Pomegranate Supplements

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The pomegranate tree, Punica granatum, and especially its fruit, has a vast history of uses for the treatment of medical and health related issues. For the purposes of this discussion the pomegranate is the fruit of the Punica granatum tree which is a long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer disease, arthritis, and obesity.

Medically beneficial compounds can be derived from the seed, juice, peel, leaf, flower, bark, and roots of the pomegranate. Each of these anatomical compartments of the plant has interesting pharmacologic activity. For example the juice and peels possess potent antioxidant properties, while juice, peel and oil are all weakly estrogenic and have potential use for the treatment of the symptoms of menopausal. The use of juice, peel and oil have also been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle progression, tumor cell invasion and angiogenesis. These latter activities may be associated with plant based anti-inflammatory effects that are due to the potent antioxidant compounds present in the plant. The broad scope and power of the pomegranate has been expanded recently with the discovery that the rind of the pomegranate contains antimicrobial activity that may be effective in the treatment of common hospital bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA).

The fruit of the pomegranate contains hundreds of phytochemicals, however, the antioxidant property of the fruit is thought to be due primarily to the action of ellagic acid (the main polyphenol in pomegranate) derived from ellagitannins. When pomegranates are consumed the ellagitannins are hydrolyzed, releasing ellagic acid, which is then converted to 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one derivatives (called urolithin A and urolithin B) by gut microflora. Pomegranates also contain hydrolyzable tannins in the form of punicalagins and punicalin as well as tannin-based complex oligomers that account for much of the antioxidant activity in juice.

structure of ellagic acid

Structure of Ellagic Acid

Pomegranate juice contains anthocyanins, glucose, ascorbic acid, ellagic acid, gallic acid, caffeic acid, catechin, epigallocatechin gallate (EGCG), quercetin, rutin, numerous minerals, particularly iron, and amino acids.

Pomegranate seed oil is nearly 100% punicic acid (also called trichosanic acid) with small amounts of ellagic acid, sterols, and other fatty acids. Punicic acid is an 18 carbon polyunsaturated fatty acid (PUFA) that is classified as a conjugated linolenic acid. Punicic acid contains three carbon-carbon double bonds, two that exist in the cis orientation and one in the trans orientation. Because punicic acid is a PUFA it is often erroneously classified using the omega fatty acid nomenclature and as such is often identified as an omega-5 PUFA. However, the correct use of the omega PUFA nomenclature can only be applied to PUFA whose carbon-carbon double bonds are all in the cis orientation. Despite the confusion regarding its naming, punicic acid has been shown to have potent anti-oxidant activities and to prevent obesity in laboratory animals.

structure of punicic acid

Structure of Punicic Acid

The peel and rind of the pomegranate contains phenolic punicalagins, gallic acid and other fatty acids, catechin, EGCG, quercetin, rutin, and other flavonols, flavones, flavonones, and anthocyanidins. Many of these polyphenolic antioxidant compounds are discussed in the Antioxidants page.

The health benefits associated with pomegranate juice have led to the development of pomegranate extracts as botanical dietary supplements. The content of ellagic acid has been used to standardize most pomegranate extract dietary supplements that are currently on the market. However, supplements can be adulterated with ellagic acid from less expensive plant sources which undermines this method of standardization. A recent comparisons was made of the phytochemical contents and antioxidant activities of 27 different commercially available pomegranate extract supplements beyond their content of ellagic acid. These supplements included capsules, tablets, and soft gels. Total phenolics were measured using both gallic acid equivalent (GAE) and ellagic acid equivalent (EAE) assays. Punicalagins, punicalin, and ellagic acid contents were determined and antioxidant capacity was measured using the Trolox equivalent antioxidant capacity (TEAC) assay. Only 5 of the tested supplements had the typical pomegranate tannin profile, 17 had ellagic acid as the predominant chemical with minor or no detectable pomegranate tannins, and 5 had no detectable tannins or ellagic acid. These results show that standardization of pomegranate extract supplements based on their ellagic acid content does not guarantee that the supplement is indeed authentic pomegranate extract. This testing demonstrates that more research is needed to assess the health impact of substituting ellagic acid for the complex mix of phytochemicals in a pomegranate extract dietary supplement.

Pomegranate extracts have been used as anticancer agents and they contain a large number of potentially bioactive substances. Punicic acid is an omega-5 long chain polyunsaturated fatty acid found in pomegranate seed oil. A number of long chain fatty acids have been reported to have cancer preventive actions. The ability of punicic acid to affect the growth of both an estrogen insensitive breast cancer cell line (MDA-MB-231) and an estrogen sensitive cell line (MDA-ERalpha7) has been examined. Treatment of these cells lines with 40 micromolar (μM) punicic acid inhibited proliferation up to 96% compared to untreated cells. In addition, punicic acid induced apoptosis in both cell lines and disrupted the mitochondrial membrane potential. To ascertain whether or not lipid oxidation was required for the function of punicic acid, the antioxidant tocotrienol was added to the assays. This addition resulted in a reversal of the effects of punicic acid on proliferation inhibition, apoptosis and disruption of the mitochondrial membrane potential. The results of these studies suggest that punicic acid has breast cancer inhibitor properties that are dependent on lipid peroxidation.

Estrogen stimulates the proliferation of breast cancer cells and the growth of estrogen-responsive tumors. The aromatase enzyme, which converts androgen to estrogen (see The Medical Biochemistry Page for information on steroid hormone synthesis), plays a key role in breast carcinogenesis. Pomegranate-derived ellagitannins have been investigated for their antiaromatase activity and inhibition of testosterone-induced breast cancer cell proliferation. A panel of 10 ellagitannin-derived compounds including ellagic acid, gallagic acid, and urolithins A and B (and their acetylated, methylated, and sulfated analogues) were examined for their ability to inhibit aromatase activity and testosterone-induced breast cancer cell proliferation. Using a microsomal aromatase assay 6 of the ellagitannin-derived compounds exhibited antiaromatase activity. Urolithin B was shown to be the most effective at inhibiting aromatase activity in a live cell assay. Proliferation assays also determined that urolithin B significantly inhibited testosterone-induced breast cancer cell proliferation. The rest of the tested compounds also exhibited antiproliferative activity, but to a lesser degree than urolithin B. Results from studies such as these suggest that pomegranate ellagitannin-derived compounds have potential for the prevention of estrogen-responsive breast cancers.

Recent data suggest that pomegranate-derived ellagitannins may have beneficial effects against colon cancer. Although similar compounds are found in other fruits and nuts, such as strawberries, the levels of ellagitannins are highest in pomegranates. As indicated above ellagitannins are hydrolyzed in the gut releasing ellagic acid which is then converted by gut bacteria to the urolithins (there are two primary urolithins termed urolithin A and urolithin B). The urolithins may persist in the colon through the action of the enterohepatic circulation. Currently little is known about the mechanisms of action of either the native ellagitannins or their metabolites on colon carcinogenesis. Components of Wnt signaling pathways are known to play a pivotal role in human colon carcinogenesis, and inappropriate activation of the signaling cascade is observed in 90% of colorectal cancers. In a recent study the effects of urolithin A, ellagic acid, and ellagitannin-rich fruit extracts on Wnt signaling in a human colon cancer cell line (293T) were examined. The ellagitannin extracts, ellagic acid, and urolithin A each inhibited Wnt signaling, suggesting that ellagitannin-rich foods, such as pomegranates, have potential against colon carcinogenesis and that urolithins are relevant bioactive constituents in the colon.

Pomegranates and pomegranate extracts are also likely to have beneficial properties related to cardiovascular health. Several studies have shown that polyphenols reduce cardiovascular insults in high-risk patients; in particular, the inhibition of platelet function may be responsible for part of this benefit. Studies have been undertaken to examine the antiplatelet effects of pomegranate products containing primarily hydrolyzed tannins such as ellagitannins. Analysis of the effects of either pomegranate juice or the polyphenol-rich extract from pomegranate fruit on platelet aggregation, calcium mobilization, thromboxane A2 (TXA2) production, and hydrogen peroxide formation, induced by collagen and arachidonic acid indicated a reduction in all platelet responses studied. These results indicate that the cardiovascular health benefits of pomegranate may in part be related to the ability of polyphenols to inhibit platelet function. In fact, pomegranate juice and pomegranate extracts have similar effects at concentrations expected following normal consumption.

Extracts from the peel of the pomegranate have demonstrated antifungal activity as well. Fractionation of crude hydroalcoholic extracts prepared from the fruit peel yields a compound (identified as punicalagin) with strong antifungal activity against Candida albicans. Of clinical significance is that the combination of punicalagin and fluconazole (Diflucan® used to treat fungal infections, including yeast infections of the vagina, mouth, throat, esophagus, abdomen, lungs, blood, and other organs and also used to treat meningitis) showed a synergistic interaction. Although these activities of punicalagin were demonstrated on the fungus in vitro, the concentrations used are achievable in vivo as well. The combination of punicalagin with fluconazole thus, represents an potentially useful treatment for the management of candidiasis.

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Supporting Research

Lansky EP, and Newman RA 2007. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J. Ethnopharmacol. 109(2):177-206.

Jurenka JS 2008. Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern. Med. Rev. 13(2):128-144.

Bell C, and Hawthorne S 2008. Ellagic acid, pomegranate and prostate cancer -- a mini review. J. Pharm. Pharmacol. 60(2):139-144.

Endo EH, Garcia Cortez DA, Ueda-Nakamura T, Nakamura CV, and Dias Filho BP 2010. Potent antifungal activity of extracts and pure compound isolated from pomegranate peels and synergism with fluconazole against Candida albicans. Res. Microbiol. Jun 9. Epub ahead of print.

Zhang Y, Wang D, Lee RP, Henning SM, and Heber D 2009. Absence of pomegranate ellagitannins in the majority of commercial pomegranate extracts: implications for standardization and quality control. J. Agric. Food Chem. 57(16):7395-7400.

Adams LS, Zhang Y, Seeram NP, Heber D, and Chen S 2010. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev. Res. (3(1):108-113.

Sharma M, Li L, Celver J, Killian C, Kovoor A, and Seeram NP 2010. Effects of fruit ellagitannin extracts, ellagic acid, and their colonic metabolite, urolithin A, on Wnt signaling. J. Agric. Food Chem. 58(7):3965-3969.

Gould SW, Fielder MD, Kelly AF, El Sankary W, and Naughton DP 2009. Antimicrobial pomegranate rind extracts: enhancement by Cu(II) and vitamin C combinations against clinical isolates of Pseudomonas aeruginosa. Br. J. Biomed. Sci. 66(3):129-132.

Gould SW, Fielder MD, Kelly AF, and Naughton DP 2009. Anti-microbial activities of pomegranate rind extracts: enhancement by cupric sulphate against clinical isolates of S. aureus, MRSA and PVL positive CA-MSSA. BMC Complement. Altern. Med. 9:23.

Mattiello T, Trifirò E, Jotti GS, and Pulcinelli FM 2009. Effects of pomegranate juice and extract polyphenols on platelet function. J. Med. Food. 12(2):334-3349.

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Last modified: September 7, 2020