, by a mechanism that appears not to involve protein tyrosine kinases. These results suggest that the flavones can modulate the immune responses and the inflammatory reactions by controlling production of nitric oxide.

Animals↗
PubMed1987

Clinical and pharmacokinetic phase I trial with the diethylaminoester of flavone acetic acid (LM985, NSC 293015).

The diethylaminoester of flavone acetic acid (LM985) is a new anticancer agent with curative effects against slow growing murine tumors. Thirty-one adult patients with solid tumors received a total of 57 courses of LM985 given on days 1 and 8 every 4 weeks. The drug was given as a short infusion (1-2 hr) at doses ranging from 120 to 1900 mg/sq.m/day. The dose-limiting toxicity consisted of acute expressive aphasia; this neurotoxicity usually appeared at the end of the infusion and resolved spontaneously within a few minutes to 1 hr after the end of the infusion. In some patients, neurotoxicity was avoided by reducing the infusion rate. Neurotoxicity was observed in 5 out of 6 patients receiving 960 mg/sq.m over 1 hr and in 3 out of 3 patients receiving 1900 mg/sq.m over 2 hr. The drug did not induce any significant myelosuppression. Other side-effects were very mild and consisted mainly of occasional nausea and/or vomiting at all dose levels. One patient with breast cancer resistant to several hormonal and chemotherapy regimens had stable disease for 6 months. LM985 was detected in plasma in very small concentrations (0-2.5 micrograms/ml) but there was extensive formation of flavone acetic acid (peak concentration ranging between 8.3 and 64 micrograms/ml). A dose of 1500 mg/sq.m on days 1 and 8 every 4 weeks could be recommended for phase II studies with LM985; however, since LM985 is a prodrug of flavone acetic acid, phase II studies with LM985 should not be activated prior to the completion of the ongoing phase I trials with flavone acetic acid, which may be devoid of the acute toxicity of LM985.

Adult↗
PubMed1988

Comparison of the effects of feeding quercetin or flavone on hepatic and intestinal drug-metabolizing enzymes of the rat.

The influence of dietary flavone and quercetin on the components of the drug metabolizing enzyme system was examined in the liver and small intestine of the rat. Quercetin given at a concentration of 1% in the diet for 14 days produced no significant changes on phase I or phase II enzyme activities. In contrast, 0.25% flavone caused significant increases in relative liver weight, microsomal and cytoplasmic proteins, and cytochrome P-450 content. The activities of hepatic ethoxyresorufin, pentoxyresorufin and ethoxycoumarin deethylases were significantly increased (by 20, 30 and 2.5-fold, respectively) over control levels. Hepatic UDP-glucuronyl transferase and glutathione transferase activities were increased 3-4-fold. In contrast, flavone induced no changes in these two intestinal enzyme activities. It is concluded that flavone produces an induction that shows both phenobarbital- and methylcholanthrene-type characteristics and that its effects on conjugating enzymes is tissue specific.

Animals↗
PubMed1995

Interaction of polycyclic aromatic hydrocarbons and flavones with cytochromes P450 in the endoplasmic reticulum: effect on CO binding kinetics.

The flash photolysis technique was used to examine the kinetics of CO binding to cytochromes P450 in rat liver microsomes. The effect of polycyclic aromatic hydrocarbons (PAHs) and flavones was used to distinguish the kinetic behavior of the PAH-metabolizing P450 1A1 from that of the remaining multiple microsomal P450s. Applying this approach to microsomes from 3-methylcholanthrene-treated rats showed that although all tested PAHs accelerated CO binding to P450 1A1, the extent varied markedly for different PAHs. The tricyclic PAHs phenanthrene and anthracene enhanced CO binding by 37- and 49-fold, respectively, while several tetracyclic and pentacyclic PAHs increased the rate by 3-16-fold. The results indicate that PAHs exert a dual effect on the rate of CO binding to P450 1A1: a general enhancement via widening of the CO access channel and a reduction that is dependent on PAH size. Although 5,6-benzoflavone increased the rate of CO binding to P450 1A1 by 3.5-fold, it additionally decelerated binding to a constitutive P450 by 15-fold. This flavone thus exerts markedly different effects on two P450s within the same microsomal sample. In contrast, the sole effect of 7,8-benzoflavone was acceleration of CO binding to P450 1A1 by 18-fold. The divergent effects of these isomeric flavones, which only differ in positioning of an aromatic ring, illustrate the sensitivity of CO binding to substrate structure. The varying effects of these PAHs and flavones on CO binding kinetics show that they differentially modulate P450 conformation and access of ligands to the P450 heme and demonstrate that binding of carcinogens to a specific target P450 can be evaluated in its native microsomal milieu.

Animals↗
PubMed2003

Flavone C-glycoside, phenolic acid, and nitrogen contents in leaves of barley subject to organic fertilization treatments.

From the leaves of barley, Hordeum vulgare, one new flavone C-glucoside and three known flavone glucosides were isolated and characterized by (1)H and (13)C NMR and MALDI-TOF-MS. The novel flavone C-glucoside was isovitexin 7-O-beta-[6' "-O-(E)-p-coumaroyl]glucoside (6' "-coumaroylsaponarin), and the known compounds were isovitexin 7-O-beta-[6' "-O-(E)-feruloyl]glucoside, isoorientin 7-O-beta-[6' "-O-(E)-feruloyl]glucoside, and tricin 7-O-beta-glucoside. The sum of all the flavone glycosides and soluble phenolic acids in the leaves decreased with increased rate of plant nutrients given in animal manure and with increased crop yield. All of the major phenylpropanoids showed the same general response to nutrient level. The concentration of nitrogen in the leaves was not directly related to nutrient application or to contents of phenylpropanoids.

Fertilizers↗
PubMed2000

Identification of flavone C-glycosides including a new flavonoid chromophore from barley leaves (Hordeum vulgare L.) by improved NMR techniques.

Six flavone C-glycosides were isolated from young leaves of barley. One of the C-glucosides has a new type of nucleus, a 2',4',5,5', 7-penta-OH-substituted flavone bearing a 6-C-beta-D-glucoside, which has apparently never been isolated before. One mono- and two di-C-glycosyl flavones were isolated for the first time from barley and identified as isoscoparin 7-O-beta-D-glucoside, carlinoside, and shaftoside, respectively. Other flavones were 7-O-beta-D-glucosides of isoorientin and isovitexin. The known problematic NMR structure elucidation of C-glycosyl flavonoids has been solved by using both a temperature close to the freezing point of the solvent (22.5 degrees C in DMSO-d(6)) and a high temperature (70, 90 degrees C) for comparison during NMR measurements. Structural determination of all the compounds was achieved by employing 1D and 2D NMR techniques.

Flavonoids↗
PubMed2001

Flavonol and flavone intake and the risk of cancer in male smokers (Finland).

OBJECTIVE: To study the associations between the intake of flavonols and flavones and the risk of cancer. METHODS: The study cohort consisted of 27,110 male smokers, aged 50-69 years, without history of cancer. They were participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study in Finland. The men completed a validated dietary questionnaire at baseline. Incident cases of cancers were identified through national registers. During an average 6.1-year follow-up, 791 lung cancers, 226 prostate cancers, 156 urothelial cancers, 133 colorectal cancers, 111 stomach cancers, and 92 renal cell cancers were diagnosed. RESULTS: Intake of flavonols and flavones was inversely associated with the risk of lung cancer; multivariate relative risk in the highest vs. the lowest quartile 0.56, 95% confidence interval 0.45-0.69, p for trend 0.0001. The risk was similar in all histological types of lung cancer. No association was found between flavonol and flavone intake and the risk of other cancers. CONCLUSIONS: Intake of flavonols and flavones seemed to be inversely associated with the risk of lung cancer, but not with that of other cancers.

Aged↗
PubMed2004

Flavonol and flavone intake and the risk of intermittent claudication in male smokers.

The objective of this study was to investigate the association between flavonol and flavone intake and the risk of intermittent claudication in male smokers. The study population consisted of participants of the Finnish alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) Study, who were free of intermittent claudication at study entry. These 25,041 male smokers were 50-69 years old at baseline. Participants completed a validated dietary questionnaire at baseline. The occurrence of intermittent claudication was assessed by annual administration of the Rose questionnaire. During the median follow-up of 4.1 years, 2412 new cases of intermittent claudication were observed. Dietary intake of flavonols and flavones was inversely associated with the risk of intermittent claudication when adjusted for cardiovascular risk factors (relative risk, RR in the highest vs. lowest quintile of intake 0.86, 95% confidence interval, CI: 0.75-0.98, p for trend 0.007). However, after further adjustment for intakes of vitamins C and E and total carotenoids, the association was attenuated (RR: 0.93, 95% CI: 0.81-1.08, p for trend 0.12). The risk of intermittent claudication was lower among men in the highest quintile of vegetable consumption (RR: 0.78, 95% CI: 0.69-0.89, p for trend 0.0001) and among wine drinkers (RR: 0.63, 95% CI: 0.41-0.98). Adjustment for flavonol and flavone intake only marginally changed these associations. In conclusion, flavonol and flavone intake was not independently associated with the risk of intermittent claudication.

Aged↗
PubMed1966

Studies on flavonoid metabolism. Metabolism of flavone in the guinea pig.

1. The metabolism of flavone has been studied in the guinea pig; after administration of the compound either orally or intraperitoneally, 4'-hydroxyflavone is excreted in the urine. 2. Small amounts of 3',4'-dihydroxyflavone were also detected in the urine after oral administration of flavone. 3. Hydroxyflavone formation is not suppressed by administering high doses of the antibacterial compounds aureomycin and phthaloylsulphathiazole. 4. Although salicylic acid appeared in trace quantities in the urine after administration of flavone, no other aromatic acid metabolites of flavone were detected.

Animals↗
PubMed2000

A membrane-potential dependent ABC-like transporter mediates the vacuolar uptake of rye flavone glucuronides: regulation of glucuronide uptake by glutathione and its conjugates.

In this paper we present results on the vacuolar uptake mechanism for two flavone glucuronides present in rye mesophyll vacuoles. In contrast to barley flavone glucosides (Klein et al. (1996) J. Biol. Chem. 271, 29666-29671), the flavones luteolin 7-O-diglucuronyl-4'-O-glucuronide (R1) and luteolin 7-O-diglucuronide (R2) were taken up into vacuoles isolated from rye via a directly energized mechanism. Kinetic studies suggested that the vacuolar glucuronide transport system is constitutively expressed throughout rye primary leaf development. Competition experiments argued for the existence of a plant MRP-like transporter for plant-specific and non-plant glucuronides such as beta-estradiol 17-(beta-D-glucuronide) (E217G). The interaction of ATP-dependent vacuolar glucuronide uptake with glutathione and its conjugates turned out to be complex: R1 transport was stimulated by dinitrobenzene-GS and reduced glutathione but was inhibited by oxidized glutathione in a concentration-dependent manner. In contrast, R2 uptake was not increased in the presence of reduced glutathione. Thus, the transport system for plant-derived glucuronides differed from the characteristic stimulation of vacuolar E217G uptake by glutathione conjugates but not by reduced glutathione (Klein et al. (1998) J. Biol. Chem. 273, 262-270). Using tonoplast vesicles isolated with an artificial K+ gradient, we demonstrate for the first time for plant MRPs that the ATP-dependent uptake of R1 is membrane-potential dependent. We discuss the kinetic capacity of the ABC-type glucuronide transporter to explain net vacuolar flavone glucuronide accumulation in planta during rye primary leaf development and the possibility of an interaction of potential substrates at both the substrate binding and allosteric sites of the MRP transporter regulating the activity towards a certain substrate.

ATP-Binding Cassette Transporters↗
PubMed1996

Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I.

Topoisomerases are involved in many aspects of DNA metabolism such as replication and transcription reactions. Camptothecins, which stabilize the covalent intermediate of topoisomerase I and DNA are effective, though toxic, drugs for cancer therapy. In this study, a new class of topoisomerase I inhibitors was identified, and their mode of action was characterized using recombinant human topoisomerase I preparations and human HL-60 leukemic cells. Quercetin and the related natural flavones, acacetin, apigenin, kaempferol, and morin, inhibit topoisomerase I-catalyzed DNA religation. In contrast to camptothecin, these compounds do not act directly on the catalytic intermediate and also do not interfere with DNA cleavage. However, formation of a ternary complex with topoisomerase I and DNA during the cleavage reaction inhibits the following DNA religation step. 3,3',4',7-Tetrahydroxy-substituted flavones stabilize the covalent topoisomerase I-DNA intermediate most efficiently. Enhanced formation of covalent topoisomerase I-DNA complexes was also demonstrated in human HL-60 cells. In contrast, synthetic 3,5'-dibromo- 4'-hydroxy-3-methylflavones bind selectively to topoisomerase I in its non-DNA-bound form and block the following DNA binding step. As a consequence, these synthetic flavonoids are capable of counteracting topoisomerase I-directed effects of camptothecin. Inhibition of DNA binding is obtained by voluminous hydrophobic substituents in 6-position of the flavone structure. Our data show that selective inhibitors of both half-reactions of topoisomerase I can be derived from the flavone structure.

Base Sequence↗