The influence of phase II conjugation on the biological activity of flavonoids
Beekmann, K. - \ 2016
Wageningen University. Promotor(en): Ivonne Rietjens; Peter van Bladeren, co-promotor(en): L. Actis-Goretta. - Wageningen : Wageningen University - ISBN 9789462577640 - 171
flavonoids - biological activity - in vitro - biosynthesis - peroxisomes - microarrays - daidzein - genistein - oestrogen receptors - isoflavones - quercetin - kaempferol - serine proteinases - threonine - flavonoïden - biologische activiteit - in vitro - biosynthese - peroxisomen - microarrays - daidzin - genisteïne - oestrogeenreceptoren - isoflavonen - quercetine - kaempferol - serine proteïnasen - threonine
Flavonoid consumption is often correlated with a wide range of health effects, such as the prevention of cardiovascular diseases, neurodegenerative diseases, and diabetes. These effects are usually ascribed to the activity of the parent flavonoid aglycones, even though these forms of the flavonoids generally have a low systemic bioavailability. During uptake, flavonoids undergo phase II metabolism and are present in the systemic circulation nearly exclusively as conjugated metabolites. The aim of this thesis was to study the effect of conjugation on the biological activity of selected flavonoids towards different endpoints relevant for human health. To this end, conjugation with glucuronic acid was taken as the model type of conjugation because this modification is generally observed to be the most important metabolic conjugation reaction for flavonoids in man.
A review of scientific literature published until early 2012 reveals that metabolic conjugation can affect the biological activity of flavonoids in different ways. Conjugation can increase, decrease, inverse or not affect the biological activity, depending on the flavonoid, the type and position of conjugation, the endpoint studied, and the assay system used. Based on the literature reviewed it is concluded that the effect of conjugation has to be studied on a case-by-case basis.
As the research on the biological activity of biologically relevant flavonoid conjugates is often hampered by the generally low commercial availability and high prices of these conjugates, a simple and versatile method for the biosynthesis of metabolically relevant flavonoid conjugates is described. Using this method, relevant conjugates can be prepared from different flavonoid substrates in sufficient quantities for in vitro bioassays. Further, an efficient strategy for the identification of these flavonoid conjugates by LC-MS and 1H-NMR using MetIDB (Metabolite Identification Database), a publicly accessible database of predicted and experimental 1H-NMR spectra of flavonoids, is presented.
To study the effect of conjugation on the biological activities of flavonoids, several different assay systems and endpoints were used to study the activity of different flavonoids and their conjugates. The effects of quercetin, kaempferol, and their main plasma conjugates quercetin-3-O-glucuronide and kaempferol-3-O-glucuronide (K-3G) on different endpoints related to peroxisome proliferator-activated receptor (PPAR)-γ were studied. PPAR-γ activation is reported to have positive health effects related to adipogenesis, insulin resistance and inflammation. The presented results show that the flavonoid aglycones increased PPAR-γ mediated gene expression in a stably transfected reporter gene cell line, and that glucuronidation diminished this effect. These observed increases in reporter gene expression were accompanied by increased PPAR-γ receptor-mRNA expression upon exposure to kaempferol, an effect that was also reduced by glucuronidation. Using the cell-free Microarray Assay for Real-time Coregulator-Nuclear receptor Interaction (MARCoNI) it was demonstrated that, unlike the known PPAR-γ agonist rosiglitazone, neither the flavonoid aglycones nor the conjugates are agonistic ligands of the PPAR-γ receptor. Supporting the hypothesis that the tested compounds have a different mode of action from normal LBD agonism, quercetin appeared to synergistically increase the effect of rosiglitazone in the reporter gene assay. The modes of action behind the observed effects remain to be elucidated and might include effects on protein kinase activities affecting expression of the PPAR-γ receptor, or posttranscriptional modifications of PPAR-γ.
Another type of nuclear receptor known to be targeted by certain flavonoids are the estrogen receptor (ER)α- and ERβ. ERs are the main targets of estrogenic compounds, and upon their activation different transcriptional responses with opposite effects on cell proliferation and apoptosis are elicited; ERα activation stimulates cell proliferation, while ERβ activation causes apoptosis and reduces ERα mediated induction of cell proliferation. Using the MARCoNI assay, the intrinsic estrogenic effects of the two main dietary isoflavones daidzein and genistein, and their plasma conjugates daidzein-7-O-glucuronide and genistein-7-O-glucuronide on the ligand induced coregulator binding of ERα- and ERβ-LBD were studied and compared to the effect of the positive control 17β-estradiol (E2). The results show that the tested isoflavone compounds are less potent agonists of ERα- and ERβ-LBD than E2, although they modulate the LBD-coregulator interactions in a manner similar to E2. Genistein is shown to be a more potent agonist than daidzein for both receptor subtypes. While in the MARCoNI assay genistein had a strong preference for ERβ-LBD activation over ERα-LBD activation, daidzein had a slight preference for ERα-LBD activation over ERβ-LBD activation. Glucuronidation reduced the intrinsic agonistic activities of both daidzein and genistein to induce ERα-LBD and ERβ-LBD - coregulator interactions and increased their average half maximal effective concentrations (EC50s) by 8 to 4,400 times. The results presented further show that glucuronidation changed the preferential activation of genistein from ERβ-LBD to ERα-LBD and increased the preferential activation of daidzein for ERα-LBD; this is of special interest given that ERβ activation, which is counteracting the possible adverse effects of ERα activation, is considered one of the supposedly beneficial modes of action of isoflavones.
Many flavonoids are reported to be inhibitors of protein kinases. To study the effect of conjugation on the inhibition of serine/threonine protein kinases by flavonoids, kaempferol and its main plasma conjugate K-3G were selected as model compounds. Protein kinases are involved in a wide range of physiological processes by controlling signaling cascades and regulating protein functions; modulation of their activities can have a wide range of biological effects. The inhibitory effects of kaempferol, K-3G, and the broad-specificity protein kinase inhibitor staurosporine on the phosphorylation activity of recombinant protein kinase A (PKA) and of a lysate prepared from the hepatocellular carcinoma cell line HepG2 were studied using a microarray platform that determines the phosphorylation of 141 putative serine/threonine phosphorylation sites derived from human proteins. The results reveal that glucuronidation reduces the intrinsic potency of kaempferol to inhibit the phosphorylation activity of PKA and HepG2 lysate on average about 16 and 3.5 times, respectively. It is shown that the inhibitory activity of K-3G in the experiments conducted was not caused by deconjugation to the aglycone. Furthermore, the results show that kaempferol and K-3G, unlike the broad-specificity protein kinase inhibitor staurosporine, did not appear to inhibit all protein kinases present in the HepG2 lysate to a similar extent, indicating that kaempferol selectively targets protein kinases, a characteristic that appeared not to be affected by glucuronidation. The fact that K-3G appeared to be only a few times less potent than kaempferol implies that K-3G does not necessarily need to be deconjugated to the aglycone to exert potential inhibitory effects on protein kinases.
The results obtained in the present thesis support the conclusion that glucuronidation of flavonoids does not necessarily abolish their activity and that flavonoid glucuronides may be biologically active themselves, albeit at higher concentrations than the parent aglycones. In line with the conclusions from the earlier literature review, an updated literature review on the effect of conjugation on the biological activity of flavonoids concludes that that the effect of conjugation on the biological activity of flavonoids depends on the type and position of conjugation, the endpoint studied and the assay system used. Based on the results described and the literature reviewed in this thesis, several recommendations and perspectives for future research are formulated. Several methodological considerations are formulated that need to be taken into account when studying the biological activity of flavonoids and their conjugates to avoid confounding results. Further, the relevance of the gut microbiome for flavonoid bioactivity is highlighted, and considerations regarding the pharmacokinetics and pharmacodynamics of flavonoids in vivo are formulated. Altogether, it can be concluded that circulating flavonoid conjugates may exert biological activities themselves, and that understanding these is a prerequisite to successfully elucidate the mechanisms of action behind the biological activities linked to flavonoid consumption.
Deconjugation of soy isoflavone glucuronides needed for estrogenic activity
Islam, M.A. ; Bekele, R. ; Berg, J.H.J. van den; Kuswanti, Y. ; Thapa, O. ; Soltani, S. ; Leeuwen, F.X.R. ; Rietjens, I.M.C.M. ; Murk, A.J. - \ 2015
Toxicology in Vitro 29 (2015)4. - ISSN 0887-2333 - p. 706 - 715.
beta-messenger-rna - in-vitro - er-beta - receptor-beta - cell-proliferation - human plasma - cancer - expression - alpha - genistein
Soy isoflavones (SIF) are present in the systemic circulation as conjugated forms of which the estrogenic potency is not yet clear. The present study provides evidence that the major SIF glucuronide metabolites in blood, genistein-7-O-glucuronide (GG) and daidzein-7-O-glucuronide (DG), only become estrogenic after deconjugation. The estrogenic potencies of genistein (Ge), daidzein (Da), GG and DG were determined using stably transfected U2OS-ERa, U2OS-ERß reporter gene cells and proliferation was tested in T47D-ERß cells mimicking the ERa/ERß ratio of healthy breast cells and inT47D breast cancer cells. In all assays applied, the estrogenic potency of the aglycones was significantly higher than that of their corresponding glucuronides. UPLC analysis revealed that in U2OS and T47D cells, 0.2-1.6% of the glucuronides were deconjugated to their corresponding aglycones. The resulting aglycone concentrations can account for the estrogenicity observed upon glucuronide exposure. Interestingly, under similar experimental conditions, rat breast tissue S9 fraction was about 30 times more potent in deconjugating these glucuronides than human breast tissue S9 fraction. Our study confirms that SIF glucuronides are not estrogenic as such, and that the small % of deconjugation in the cell is enough to explain the slight bioactivity observed for the SIF-glucuronides. Species differences in deconjugation capacity should be taken into account when basing risk-benefit assessment of these SIF for the human population on animal data.
Structural Changes of 6a-Hydroxy-Pterocarpans Upon Heating Modulate Their Estrogenicity
Schans, M.G.M. van de; Vincken, J.P. ; Bovee, T.F.H. ; Cervantes, A.D. ; Logtenberg, M.J. ; Gruppen, H. - \ 2014
Journal of Agricultural and Food Chemistry 62 (2014). - ISSN 0021-8561 - p. 10475 - 10484.
ionization mass-spectrometry - isoflavonoid composition - phytoestrogens - flavonoids - aglycones - genistein - seedlings - daidzein - soy
The isoflavonoid composition of an ethanolic extract of fungus-treated soybean sprouts was strongly altered by a combined acid/heat treatment. UHPLC-MS analysis showed that 6a-hydroxy-pterocarpans were completely converted to their respective, more stable, 6a,11a-pterocarpenes, whereas other isoflavonoids, from the isoflavone and coumestan subclasses, were affected to a much lesser extent (loss of ~15%). Subsequently, mixtures enriched in prenylated 6a-hydroxy-pterocarpans (pools of glyceollin I/II/III and glyceollin IV/VI) or prenylated 6a,11a-pterocarpenes (pools of dehydroglyceollin I/II/III and dehydroglyceollin IV/VI) were purified, and tested for activity on both human estrogen receptors (ERa and ERß). In particular, the response toward ERa changed, from agonistic for glyceollins to antagonistic for dehydroglyceollins. Toward ERß a decrease in agonistic activity was observed. These results indicate that the introduction of a double bond with the concomitant loss of a hydroxyl group in 6a-hydroxy-pterocarpans extensively modulates their estrogenic activity.
Isoflavone extraction from okara using water as extractant
Jankowiak, L. ; Kantzas, N. ; Boom, R.M. ; Goot, A.J. van der - \ 2014
Food Chemistry 160 (2014). - ISSN 0308-8146 - p. 371 - 378.
defatted soybean flakes - soy foods - solubility - soymilk - ph - temperature - stability - genistein - daidzein - proteins
We here report on the use of water as a ‘green’ extraction solvent for the isolation of isoflavones from okara, a by-product of soymilk production. At a low liquid-to-solid ratio of 20 to 1 and 20 °C, 47% of the isoflavones that can be extracted with 70% aqueous ethanol were extracted. The malonyl-glucosides were fully recovered with a ratio of 20 to 1, while ß-glucosides were recovered with an increased liquid-to-solid ratio of 40 to 1. The extraction of aglycones was better at higher ratios, but leveled off before reaching a 100% yield. Temperature hardly affected the total amount of isoflavones. At a 20 to 1 ratio, 20 °C, and pH 10, there was no significant difference (p > 0.05) between isoflavone extraction in water and in 70% aqueous ethanol. The results suggest that water may be used as a green alternative for separation of isoflavones from okara.
exposure of growing and adult captive cheetahs (Acinony Jubatus) to dietary isoflavones: twenty years later
Bell, K.M. ; Rutherfurd, S.M. ; Hendriks, W.H. - \ 2010
Journal of Animal Physiology and Animal Nutrition 94 (2010)6. - ISSN 0931-2439 - p. e329 - e338.
female reproductive-system - veno-occlusive disease - soy isoflavones - neonatal exposure - phyto-estrogens - food-intake - genistein - phytoestrogens - cats - rats
Dietary isoflavones are associated with oestrogenic and anti-oestrogenic effects, and have been linked to infertility in cheetahs. This study aimed to determine the isoflavone content of commercially prepared diets consumed by captive cheetahs. Sixteen international zoological facilities provided diets, and the isoflavone content of each diet was determined by acid hydrolysis and HPLC quantification. Proximate nutritional composition was also determined. Over half the diets analysed contained detectable concentrations of isoflavones, whereby total isoflavone content ranged from 1.75-183 mg/kg dry matter. The zoo-specific diets were calculated to deliver a median isoflavone dose of 0.07 mg/kg body weight (BW) and a maximum of 1.95 mg/kg BW to captive cheetahs. On a metabolic body weight basis this equates to a maximum of 4.90-5.43 mg/kg(0.75). Some diets prepared for hand-rearing neonatal cheetahs could expose neonates to doses of up to 4.24 mg/kg BW (or 4.24-6.33 mg/kg(0.75) for cubs under 3 months of age). Only one of six zoo-specific diets was found to deliver isoflavones in doses shown to possess biological activity in other species. Therefore, on average, dietary isoflavones were not found in commercially prepared diets consumed by captive cheetahs in concentrations predicted to cause physiological changes. However, a small proportion of these diets, including hand-rearing formulas, contained elevated isoflavones concentrations which may influence cheetah fertility, behaviour or other physiological parameters.
Superinduction of estrogen receptor mediated gene expression in luciferase based reporter gene assays is mediated by a post-transcriptional mechanism
Sotoca Covaleda, A.M. ; Bovee, T.F.H. ; Brand, W. ; Velikova, N.R. ; Murk, A.J. ; Vervoort, J.J.M. ; Rietjens, I.M.C.M. - \ 2010
Journal of Steroid Biochemistry and Molecular Biology 122 (2010)4. - ISSN 0960-0760 - p. 204 - 211.
human breast-cancer - in-vitro - er-beta - firefly luciferase - cell-proliferation - genistein - phytoestrogens - metabolites - daidzein - alpha
Several estrogenic compounds including the isoflavonoid genistein have been reported to induce a higher maximal response than the natural estrogen 17ß-estradiol in in vitro luciferase based reporter gene bioassays for testing estrogenicity. The phenomenon has been referred to as superinduction. The mechanism underlying this effect and thus also its biological relevance remain to be elucidated. In the present study several hypotheses for the possible mechanisms underlying this superinduction were investigated using genistein as the model compound. These hypotheses included (i) a non-estrogen receptor (ER)-mediated mechanism, (ii) a role for an ER activating genistein metabolite with higher ER inducing activity than genistein itself, and (iii) a post-transcriptional mechanism that is not biologically relevant but specific for the luciferase based reporter gene assays. The data presented in this study indicate that induction and also superinduction of the reporter gene is ER-mediated, and that superinduction by genistein could be ascribed to stabilization of the firefly luciferase reporter enzyme increasing the bioluminescent signal during the cell-based assay. This indicates that the phenomenon of superinduction may not be biologically relevant but may rather represent a post-transcriptional effect on enzyme stability.
Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ER/ER ratio
Sotoca Covaleda, A.M. ; Ratman, D. ; Saag, P. van der; Ström, A. ; Gustafsson, J.A. ; Vervoort, J.J.M. - \ 2008
Journal of Steroid Biochemistry and Molecular Biology 112 (2008)4-5. - ISSN 0960-0760 - p. 171 - 178.
estrogen-receptor-beta - luciferase reporter - nuclear - quercetin - line - recruitment - modulation - expression - genistein - prostate
This study investigates the importance of the intracellular ratio of the two estrogen receptors ER¿ and ERß for the ultimate potential of the phytoestrogens genistein and quercetin to stimulate or inhibit cancer cell proliferation. This is of importance because (i) ERß has been postulated to play a role in modulating ER¿-mediated cell proliferation, (ii) genistein and quercetin may be agonists for both receptor types and (iii) the ratio of ER¿ to ERß is known to vary between tissues. Using human osteosarcoma (U2OS) ER¿ or ERß reporter cells it was shown that compared to estradiol (E2), genistein and quercetin have not only a relatively greater preference for ERß but also a higher maximal potential for activating ERß-mediated gene expression. Using the human T47D breast cancer cell line with tetracycline-dependent ERß expression (T47D-ERß), the effect of a varying intracellular ER¿/ERß ratio on E2- or pythoestrogen-induced cell proliferation was characterised. E2-induced proliferation of cells in which ERß expression was inhibited was similar to that of the T47D wild type cells, whereas this E2-induced cell proliferation was no longer observed when ERß expression was increased. With increased expression of ERß the phytoestrogen-induced cell proliferation was also reduced. These results point at the importance of the cellular ER¿/ERß ratio for the ultimate effect of (phyto)estrogens on cell proliferation.
Proteome analysis suggests that mitochondrial dysfunction in stressed endothelial cells is reversed by a soy extract and isolated isoflavones
Fuchs, D. ; Dirscherl, B. ; Schroot, J.H. ; Daniel, H. ; Wenzel, U. - \ 2007
Journal of Proteome Research 6 (2007)6. - ISSN 1535-3893 - p. 2132 - 2142.
low-density-lipoprotein - smooth-muscle cells - oxidized-ldl - platelet-aggregation - hyperglycemic damage - phyto-estrogens - genistein - pathways - superoxide - expression
Apoptosis is a driving force in atherosclerosis development. A soy extract or a combination of the soy isoflavones genistein and daidzein inhibited apoptosis induced by oxidized LDL in endothelial cells. Proteome analysis revealed that the LDL-induced alterations of numerous proteins were reversed by the extract and the genistein/daidzein mixture but only three protein entities, all functionally linked to mitochondrial dysfunction, were regulated in common by both treatments.
The isoflavone content of commercially-available feline diets in New Zealand
Bell, K.M. ; Rutherfurd, S.M. ; Hendriks, W.H. - \ 2006
New Zealand Veterinary Journal 54 (2006)3. - ISSN 0048-0169 - p. 103 - 108.
soy isoflavones - postmenopausal women - phytoestrogens - estrogens - foods - cats - identification - genistein - disease - health
To identify and quantify concentrations of the isoflavones genistein, daidzein, biochanin A and formononetin in commercially-prepared feline diets sold in New Zealand. METHODS: Feline diets (n=138) were collected from supermarkets, pet stores and veterinary clinics in New Zealand. Diets were classified into five categories based on the following criteria: the presence/absence of soy, the presence/absence of non-soy plant material, and dry matter (DM) content. A high performance liquid chromatography (HPLC)-based assay was developed and validated to identify and quantify concentrations of the isoflavones genistein, daidzein, biochanin A and formononetin. RESULTS: Isoflavones were detected in all categories of diet, and at quantifiable concentrations in 104/138 (75%) of the diets tested. More dry diets (127/138; 92%) contained isoflavones at quantifiable concentrations than moist diets (83/138; 60%, p
Modulatory effects of quercetin on proliferation and differentiation of the human colorectal cell line Caco-2
Dihal, A.A. ; Woutersen, R.A. ; Ommen, B. van; Rietjens, I.M.C.M. ; Stierum, R.H. - \ 2006
Cancer Letters 238 (2006)2. - ISSN 0304-3835 - p. 248 - 259.
colon-cancer cells - estrogen-receptor - in-vitro - dietary flavonoids - absorption - expression - metabolism - glycosides - genistein - apoptosis
The effect of the dietary flavonoid quercetin was investigated on proliferation and differentiation of the human colon cancer cell line Caco-2. Confluent Caco-2 monolayers exposed to quercetin showed a biphasic effect on cell proliferation and a decrease in cell differentiation (0.001
Bioavailability of genistein and its glycoside genistin
Steensma, A. - \ 2006
Wageningen University. Promotor(en): Ivonne Rietjens, co-promotor(en): H.P.J.M. Noteborn. - [S.l.] : S.n. - ISBN 9789085044031 - 161
genisteïne - derivaten - glycosiden - biologische beschikbaarheid - darmslijmvlies - cellen - ratten - genistein - derivatives - glycosides - bioavailability - intestinal mucosa - cells - rats
Genistein belongs to the class of isoflavones. The main sources of isofiavones in food are soybeans and soy-based products. Most isoflavones in plants are bound to sugars such as the glycosides genistin and daidzin. Understanding the various factors that influence absorption and metabolism of isoflavones and especially of their naturally occurring glycosides, is essential to fully elucidate and understand the physiological activity of these dietary ingredients in the human body. It is also essential to fully explore the possible beneficial health effects of the isoflavones, which are considered to be promising as healthy constituents in enriched (novel) foods or supplements. The aim of this thesis is to obtain data on the transport (uptake) and metabolism of the isoflavones genistein and daidzein and their glycosides genistin and diadzin. Special focus is directed to the possible role of SGLTl in the mechanism involved in the transport and absorption of the isoflavonic glycoside genistin. Another objective is to explore, develop, validate and optimise in vitro, in situ and in vivo gastrointestinal model systems for studying the bioavailability and metabolism of genistein, daidzein and their glycosides.
This thesis reveals that in all intestinal models studied genistein is more bioavailable than its glycoside genistin. The major route of absorption of genistin appeared to be deglycosylation of genistin to genistein and the subsequent intestinal metabolism of genistein to genistein glucuronides and sulfates. Mechanistic studies show that the bioavailability of genistin could be improved by the naturally occurring compound phloridzin, present in apples, because phloridzin inhibits the efflux-transporters located at the brush border (apical) membrane of the enterocyte. On the basis the results described in this thesis, it is concluded that the best gastrointestinal model system appears to be freely moving unanaesthetized cannulated rats. However, animal experiments are expensive and time-consuming and should be reduced, refined or replaced whenever feasible also for ethical reasons. The Caco-2 cells provide a good alternative for studying the mechanism of isoflavones absorption, although the hydrolase activity in this cell line should be improved to mimic the human situation to a better extent.
All together the results presented in this thesis provides an insight in the mechanisms underlying the bioavailability of this important class of health beneficial soy based food ingredients and even point at inhibition of apical transporters as a way to improve the bioavailability of genistin and genistein.
Soy extract has different effects compared with the isolated isoflavones on the proteome of homocysteine-stressed endothelial cells
Fuchs, D. ; Dirscherl, B. ; Schroot, J.H. ; Daniel, H. ; Wenzel, U. - \ 2006
Molecular Nutrition & Food Research 50 (2006)1. - ISSN 1613-4125 - p. 58 - 69.
platelet-aggregation - in-vitro - atherosclerosis - genistein - women - expression - apoptosis - monocyte - metabolism - inhibitor
Epidemiological studies suggest that soy consumption may provide a protection in the development and progression of atherosclerosis. It is under debate, however, whether the soy isoflavones or other compounds are the active principle. As apoptosis is a driving force in the process of atherosclerosis, we tested whether a soy extract or a combination of the two predominant isoflavones genistein and daidzein, in concentrations as found in the extract, exert similar or different effects on apoptosis in EA.hy 926 endothelial cells after exposure to the endothelial stressor homocysteine. Plasma membrane disintegration and nuclear fragmentation served as relevant apoptosis markers. To assess whether the extract and the genistein/daidzein mixture differently affect cellular target proteins changed in amount by homocysteine treatment, proteome analysis was performed by two-dimensional gel-electrophoresis and peptide mass fingerprinting of regulated protein spots. Homocysteine induced apoptosis in the cells, and both extract and genistein/daidzein inhibited apoptosis to a comparable extent. Whereas the extract prevented for 10 proteins the changes in expression levels as caused by homocysteine, the genistein/daidzein mixture reversed the homocysteine effects on the proteome for 13 proteins. The cytoskeletal protein matrin 3 and a U5 snRNP-specific 40-kDa protein were the only protein entities where both extract and genistein/daidzein reversed the homocysteine-induced changes in a common way. In conclusion, our studies provide evidence that an isoflavone containing soy extract and isolated isoflavones, despite similar effects on inhibition of homocysteine-induced apoptosis in endothelial cells, affect a quite different spectrum of cellular target proteins.
Absorption of isoflavones in humans: effects of food matrix and processing
Pascual-Teresa, S. de; Hallund, J. ; Talbot, D. ; Schroot, J.H. ; Williams, C.H. ; Bugel, S. ; Cassidy, A. - \ 2006
Journal of Nutritional Biochemistry 17 (2006)4. - ISSN 0955-2863 - p. 257 - 264.
soybean isoflavones - chemical-composition - beta-glucosidase - estrogen equol - human-urine - soy - genistein - daidzein - women - phytoestrogens
If soy isoflavones are to be effective in preventing or treating a range of diseases, they must be bioavailable, and thus understanding factors which may alter their bioavailability needs to be elucidated. However, to date there is little information on whether the pharmacokinetic profile following ingestion of a defined dose is influenced by the food matrix in which the isoflavone is given or by the processing method used. Three different foods (cookies, chocolate bars and juice) were prepared, and their isoflavone contents were determined. We compared the urinary and serum concentrations of daidzein, genistein and equol following the consumption of three different foods, each of which contained 50 mg of isoflavones. After the technological processing of the different test foods, differences in aglycone levels were observed. The plasma levels of the isoflavone precursor daidzein were not altered by food matrix. Urinary daidzein recovery was similar for all three foods ingested with total urinary output of 33¿34% of ingested dose. Peak genistein concentrations were attained in serum earlier following consumption of a liquid matrix rather than a solid matrix, although there was a lower total urinary recovery of genistein following ingestion of juice than that of the two other foods.
Biphasic modulation of cell proliferation by quercetin at concentrations physiologically relevant in humans
Woude, H. van der; Gliszczynska-Swiglo, A. ; Struijs, K. ; Smeets, A. ; Alink, G.M. ; Rietjens, I.M.C.M. - \ 2003
Cancer Letters 200 (2003)1. - ISSN 0304-3835 - p. 41 - 47.
estrogen-binding-sites - breast-cancer cells - in-vitro - phosphatidylinositol 3-kinase - dietary flavonoids - growth - genistein - inhibition - metabolism - phytoestrogens
Optimal in vitro conditions regarding quercetin solubility and stability were defined. Using these conditions, the effect of quercetin on proliferation of the colon carcinoma cell lines HCT-116 and HT29 and the mammary adenocarcinoma cell line MCF-7 was investigated. For the colon carcinoma cell lines, at relatively high concentrations, a significant decrease in cell proliferation was observed, providing a basis for claims on the anti-carcinogenic activity of quercetin. However, at lower concentrations, a subtle but significant stimulation of cell proliferation was observed for all cell lines tested. These results point at a dualistic influence of quercetin on cell proliferation that may affect present views on its supposed beneficial anti-proliferative effect. (C) 2003 Elsevier Ireland Ltd. All rights reserved.