Pharmacological benefits of Ellagic acid:
1. Antioxidant potential
Antioxidants are the naturally occurring substances in plants that protect the body from free radicals, which are highly reactive atoms or molecules that interfere with normal cellular functions. Free radicals can cause cellular damage to cellular components including RNA/DNA, which can potentially lead to cancer. They can also alter cholesterol in an oxidation process in the arteries. This process appears to speed up the onset of atherosclerosis. Kishore R.K. et al2 evaluated the protective role of pomegranate (Punica granatum L.) fruit extract (200μg/egg) which has shown antioxidant capacity higher than that of red wine and green tea against Adriamycin-induced oxidative stress in chick embryos.
2. Skin lightening / Anti - Ageing potential.
Pacheco - Palenica LA et al3 investigated potential protective effects of pomegranate fruit extract against UVA- and UVB-induced damage in SKU-1064 human skin fibroblast cells. Pomegranate extract, within 5 to 60 mg/L range was effective in protecting human skin fibroblasts from cell death following UV exposure. They also found that higher polyphenolic concentrations (500-10000 mg/L) were needed to achieve a significant reduction in UV-induced reactive oxygen species levels and increased intracellular antioxidant capacity (from 1.9 to 8.6 M Trolox equivalents/mL). The above study concluded that the Pomegranate extract has a © 2010 SABINSA CORPORATION Page 3 protective effect against UVA- and UVB-induced cell damage and thus has potential use in topical applications.
Pomegranate extract in Nutricosmetics (Oral Cosmetics):
The efficacy of ellagic acid in inhibiting melanogenesis was examined by Shimogaki et al5 in vitro and in vivo. Ellagic acid was found to react specifically with copper located at the active centre of the tyrosinase molecule and hence suppress skin pigmentation. In another set of experiments Shimogaki et al5 showed that Ellagic acid is comparable to Hydroquinone at 1% concentration in suppressing skin pigmentation. Also, they concluded that Ellagic acid reacts with UV induced and activated melanocytes and does not affect the normal cells. Ellagic acid was found to be better than the other well known skin-lightening agents like Kojic acid and Arbutin. The authors from Japan concluded that Ellagic acid is a safe skin-whitening agent for use in cosmetic and quasi-products.
Clinical Trial on Ellagic Acid:
Kouichi Kasai et al6 conducted a double blind, placebo – controlled clinical trial, to evaluate the protective and ameliorative effects of Ellagic acid on pigmentation in the skin after ultraviolet ray (UV) radiation. The Ellagic acid rich pomegranate extract was sponsored by SABINSA JAPAN. © 2010 SABINSA CORPORATION Page 4 39 female subjects in their 20s and 40s were considered for this study. The authors found that the Ellagic acid rich Pomegranate extract, ingested orally, has a protective effect on slight sunburn caused by UV irradiation even at very low doses (100mg/d).
Safety studies
A 90-day sub-chronic toxicity study was performed by M. Tasaki et al7 in F344 rats at dose levels of 0, 1.25, 2.5 and 5% in powdered basal diet, with actual doses of 9.4, 19.1, 39.1 g/kg b.w., respectively, in males, and 10.1, 20.1, 42.3 g/kg b.w., respectively in females. No mortality or treatment-related clinical signs were observed throughout the experimental period. The no-observed-effect level (NOEL) was estimated to be 5% for males and females.
5 Pages Write up written by Sabinsa on Pomegranat Ellagic acid extract

Punica granatum, commonly known as pomegranate, is a member of the monogeneric family, Punicaceae, and is mainly found in Iran which is considered to be its primary centre of origin. Pg and its chemical components possess various pharmacological and toxicological properties including antioxidant, anti-inflammatory (by inhibiting pro-inflammatory cytokines), anti-cancer and anti-angiogenesis activities. They also show inhibitory effects on invasion/motility, cell cycle, apoptosis, and vital enzymes such as cyclooxygenase (COX), lipooxygenase (LOX), cytochrome P450 (CYP450), phospholipase A2 (PLA2), ornithine decarboxylase (ODC), carbonic anhydrase (CA), 17 beta-hydroxysteroid dehydrogenase (17β-HSDs) and serine protease (SP). Furthermore, they can stimulate cell differentiation and possess anti-mutagenic effects. Pg can also interfere with several signaling pathways including PI3K/AKT, mTOR, PI3K, Bcl-X, Bax, Bad, MAPK, ERK1/2, P38, JNK, and caspase. However, the exact mechanisms for its pharmacological and toxicological properties remain to be unclear and need further evaluation. These properties strongly suggest a wide range use of pomegranate for clinical applications. This review will discuss the areas for which pomegranate has shown therapeutic properties in different mechanisms.
This suggests that Pg can be extensively used as a possible therapy for prevention and treatment of several types of diseases including prostate cancer, colon cancer, breast cancer, lung cancer, skin cancer, leukemia, anti-atherosclerosis, hyperlipidemia, hypertension, myocardial ischemia, myocardial perfusion, diabetes, oral inflammation, infection, anti-erectile dysfunction, male infertility, neonatal hypoxia-ischemic brain injury, alzheimer and obesity.
Keywords: Punica granatum; Chemical components; Toxicological properties; Signaling pathway; Clinical applications. [PTPOMEG40P]
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A Comprehensive Review of Punica granatum (Pomegranate) Properties inToxicological, Pharmacological, Cellular and Molecular Biology Researches - Iranian Journal of Pharmaceutical Research (2012), 11 (2): 385-400 - Hamid Reza Rahimia, Mohammad Arastoob and Seyed Nasser Ostada

Multiple strands of research provide growing evidence that diet, nutrition, and life style play a role in the development and the course of urological diseases. Numerous micronutrients and polyphenols found in soy, green tea, and many fruits and vegetables have been described to impact diseases including erectile dysfunction, benign prostatic hyperplasia, and prostate cancer. However, oftentimes these reports lack both a scientific rationale and supportive evidence base. The efficacy of pomegranate, on the other hand, in the modulation of central biological processes like inflammation, hypoxia, and oxidative stress that are important in the pathogenesis of urological maladies has been robustly demonstrated in preclinical in vitro and in vivo studies. Moreover, clinical trials have further supported its use in the treatment of several diseases, in particular in themanagement of prostate cancer. Herein, we critically review the scientific knowledge about the current role and future prospects for the use of pomegranate extracts in the therapy of erectile dysfunction, benign prostatic hyperplasia, and prostate cancer.   The biological processes of inflammation, hypoxia, and oxidative stress have a crucial function in the natural biology of men’s urological diseases including ED, BPH, and PCA. In vitro and in vivo preclinical experiments provide evidence supporting that pomegranate extracts are able to :
(i) inhibit proliferation, invasion, metastatic spread, development of castration-resistant PCA growth, and angiogenesis,
(ii) modulate inflammatory pathways, and
(iii) reduce oxidative stress. Clinical biologic activities of pomegranate have been tested in subjects with PCA and ED. Further randomized, double-blind, controlled trials are under way and will be completed soon.
Pomegranate Extracts in the Management of Men’s Urologic Health: Scientific Rationale and Preclinical and Clinical Data Kroeger N., Belldegrun A. S., and Pantuck A. J. - Evidence-Based Complementary and Alternative Medicine - Volume 2013

Prostate cancer is the second leading cause of cancer deaths in men in the United States. There is a major need for less toxic but yet effective therapies to treat prostate cancer. Pomegranate fruit from the tree Punica granatum has been used for centuries for medicinal purposes and is described as “nature’s power fruit”. Recent research has shown that pomegranate juice (PJ) and/or pomegranate extracts (PE) significantly inhibit the growth of prostate cancer cells in culture. In preclinical murine models, PJ and/or PE inhibit growth and angiogenesis of prostate tumors. More recently, we have shown that three components of PJ, luteolin, ellagic acid and punicic acid together, have similar inhibitory effects on prostate cancer growth, angiogenesis and metastasis. Results from clinical trials are also promising. PJ and/or PE significantly prolonged the prostate specific antigen (PSA) doubling time in patients with prostate cancer. In this review we discuss data on the effects of PJ and PE on prostate cancer. We also discuss the effects of specific components of the pomegranate fruit and how they have been used to study the mechanisms involved in prostate cancer progression and their potential to be used in deterring prostate cancer metastasis.
Keywords: natural products; metastasis; luteolin; ellagic acid; punicic acid
In summary, the biological activity of pomegranate-derived products, especially the chemotherapeutic and chemopreventive properties, has been investigated in cell, animal and clinical studies. The findings discussed in this review show that pomegranate and its components interfere with multiple biological processes involved in tumor growth, angiogenesis and metastasis of PCa. Because many of the molecular mechanisms are shared by different types of cancers, and the fact that PE has been shown to be effective against breast, lung, colon and skin cancer [105] further enhances the therapeutic potential of PE. Therefore, further studies are warranted, including clinical trials with appropriate control groups using well-characterized and standardized amounts of PJ, PE and specific components as primary or adjuvant therapy in men with PCa. Many of the molecular mechanisms involved in the PJ/PE or L + E + P are amenable to drug treatment and to the development of small inhibitory molecules and therefore allow for combination therapy. Therefore, pomegranate and its components can potentially be used to prevent development and progression of PCa as well as other cancers. What is not known and is of great importance is whether the power of PJ/PE or L + E + P can be used as preventive therapies.
Pomegranate and Its Components as Alternative Treatment for Prostate Cancer - Lei Wang and Manuela Martins-Green - Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, CA 92521, USA

Abstract : The consumption of pomegranate juice (PJ), a rich source of antioxidant polyphenols, has grown tremendously due to its reported health benefits. Pomegranate extracts, which incorporate the major antioxidants found in pomegranates, namely, ellagitannins, have been developed as botanical dietary supplements to provide an alternative convenient form for consuming the bioactive polyphenols found in PJ. Despite the commercial availability of pomegranate extract dietary supplements, there have been no studies evaluating their safety in human subjects. A pomegranate ellagitannin-enriched polyphenol extract (POMx) was prepared for dietary supplement use and evaluated in two pilot clinical studies. Study 1 was designed for safety assessment in 64 overweight individuals with increased waist size. The subjects consumed either one or two POMx capsules per day providing 710 mg (435 mg of gallic acid equivalents, GAEs) or 1420 mg (870 mg of GAEs) of extracts, respectively, and placebo (0 mg of GAEs). Safety laboratory determinations, including complete blood count (CBC), chemistry, and urinalysis, were made at each of three visits. Study 2 was designed for antioxidant activity assessment in 22 overweight subjects by administration of two POMx capsules per day providing 1000 mg (610 mg of GAEs) of extract versus baseline measurements. Measurement of antioxidant activity as evidenced by thiobarbituric acid reactive substances (TBARS) in plasma were measured before and after POMx supplementation. There was evidence of antioxidant activity through a significant reduction in TBARS linked with cardiovascular disease risk. There were no serious adverse events in any subject studied at either site. These studies demonstrate the safety of a pomegranate ellagitannin-enriched polyphenol dietary supplement in humans and provide evidence of antioxidant activity in humans.
Keyword : Pomegranate extract; polyphenol; POMx; ellagitannins; safety; TBARS; human; Pomegranate; Punicosides
Safety and Antioxidant Activity of a Pomegranate Ellagitannin-Enriched Polyphenol Dietary Supplement in Overweight Individuals with Increased Waist Size, David Heber, Navindra P. Seeram, Holly Wyatt, 10050 J. Agric. Food Chem. 2007, 55 10050– 10054

Cancer is the second leading cause of death and is becoming the leading one in old age. Vegetable and fruit consumption is inversely associated with cancer incidence and mortality. Currently, interest in a number of fruits high in polyphenols has been raised due to their reported chemopreventive and/or chemotherapeutic potential. Pomegranate has been shown to exert anticancer activity, which is generally attributed to its high content of polyphenols. This review provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of pomegranate polyphenols as future anticancer agents. Pomegranate evokes antiproliferative, anti-invasive, and antimetastatic effects, induces apoptosis through the modulation of Bcl-2 proteins, upregulates p21 and p27, and downregulates cyclin-cdk network. Furthermore, pomegranate blocks the activation of inflammatory pathways including, but not limited to, the NF-𝜅B pathway.The strongest evidence for its anticancer activity comes from studies on prostate cancer. Accordingly, some exploratory clinical studies investigating pomegranate found a trend of efficacy in increasing prostatespecific antigen doubling time in patients with prostate cancer. However, the genotoxicity reported for pomegranate raised certain concerns over its safety and an accurate assessment of the risk/benefit should be performed before suggesting the use of pomegranate or its polyphenols for cancer-related therapeutic purposes.
Potential Effects of Pomegranate Polyphenols in Cancer, Prevention and Therapy, Eleonora Turrini, Lorenzo Ferruzzi, and Carmela Fimognari, Oxidative Medicine and Cellular Longevity, Volume 2015, Article ID 938475, 19 pages

Abstract : We completed a multicenter study of the effects of pomegranate cold-pressed (Oil) or supercritical CO2-extracted (S) seed oil, fermented juice polyphenols (W), and pericarp polyphenols (P) on human prostate cancer cell xenograft growth in vivo, and/or proliferation, cell cycle distribution, apoptosis, gene expression, and invasion across Matrigel, in vitro. Oil, W, and P each acutely inhibited in vitro proliferation of LNCaP, PC-3, and DU 145 human cancer cell lines.
Growth of the prostate gland is governed by a complex milieu of hormonal factors signaling, in part, via a range of nuclear receptors. The receptors act as a homeostatic mechanism by sensing a diverse range of dietary, xenobiotic, and environmental factors. For example, phytoestrogens and flavonoids are able to regulate estrogen and peroxisome proliferator-activated receptors. The pomegranate fractions may target nuclear receptor- mediated gene regulation and thereby regulate cell proliferation.
The dose of P required to inhibit cell proliferation of the prostate cancer cell line LNCaP by 50% (ED50) was 70 mg/mL, whereas normal prostate epithelial cells (hPrEC) were significantly less affected (ED50 5 250 mg/mL). These effects were mediated by changes in both cell cycle distribution and induction of apoptosis. For example, the androgenindependent cell line DU 145 showed a significant increase from 11% to 22% in G2/M cells (P , .05) by treatment with Oil (35 μg/mL) with a modest induction of apoptosis. In other cell lines/treatments, the apoptotic response predominated, for example, in PC-3 cells treated with P, at least partially through a caspase 3-mediated pathway.
These cellular effects coincided with rapid changes in mRNA levels of gene targets. Thus, 4-hour treatment of DU 145 cells with Oil (35 μg/mL) resulted in significant 2.3 ± 0.001-fold (mean ± SEM) up-regulation of the cyclin-dependent kinase inhibitor p21(waf1/cip1) (P max .01) and 0.6 ± 0.14-fold down-regulation of c-myc (P max .05). In parallel, all agents potently suppressed PC-3 invasion through Matrigel, and furthermore P and S demonstrated potent inhibition of PC-3 xenograft growth in athymic mice. Overall, this study demonstrates significant antitumor activity of pomegranatederived materials against human prostate cancer.
Pomegranate Extracts Potently Suppress Proliferation, Xenograft Growth, and Invasion of Human Prostate Cancer Cells - Martin Albrecht, Wen guo Jiang, James Kumi-Diaka, Ephraim P. Lansky, Lyndon M. Gommersall, Amit Patel, Robert E. Mansel, Ishak Neeman, Albert A. Geldof, and Moray J. Campbell. Journal of Medicinal Food. September 2004

Abstract : Breast cancer is the most common cancer and the second leading cause of cancer death and morbidity among women in the western world. Pomegranate juice (PJ) and three of its specific components have been shown to inhibit processes involved in prostate cancer metastasis. If this also proves to be true for breast cancer, these natural treatments will be promising agents against breast cancer that can serve as potentially effective and nontoxic alternatives or adjuncts to the use of conventional selective estrogen receptor modulators for breast cancer prevention and treatment. To test this possibility, we have used two breast cancer cell lines, MDA-MB-231 cells (ER ) and MCF7 (ER ), and the non-neoplastic cell line MCF10A. We show that, in addition to inhibiting growth of the breast cancer cells, PJ or a combination of its components luteolin (L) + ellagic acid (E) + punicic acid (P) increase cancer cell adhesion and decrease cancer cell migration but do not affect normal cells. These treatments also inhibit chemotaxis of the cancer cells to SDF1α, a chemokine that attracts breast cancer cells to the bone. We hypothesized that PJ and L + E + P stimulate expression of genes that increase adhesion and inhibit genes that stimulate cell migration and inhibit chemotaxis to SDF1α. Using qPCR, we confirmed these proposed effects on gene expression and in addition we found that a gene important in epithelial- to- meshenchymal transitions is decreased. We also found that proinflammatory cytokines/chemokines are significantly reduced by these treatments, thereby having the potential to decrease inflammation and its impact on cancer progression. Discovery that PJ and L + E + P are inhibitory of metastatic processes in breast cancer cells in addition to prostate cancer cells indicate that they are potentially a very effective treatment to prevent cancer progression in general.
Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer Breast Cancer, Research and Treatment December 2012, Volume 136, Issue 3, pp 647–658 Ana Rocha, Lei Wang, Manuel Penichet, Manuela Martins-Green

Abstract This article aims to determine the phenolic, tocopherol contents, and antioxidant capacities from fruits (juices, peels, and seed oils) of 6 Tunisian pomegranate ecotypes. Total anthocyanins were determined by a differential pH method. Hydrolyzable tannins were determined with potassium iodate. The tocopherol (α-tocopherol, γ -tocopherol, and δ-tocopherol) contents were, respectively, 165.77, 107.38, and 27.29 mg/100 g from dry seed. Four phenolic compounds were identified and quantified in pomegranate peel and pulp using the high-performance liquid chromatography - ultraviolet method: 2 hydroxybenzoic acids (gallic and ellagic acids) and 2 hydroxycinnamic acids (caffeic and p-coumaric acids). Juice, peel, and seed oil antioxidants were confirmed by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) methods. The highest values were recorded in peels with 25.63 mmol trolox equivalent/100 g and 22.08 mmol TE/100 g for FRAP and ORAC assay, respectively.
Results showed that the antioxidant potency of pomegranate extracts was correlated with their phenolic compound content. In particular, the highest correlation was reported in peels. High correlations were also found between peel hydroxybenzoic acids and FRAP ORAC antioxidant capacities. Identified tocopherols seem to contribute in major part to the antioxidant activity of seed oil. The results implied that bioactive compounds from the peel might be potential resources for the development of antioxidant function dietary food.
Keyword antioxidant capacities, hydrolyzable tannins, Punica granatum L., tocopherols, total phenolics.
Antioxidant Capacities of Phenolic Compounds and Tocopherols from Pomegranate (Punica granatum) Fruits, 2011 Institute of Food Technologists, doi: 10.1111/ j.1750 - 3841. 2011. 02179.x, Walid Elfalleh, Nizar Tlili, Nizar Nasri, Yassine Yahia, H´edia Hannachi, Nizar Chaira, Ma Ying, and Ali Ferchichi

Abstract : Inhibition of lipid peroxidation contributes to the attenuation of macrophage cholesterol accumulation, foam-cell formation and atherosclerosis. Evidence suggests that nutritional antioxidants such as pomegranate juice (PJ) can contribute to the reduction of oxidative stress and atherogenesis. The goals of the present study were to determine whether such beneficial effects of PJ exist when supplemented to apolipoprotein E-deficient (E0) mice with advanced atherosclerosis and to analyze the antiatherosclerotic activity of a tannin-fraction isolated from PJ. Mice (4-mo-old) were supplemented with PJ in their drinking water for 2 mo and compared with age-matched placebo-treated mice, as well as to young (4-mo-old) control mice, for their mouse peritoneal macrophage (MPM) oxidative state, cholesterol flux and mice atherosclerotic lesion size. PJ supplementation reduced each of the proatherogenic variables determined in the present study compared with age-matched placebo-treated mice. It significantly induced serum paraoxonase activity and reduced MPM lipid peroxide content compared with placebo-treated mice and control mice. PJ administration to E0 mice significantly reduced the oxidized (Ox)-LDL MPM uptake by 31% and MPM cholesterol esterification and increased macrophage cholesterol efflux by 39% compared with age-matched, placebo-treated mice. PJ consumption reduced macrophage Ox-LDL uptake and cholesterol esterification to levels lower than those in 4-mo-old, unsupplemented controls. PJ supplementation to E0 mice with advanced atherosclerosis reduced the lesion size by 17% compared with placebo-treated mice. In a separate study, supplementation of young (2-mo-old) E0 mice for 2 mo with a tannin fraction isolated from PJ reduced their atherosclerotic lesion size, paralleled by reduced plasma lipid peroxidation and decreased Ox-LDL MPM uptake. PJ supplementation to mice with advanced atherosclerosis reduced their macrophage oxidative stress, their macrophage cholesterol flux and even attenuated the development of atherosclerosis. Moreover, a tannin-fraction isolated from PJ had a significant antiatherosclerotic activity.
In conclusion, PJ supplementation to E° mice possesses very impressive antiatherogenic properties, which could be related to its potent antioxidative activity and beneficial effect on macrophage cholesterol flux, which results in decreased macrophage cholesterol accumulation. The effect of PJ consumption on atherosclerosis was shown not only when supplementation of PJ to E° mice started before they developed atherosclerotic lesions, but also in mice with extensive atherosclerosis. The above antiatherosclerotic properties of PJ could be related to the presence of a tannin fraction in PJ with potent antioxidative characteristics.
Pomegranate Juice Supplementation to Atherosclerotic Mice Reduces Macrophage Lipid Peroxidation, Cellular Cholesterol Accumulation and Development of Atherosclerosis, 2001 American Society for Nutritional Sciences, J. Nutr. 131: 2082–2089, 2001

Atherosclerosis is enhanced in arterial segments exposed to disturbed flow. Perturbed shear stress increases the expression of oxidation-sensitive responsive genes (such as ELK-1 and p-JUN) in the endothelium. Evidence suggests that polyphenolic antioxidants contained in the juice derived from the pomegranate can contribute to the reduction of oxidative stress and atherogenesis.
The aim of the present study was to evaluate the effects of intervention with pomegranate juice (PJ) on oxidation-sensitive genes and endothelial NO synthase (eNOS) expression induced by high shear stress in vitro and in vivo. Cultured human coronary artery endothelial cells (EC) exposed to high shear stress in vitro and hypercholesterolemic mice were used in this study. PJ concentrate reduced the activation of redox-sensitive genes (ELK-1 and p-JUN) and increased eNOS expression (which was decreased by perturbed shear stress) in cultured EC and in atherosclerosis-prone areas of hypercholesterolemic mice. Moreover, oral administration of PJ to hypercholesterolemic mice at various stages of disease reduced significantly the progression of atherosclerosis. This experimental study indicates that the proatherogenic effects induced by perturbed shear stress can be reversed by chronic administration of PJ. This approach may have implications for the preventionor treatment of atherosclerosis and its clinical manifestations.
Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress, 4896–490, PNAS March 29, 2005 vol. 102 no. 13 Filomena de Nigris, Sharon Williams-Ignarro, Lilach O. Lerman, Ettore Crimi, Chiara Botti

Abstract : Current investigation focuses on the toxicity evaluation of whole fruit hydroalcoholic extract of Punica granatum L. Punicaceae), used in Cuban traditional medicine a.o. for the treatment of respiratory diseases. Previous findings on the anti-influenza activity of Punica granatum extracts has given support to the ethnopharmacological application. In our study, in chick embryo model, it was found that doses of the extract of less than 0.1 mg per embryo are not toxic. The LD50 of the extract, determined in OF-1 mice of both sexes after intraperitoneal administration, was 731 mg/kg. Confidence limits were 565–945 mg/kg. At the doses of 0.4 and 1.2 mg/kg of extract, the repeated intranasal administration toWistar rats produced no toxic effects in terms of food intake, weight gain, behavioural or biochemical parameters, or results of histopathological studies. We conclude that toxic effects of Punica granatum fruit extract occurred at higher doses than those effective in the models where the anti-viral activity has been studied or than those doses used in Cuban folk medicine.
Conclusion : The investigations described here were intended to reveal possible toxic effects of Punica granatum extracts in view of their anti-influenza activity. It was shown that toxic effects of Punica granatum fruit extract occurred at higher doses than those effective in the models where its anti-viral activity has been studied or those used in Cuban traditional medicine. Studies of this kind are always needed before a phytotherapeutic agent can be generally introduced (Lapa et al., 1999). Having regard to the high doses and lengthy treatment times used in the dose repeated toxicity study, it would seem that hydroalcoholic extracts of Punica granatum fruit are innocuous when directly administered via the nasal cavity.
Studies on the toxicity of Punica granatum L. (Punicaceae) whole fruit extracts, Journal of Ethnopharmacology 89 (2003) 295– 300, Alexis Vidal, Adyary Fallarero, Blanca R. Pena, Maria E. Medina, Bienvenido Gra, Felicia Rivera, Yamilet Gutierrez, Pia M. Vuorela

Abstract : Pomegranate (Punica granatum L.) fruit is widely consumed as fresh fruit and juice. Because of its potential for health benefits, pomegranate fruit extracts have been commonly marketed as dietary supplements in recent years. The objective of the present study was to investigate potential adverse effects, if any, of a standardized pomegranate fruit extract in rats following subchronic administration. The extract was standardized to 30% punicalagins, the active anomeric ellagitannins responsible for over 50% of the antioxidant potential of the juice. The oral LD50 of the extract in rats and mice was found to be greater than 5 g/kg body weight. The intraperitoneal LD50 in rats and mice was determined as 217 and 187 mg/kg body weight, respectively. In the subchronic study, Wistar strain rats (10/sex/group) were administered via gavage 0 (control), 60, 240 and 600 mg/kg body weight/day of the extract for 90 days. Two additional groups received 0 and 600 mg/kg/day of the extract for 90 days, followed by a 28 day recovery phase. Compared to the control group, administration of the extract did not result in any toxicologically significant treatment-related changes in clinical observations, ophthalmic examinations, body weights, body weight gains, feed consumption, clinical pathology evaluations and organ weights. The hematology and serum chemistry parameters that showed statistical significant changes compared to control group were within the normal laboratory limits and were considered as biological variations and not the toxic effect of the extract. Terminal necropsy did not reveal any treatment-related gross or histopathology findings. Based on the results of this study, the no observed-adverse-effect level (NOAEL) for this standardized pomegranate fruit extract was determined as 600 mg/kg body weight/day, the highest dose tested.
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Safety assessment of pomegranate fruit extract: Acute and subchronic toxicity studies - by Chintan Patel, Paresh Dadhaniya, Lal Hingorani, M.G. Soni, Food and Chemical Toxicology 46 (2008) 2728– 2735

Several mechanistic studies in cell culture and mouse models suggest possible estrogen receptor-mediated and non-estrogen receptor-mediated benefits of pomegranate juice with respect to breast cancer risk. These studies demonstrate that various constituents of pomegranates can inhibit aromatase and 17β-hydroxysteroid dehydrogenase enzymes or have antiestrogenic activity. Additional large, well-controlled human studies are warranted to elucidate the effects of pomegranate juice intake on serum hormone levels. Clarifying the effects of pomegranate constituents on key hormones known to be involved in breast cancer could result in important information for consumers and shed further light on the impact of diet on breast cancer risk
Pomegranate and breast cancer: possible mechanisms of prevention - Susan R Sturgeon, Alayne G Ronnenberg