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PubMed1985

Effect of ellagic acid and hydroxylated flavonoids on the tumorigenicity of benzo[a]pyrene and (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on mouse skin and in the newborn mouse.

Ellagic acid, quercetin and robinetin were tested for their ability to antagonize the tumor-initiating activity of benzo[a]pyrene (B[a]P) and (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), the ultimate carcinogenic metabolite of benzo[a]-pyrene. Ellagic acid, robinetin or quercetin (2500 nmol) had no tumor-initiating activity on mouse skin, but the topical application of 2500 nmol of ellagic acid 5 min before a tumor-initiating dose of 200 nmol of B[a]P 7,8-diol-9,10-epoxide-2 caused a 59-66% inhibition in the number of skin tumors per mouse that were observed after 15-20 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Similar treatment with 2500 nmol of robinetin or quercetin caused a statistically insignificant 16-24% inhibition in the tumor-initiating activity of 200 nmol of B[a]P 7,8-diol-9,10-epoxide-2 applied 5 min later. Treatment of mice with 2500 nmol of ellagic acid 5 min before the application of 50 nmol of B[a]P inhibited the mean number of skin tumors per mouse by 28-33% after 15-20 weeks of promotion, but these decreases were not statistically significant. Robinetin and quercetin had little or no effect on the tumor-initiating activity of B[a]P on mouse skin. Treatment of preweanling mice with 1/7, 2/7 and 4/7 of the total dose of ellagic acid (300 nmol), robinetin (1400 nmol), myricetin (1400 nmol) or quercetin (1400 nmol) i.p. on their first, eighth and fifteenth day of life, respectively, did not cause the formation of tumors in animals that were killed 9-11 months later. Similar treatment of preweanling mice with the above doses of the phenolic compounds 10 min before the i.p. injection of a total dose of 30 nmol of B[a]P 7,8-diol-9,10-epoxide-2 during the animal's first 15 days of life caused a 44-75% inhibition in the number of diol-epoxide-induced pulmonary tumors per mouse. Similar treatment with these plant phenols had little or no effect on B[a]P-induced pulmonary tumors.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Studies on the vascular and hematological changes induced by ellagic acid in rats.

We compared the major changes induced by ellagic acid (EA), a Hageman factor activator, in normal rats and in kininogen-deficient Brown Norway rats. In normal rats, large doses of EA induced a congestion of lymph nodes, spleen and liver, a prolongation of activated partial thromboplastin time, the consumption of prekallikrein, high molecular weight kininogen and fibrinogen, as well as the stimulation of platelets with their accumulation in lungs, liver and spleen. A systemic hypotension of long duration was also observed. The fibrinogen consumption, the thrombocytopenia and the lengthening of activated partial thromboplastin time were dose-dependent. In kininogen-deficient rats, EA induced only a minimal congestion of lymphoid tissues, the accumulation of platelets in lungs, a decrease of plasma fibrinogen and a short-lasting hypotension. It is concluded that the vascular changes induced by blood coagulation with ellagic acid resulted mainly from kinin formation.

Animals↗
PubMed2001

Ellagic acid inhibited 2-aminofluorene and p-aminobenzoic acid acetylation by mononuclear leucocytes from Sprague-Dawley rats.

Following exposure of rats to the arylamine carcinogen 2-aminofluorene, DNA-carcinogen adducts were found in the liver and bladder target tissues, and also in circulating leucocytes. This work investigated the effect of ellagic acid on arylamine (2-aminofluorene and p-aminobenzoic acid) acetylations in rat leucocytes. Evidence is presented that rat mononuclear leucocytes are capable of acetylating 2-aminofluorene and p-aminobenzoic acid. Both lymphocytes and monocytes were able to acetylate arylamines during 18 h of culture. Cultured lymphocytes produced about twice as much N-acetyl-2-aminofluorene from 2-aminofluorene and 2.2-fold as much N-acetyl-p-aminobenzoic acid from p-aminobenzoic acid as monocytes. After cotreatment with ellagic acid the lymphocyte and monocyte cultures indicated that ellagic acid reduced 2-aminofluorene acetylation.

4-Aminobenzoic Acid↗
PubMed2006

The flavonoid ellagic acid from a medicinal herb inhibits host immune tolerance induced by the hepatitis B virus-e antigen.

The aim of this study is to characterize the role of ellagic acid, a flavonoid from a medicinal herb which blocks HBeAg secretion in a HBV infected cell line and in HBeAg transgenic mice, in immune tolerance in chronic HBV infection. Using the mouse strain C57ML/6, HBeAg-producing transgenic mice (HBeAg-Tg), under the control of metal ion-inducible promoter were generated. The effect on immune tolerance of HBeAg-Tg and the release of immune tolerance by the inhibitor of HBeAg secretion, ellagic acid, was tested using T/B cell proliferation, HBeAg/HBeAb production, cytotoxic T-lymphocyte (CTL) and cytokine assays. C57ML/6 based HBeAg-producing HBeAg-Tg mice were tolerant to HBeAg at the T and B-cell level, did not produce antibodies to HBeAg in vivo and in vitro, produced minimal levels of cytokines (IL-4 and IFN-gamma) and decreased CTL responses, while feeding mice with ellagic acid (5mg/kg body weight) blocked the immune tolerance caused by HBeAg. Our results suggest that host immune tolerance induced by HBeAg during HBV infection, a viral strategy to guarantee HBV infection, can be overcome by ellagic acid, thus it can be used as a therapeutic for HBV-carriers.

Animals↗
PubMed2005

Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells.

Anticarcinogenic effects of polyphenolic compounds in fruits and vegetables are well established. Although polyphenols naturally occur as combinations, little information is available regarding possible synergistic or antagonistic biochemical interactions between compounds. Identifying potential interactions between polyphenols may provide information regarding the efficiency of polyphenol-containing foods in cancer prevention. The objective of this study was to investigate the interactions of ellagic acid and quercetin with resveratrol, polyphenols which occur in muscadine grapes, with the hypothesis that the selected polyphenols would interact synergistically in the induction of apoptosis and reduction of cell growth in human leukemia cells (MOLT-4). To test this hypothesis, alterations in cell cycle kinetics, proliferation, and apoptosis (caspase-3 activity) were examined after incubation with ellagic acid, quercetin, and resveratrol as single compounds and in combination. Results showed a more than additive interaction for the combination of ellagic acid with resveratrol and furthermore, significant alterations in cell cycle kinetics induced by single compounds and combinations were observed. An isobolographic analysis was performed to assess the apparent synergistic interaction for the combinations of ellagic acid with resveratrol and quercetin with resveratrol in the induction of caspase 3 activity, confirming a synergistic interaction with a combination index of 0.64 for the combination of ellagic acid and resveratrol and 0.68 for quercetin and resveratrol. Results indicate that the anticarcinogenic potential of foods containing polyphenols may not be based on the effects of individual compounds, but may involve a synergistic enhancement of the anticancer effects.

Anticarcinogenic Agents↗
PubMed1986

Inhibition of 3-methylcholanthrene-induced skin tumorigenicity in BALB/c mice by chronic oral feeding of trace amounts of ellagic acid in drinking water.

Chronic p.o. feeding of small amounts of ellagic acid, a naturally occurring dietary plant phenol, to BALB/c mice in drinking water afforded significant protection against skin tumorigenesis induced by 3-methylcholanthrene, a polycyclic aromatic hydrocarbon carcinogen. A significant increase in the latent period for the development of skin tumors by 3-methylcholanthrene was observed in the ellagic acid-fed group of mice (9 wk on test) as compared to the control group of animals (6 wk on test). The observed protection against tumor induction in the ellagic acid-fed group of animals may be due to the inhibition of the metabolic activation of the polycyclic aromatic hydrocarbon since epidermal aryl hydrocarbon hydroxylase activity was found to be significantly inhibited. Our results suggest that dietary supplementation with small amounts of ellagic acid may prove useful in reducing the risk of skin carcinogenesis induced by environmental chemicals.

7-Alkoxycoumarin O-Dealkylase↗
PubMed2002

Ellagic acid and ellagitannins affect on sedimentation in muscadine juice and wine.

A mechanism for the formation of water-insoluble sediments in wines and juices made from red and white muscadine grapes (Vitis rotundifolia) was investigated as a function of processing methodology and storage. Sediments are considered quality defects in muscadine grape products, and their presence may influence consumer acceptability and expansion of retail markets. Processing regimes included both hot (70 degrees C) and cold (25 degrees C) press techniques for wine or juice production, and fermentations in contact with grape skins for 3, 5, and 7 days. Relationships between free ellagic acid (FE), total ellagitannins (ET), and total ellagic acid (TE) concentrations were evaluated initially in each product and in sediments that formed during storage for 50 and 120 days at 20 degrees C. Processing techniques influenced initial concentrations of these compounds and the extent of sediment formation. Following storage, juices generally had higher concentrations of FE in sediments compared to wines, but sedimentation was independent of initial FE or TE concentrations. Decreases in ET were observed for hot-pressed juice and skin-fermented wines after storage indicating their hydrolysis during storage and possible contribution to FE in sediments. However, quantitative analysis of the collected sediments revealed that no more than 12% FE by weight was actually present in the sediments, with the remainder consisting of either unidentified compounds or conjugated forms of ellagic acid. This work elucidated a potential mechanism for the presence of FE in muscadine wine and juice sediments through ellagitannin hydrolysis and suggests that sedimentation from mechanisms other than ellagic acid precipitation may also contribute to wine and juice quality.

Beverages↗
PubMed2006

Modulation by ellagic acid of DCA-induced developmental toxicity in the zebrafish (Danio rerio).

The ability of ellagic acid (EA) to modulate dichloroacetic acid (DCA)-induced developmental toxicity and oxidative damage was examined in zebrafish embryos. Embryos were exposed to 20 mM EA administered concomitantly with 32 mM DCA at 4 hours postfertilization (hpf) and 20 h later. Embryos were observed through 144 hpf for developmental malformations, and production of superoxide anion (SA) and nitric oxide (NO) was determined in embryonic homogenates. DCA was shown to produce developmental abnormalities and significant levels of SA and NO in zebrafish embryos. EA exposure alleviated the developmental malformations observed in treated embryos and decreased the levels of SA and NO in those same embryos. Less than 10% of DCA + EA exposed embryos showed developmental malformations compared to 100% of embryos treated with DCA alone. Animals in this group that developed malformations were shown to have fewer defects than those treated with DCA only. Taken together, the results confirm the involvement of oxidative stress in the developmental toxicity of DCA in zebrafish embryos, and suggest possible protection against those effects with the use of antioxidants.

Animals↗
PubMedDate not supplied

Effects of ellagic acid by oral administration on distribution and metabolism of 2-aminofluorene in Sprague-Dawley rats.

The effects of ellagic acid on the in vivo N-acetylation and metabolism of 2-aminofluorene (2-AF) were investigated in bladder, blood, colon, kidney, liver, feces and urine samples from male Sprague-Dawley rats. Major metabolites such as 1-OH-2-AAF, 8-OH-2-AAF and 9-OH-2-AAF were found in bladder tissues, 1-OH-2-AAF, 5-OH-2-AAF and 8-OH-2-AAF were found in blood samples, 1-OH-2-AAF, 3-OH-2-AAF, 5-OH-2-AAF, 8-OH-2-AAF and 9-OH-2-AAF were found in colon tissues, 1-OH-2-AAF, 3-OH-2-AAF and 9-OH-2-AAF were found in kidney tissues, 1-OH-2-AAF, 3-OH-2-AAF and 8-OH-2-AAF were found in liver tissues, 1-OH-2-AAF, 3-OH-2-AAF, 5-OH-2-AAF and 8-OH-2-AAF were found in feces samples and 1-OH-2-AAF, 3-OH-2-AAF, 5-OH-2-AAF and 8-OH-2-AAF were also found in urine samples after rats had been orally treated with 2-AF (50 mg/kg) for 24 h. Pretreatment of male rats with ellagic acid (10 mg/kg) 24 h prior to the administration of 2-AF (50 mg/kg) resulted in absence of 8-OH-2-AAF in bladder tissues, and there were significant decreases of 8-OH-2-AAF in blood and urine samples. In blood samples, amounts of 2-AAF and 8-OH-2-AAF were significantly decreased; in colon tissues, amounts of 2-AF, 1-OH-2-AAF and 3-OH-2-AAF, in liver tissues, amounts of 2-AAF, 1-OH-2-AAF and 3-OH-2-AAF, and in urine samples, amounts of 2-AF and 8-OH-2-AAF were significantly decreased in 24-h ellagic acid (EA)-treated rats before 2-AF was added to the diet. However, significantly increased 1-OH-2-AAF concentrations were found in urine samples in 24-h EA-treated rats before 2-AF was administered. In the EA and 2-AF rats, in the same time treated groups, bladder, colon and liver tissues, and feces and urine samples showed significant differences when compared to the ones without EA co-treatment. We saw significant decreases of the amounts of 2-AF and 1-OH-2-AAF in colon tissues. The feces samples showed increased amounts of 2-AAF in EA- and in 2-AF- treated rats in the same time groups, but urine samples showed a decreased amount of 8-OH-2-AAF in both EA-treated groups. The total amounts of 2-AF metabolites in bladder, blood, kidney and liver tissues showed significant difference between control and the group which was EA-treated 24 h before 2-AF was added. The total amounts of 2-AF metabolites in the liver, feces and urine showed significant decreases between control and EA-treated at the same time with 2-AF groups. This is the first report of EA affecting the N-acetylation and metabolism of 2-AF in rat tissues in vivo.

2-Acetylaminofluorene↗
PubMedDate not supplied

Reaction between ellagic acid and an ultimate carcinogen.

The reaction coordinate between a typical ultimate carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) and ellagic acid, a proven chemopreventive agent active against cancers caused by polycyclic aromatic hydrocarbons (PAHs), was examined by density functional theory (DFT) and semiempirical MO calculations, and activation energy was calculated. The effect of a polar environment was included using Tomasi and the Langevin dipoles methods. The calculated BPDE/ellagic acid reaction free energy of activation is found to be in decent agreement with experimental data [Sayer, J. M. et al. J. Am. Chem. Soc. 1982, 104, 5562-5564]. This work sheds light on the mechanism of action of ellagic acid. Quantum chemical calculations of this kind are valuable for the design of ellagic acid derivatives with even lower activation energy and increased reactivity toward ultimate carcinogens as well as controlled reactivity toward DNA.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2003

In vitro studies on the mechanism of action of two compounds with antiplasmodial activity: ellagic acid and 3,4,5-trimethoxyphenyl(6'-O-aalloyl)-beta-D-glucopyranoside.

To investigate the mechanism of action of two antiplasmodial compounds, ellagic acid and 3,4,5-trimethoxyphenyl (6'-O-galloyl)-beta-D-glucopyranoside (TMPGG), we studied in vitro two metabolic reactions of intraerythrocytic parasites: the activity of recombinant plasmepsin II, one of the haemoglobin proteases, and the detoxification of haematin into beta-haematin. Both compounds inhibited plasmepsin II activity, but at concentrations ten-fold higher than those needed for inhibiting parasite growth. Moreover, ellagic acid inhibited the formation of beta-haematin, with an IC50 only 3-fold higher than that of chloroquine. These data suggest that the antiplasmodial activity of ellagic acid could be related to the inhibition of beta-haematin formation, whereas plasmepsin II does not represent the main target of the two compounds.

Animals↗
PubMed2005

The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1.

Ellagic acid (EA), a polyphenol present in berries, has been demonstrated to be preventive of esophageal and colon cancer in animals. Here, we have studied the ability of organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs) to transport EA. The accumulation of radiolabeled (14)C]EA, [(3)H]p-aminohippuric acid (PAH), [(14)C]glutarate, [(3)H]estrone sulfate, [(3)H]ochratoxin A, and [(3)H]taurocholic acid +/- inhibitor(s) was tested in OAT- and OATP-expressing oocytes. Oocytes expressing human (h)OAT1, rat (r)Oat1, and hOAT4 accumulated 6.5-, 7.1-, and 8.9-fold more EA, respectively, than did water-injected oocytes. This accumulation was prevented by the prototype OAT inhibitors bromosulfophthalein and probenecid. rOatp1, mouse (m)Oat2, hOAT3, and mOat5 showed no EA transport. The uptake of the prototype OAT substrate PAH in hOAT1-expressing oocytes was dose dependently and potently inhibited by EA with an IC(50)of 207 nM. In conclusion, we have demonstrated that the OAT family members hOAT1, rOat1, and hOAT4 mediate transport of EA, with a very high affinity for hOAT1.

Animals↗
PubMed2003

Intestinal epithelial cell accumulation of the cancer preventive polyphenol ellagic acid--extensive binding to protein and DNA.

Ellagic acid (EA), a polyphenol present in many berries, has been demonstrated to be preventive of esophageal cancer in animals both at the initiation and promotion stages. To be able to extrapolate these findings to humans we have studied the transcellular absorption and epithelial cell accumulation of [14C]EA in the human intestinal Caco-2 cells. The apical (mucosal) to basolateral (serosal) transcellular transport of 10 microM [14C]EA was minimal with a P(app) of only 0.13 x 10(-6)cm/s, which is less than for the paracellular transport marker mannitol. In spite of observations of basolateral to apical efflux, Caco-2 cell uptake studies showed high accumulation of EA in the cells (1054+/-136 pmol/mg protein), indicating facile absorptive transport across the apical membrane. Surprisingly, as much as 93% of the cellular EA was irreversibly bound to macromolecules (982+/-151 pmol/mg protein). To confirm the irreversible nature of the binding to protein, Caco-2 cells treated with 10 microM [14C]EA were subjected to SDS-PAGE analysis. This resulted in radiolabeled protein bands trapped in the stacking gel, consistent with [14C]EA-crosslinked proteins. Treatment of Caco-2 cells with 10 microM [14C]EA also revealed irreversible binding of EA to cellular DNA as much as five times higher than for protein (5020+/-773 pmol/mg DNA). Whereas the irreversible binding to protein required oxidation of EA by reactive oxygen species, this did not seem to be the case with the DNA binding. The avid irreversible binding to cellular DNA and protein may be the reason for its highly limited transcellular absorption. Thus, EA appears to accumulate selectively in the epithelial cells of the aerodigestive tract, where its cancer preventive actions may be displayed.

Biological Transport↗
PubMed1975

Failure of ellagic acid to affect platelet aggregation in normal and in factor XII deficient plasma.

Ellagic acid solutions, regardless of the concentration, failed to alter platelet aggregation induced by ADP, Adrenalin, Collagen, Thrombofax and Ristocetin in normal and in factor XII deficient plasma. A moderate inhibition was noted after addition of ADP both in normal and in factor XII deficient plasma but this was present also in the control systems and was therefore due to the buffer-dextrose solution and not to ellagic acid. These data indicate that Hageman factor plays on role in platelet aggregation.

Adenosine Diphosphate↗
PubMedDate not supplied

Ellagic acid induced p53/p21 expression, G1 arrest and apoptosis in human bladder cancer T24 cells.

It is well known that dietary phenolic compounds can elicit vital cellular responses such as cytotoxicity, cell cycle arrest and apoptosis by activating a cascade of molecular events. Ellagic acid is one of these phenolic compounds, but the exact mechanism of its action is still unclear. The objective of this study was to investigate ellagic acid-induced cell cycle arrest and apoptosis in T24 human bladder cancer cells in vitro. Assays were performed to determine cell viability, cell cycle arrest, apoptosis, caspases-3 activity and gene expression, measured by flow cytometric assay, polymerase chain reaction (PCR) and determination of caspase-3 activity. Ellagic acid significantly reduced the viable cells, induced G0/G1-phase arrest of the cell cycle and apoptosis. Ellagic acid also increased p53 and p21 and decreased CDK2 gene expression, that may lead to the G0/G1 arrest of T24 cells. Ellagic acid also promoted caspase-3 activity after exposure for 1, 3, 6, 12 and 24 h, which led to induction of apoptosis. Furthermore, the ellagic acid-induced apoptosis on T24 cells was blocked by the broad-spectrum caspase inhibitor (z-VAD-fmk).

Aged↗
PubMed2006

The inhibition of human glutathione S-transferases activity by plant polyphenolic compounds ellagic acid and curcumin.

Glutathione S-transferases (GSTs) are multifunctional detoxification proteins that protect the cell from electrophilic compounds. Overexpression of GSTs in cancer results in resistance to chemotherapeutic agents and inhibition of the over expressed GST has been suggested as an approach to combat GST-induced resistance. The inhibition of human recombinant GSTs by natural plant products was investigated in this study. Using 1-chloro-2,4 dinitrobenzene (CDNB) as a substrate, ellagic acid and curcumin were shown to inhibit GSTs A1-1, A2-2, M1-1, M2-2 and P1-1 with IC(50) values ranging from 0.04 to 5 microM whilst genistein, kaempferol and quercetin inhibited GSTs M1-1 and M2-2 only. The predominant mode of inhibition with respect to the G and H-sites were mixed inhibition and uncompetitive to a lesser extent. The K(i) (K(i)(')) values for ellagic acid and curcumin with respect to GSH and CDNB were in the range 0.04-6 microM showing the inhibitory potency of these polyphenolic compounds. Ellagic acid and curcumin also showed time- and concentration-dependent inactivation of GSTs M1-1, M2-2 and P1-1 with curcumin being a more potent inactivator than ellagic acid. These results facilitate the understanding of the interaction of human GSTs with plant polyphenolic compounds with regards to their role as chemomodulators in cases of GST-overexpression in malignancies.

Curcumin↗