All Essential Benefits/Effects/Facts & Information

Punicalagins are large molecules (ellagitannins) found in Pomegranates and Pomegranate Juice.

They themselves are very potent anti-oxidants, and they can be metabolized into other compounds (ellagic acid, urolithins) that themselves have anti-oxidant capabilities (although lesser). This large anti-oxidant value of punicalagins, about thrice that of red wine and green tea, is what brought Pomegranates to fame. That being said, the overall amount of punicalagins that get into the bloodstream after oral ingestion is quite small (6% is the highest noted and was in rats, sometimes human studies don't even notice punicalagins in the blood).

The ellagic acid and urolithins still confer a lot of health benefits, but their anti-oxidant capabilities are on par with green tea and red wine if not a bit less potent.

There is a very high variation between individuals, and like daidzein (one of the soy isoflavones) it may be genetically dependent on what intestinal microflora one possesses.

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Things To Know

Also Known As

Pomegranate Extract, Punica Granatum L., Pomegranate Juice

Things to Note

  • There is a large inter-individual difference of ellagic acid and urolithins (punicalagin derivatives) in the blood, due to varying levels of colonic bacteria capable of producing them

  • Commercial juices tend to have more punicalagins than do naturally pressed juices, as commerical juices have less overall time before packaging for punicalagins to hydroylze into ellagic acid

How to Take

Recommended dosage, active amounts, other details

Anti-oxidant potential of the blood increases at an oral dose of 800mg Pomegranate Extract (318mg punicalagins), which may be a good starting point for a bioactive dose. The optimal dose is currently not known.

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Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects punicalagins has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Prostate Cancer Risk Notable Very High See 2 studies
Notable as consumption of pomegranate juice is associated with a prolongation in the time require for PSA (biomarker of prostate cancer) to double, from 15 months to 54 months
General Oxidation Minor Very High See study
A decrease in general oxidation has been noted with punicalagins
Lipid Peroxidation Minor Very High See study
A decrease in lipid peroxidation has been noted
Nitric Oxide Minor Very High See study
An increase in metabolites of nitric oxide metabolism have been noted and thought to be indicative of increased nitric oxide production
Prostate Specific Antigen Minor Very High See 2 studies
Does not appear to be able to reduce PSA levels outright, although it can attenuate the rate of which PSA increases over time (relative to untreated control, this is a reduction)
Estrogen - Very High See study
No significant influence on estrogen
Testosterone - Very High See study
No significant influence on testosterone levels in men at risk for prostate cancer

Scientific Research

Table of Contents:

  1. 1 Sources and Structure
    1. 1.1 Sources
    2. 1.2 Structure
  2. 2 Pharmacology
    1. 2.1 Intestinal Transit
    2. 2.2 Serum values and metabolites
    3. 2.3 Colonic Fermentation
  3. 3 Neurology
    1. 3.1 Mechanisms
  4. 4 Interactions with Organ systems
    1. 4.1 Stomach
    2. 4.2 Intestines
    3. 4.3 Liver
    4. 4.4 Kidneys
  5. 5 Effects on Oxidation
  6. 6 Interactions with Blood Dynamics
    1. 6.1 Nitric Oxide
    2. 6.2 Angiotension-Renin System
  7. 7 Interactions with Cancer
    1. 7.1 Prostate
    2. 7.2 Breast
  8. 8 Interactions with Bacteria
    1. 8.1 Dental Health
    2. 8.2 Urinary Health
  9. 9 Nutrient-Nutrient Interactions
    1. 9.1 Viagra
  10. 10 Safety and Toxicity

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1Sources and Structure

1.1. Sources

Punicalagins are the main ellagitannins in Pomegranate juice, comprising most of the polyphenol content (alongside Anthocyanins like Delphinidin). It is found in the rind of the pomegranate, and is the molecule that imparts the yellowish color; due to its water-solubility, it is extracted in juice.[1] Commercial juices seem to have higher in vitro anti-oxidant capacity than do hand-pressed pomegranate juices[1] which may be due to commercial juices having less time for ellagitannins such as punicalagins to hydrolyze into ellagic acid, and punicalagins being much more potent anti-oxidants than ellagic acid.[2][3] Beyond pomegranates, punicalagins are found in:

  • Terminalia myriocarpa[4]

1.2. Structure

Punicalagins are a polyphenolic compound, and a very large molecule. In rats, they are the largest known molecules to appear in circulation after oral ingestion.[5] Structurally, punicalagins are a gallagic acid moiety and a ellagic acid moiety bound to glucose; all three may be bioactive after ingestion. It is pluralized (Punicalagins) as the punicalagin structure exists in two reversible anomer forms, α and β)

The compound in the top right, dihydroxy-6H-dibenzo{b,d}pyran-6-one, is also called Urolithin.[6]


2.1. Intestinal Transit

While in the intestines, pomegranate juice can inhibit P450 sulfation with a 50% inhibition IC50 value of 45um for punicalagins; no interaction with SULT gene transcription or glucuronidation was noted.[7]

2.2. Serum values and metabolites

About 3-6% of an oral dose, in rats, is found in urine or faeces after ingestion[5] suggesting a large component is metabolized. After 0.6-1.2g ingestion, circulating levels of around 30mcg/mL were noted.

In humans, the sum of metabolites (punicalagins and derivatives) shows wide variability; one study noted it ranging from 0.7 to 52.7%.[8] Doses as low as 330.4mg punicalagins (800mg Pomegranate extract) are not detected in serum[3] although urolithins A/B and ellagic acid variants were detected either in free form or as glucuronides (current study had a 21.6mg oral dose of ellagic acid as well). Again, large variability is seen in the quantities of these metabolites, which may be due to varying levels of colonic fermentation.[9] Despite this variation in metabolites, this study noted the average Cmax of 33.8±12.7 ng/mL at 1 hour before dropping to 12 and 6ug/mL at 2 and 4 hours, respectively. This Cmax is similar to a previous study noting 31.9ng/mL after 1 hour with 318mg punicalagins and 25mg ellagic acid.[10]

A study using juice rather than encapsulated pomegranate extract (180mL juice, 318mg punicalagins) the Cmax was found to be 18.64ng/mL at 0.98 hours (the Tmax).[11]

In the colon, punicalagins appears to be metabolied into 6H-dibenzo{b,d}pyran-6-one derivatives, which are excreted in the urine or subject to P450 glucuronidation.[5]

2.3. Colonic Fermentation

A good deal of punicalagins are metabolized by colonic microflora into ellagic acid derivatives,[8] namely the urolithins.[12] As mentioned before, varying levels of colonic bacteria capable of conducting this fermentation may explain the high levels of variation seen in individuals.[9]


3.1. Mechanisms

The ethanolic extract of pomegranate appears to inhibit both acetylcholinesterase and butylcholinesterase with IC50 values of 14.83 and 2.65mcg/mL, respectively, which was thought to be due to the high polyphenolic content.[13]

4Interactions with Organ systems

4.1. Stomach

Pomegranate ellagitannins (Punicalagins) at high doses (50-500mg/kg bodyweight) has been implicated in rats for having protective effects in those with gastric ulcers in a dose-dependent manner[14] and may be protective against aspirin and ethanol-induced ulcers.[15] The mechanism of protection appears to be anti-oxidative in mechanism[15] and about 29% of an oral dose of punicalagins survive acid digestion in the stomach[16]; the stomach may be the one organ where punicalagins' high anti-oxidant capabilities in vitro[1] may be physiologically relevant.

4.2. Intestines

In an animal model of Crohn's disease, the metabolite Urolithin shows anti-inflammatory protective effects and beneficially modulates intestinal microflora.[17] When co-cultured with pomegranate extract, Urolithins can increase rate of growth of some bacterial strains.[18] The former effects were also seen with Urolithin's parent compound, Ellagic Acid[19] and the larger molecule of Ellagitannin,[20] although relative to both Ellagic acid and the parent ellagitannin compounds Urolithins are more anti-inflammatory.[21] Urolithin A appears to possess a few anti-inflammatory mechanisms that Urolithin B does not (COX-2 inhibition and c-Jun N-Terminal Kinase inhibition).[21]

Similar to many isolated plant bioactives, pomegranate extract is able to inhibit glucose uptake in the intestines.[22] Its IC50 value was 424ug/mL and the protein content of SGLT-1 downregulated. These are possible mechanisms for Pomegranate having an anti-diabetic effect.[22]

4.3. Liver

The inhibition of sulfurotransferases in the intestines carries over to the liver for pomegranate.[23]

Pomegranate seed extract, at a dose of 300mg/kg bodyweight in rats, is effective in protecting the liver from injury induced by Cisplatin.[24] Interestingly, ethanol extracts of pomegranate flower share this effect when injected at 9mg/kg bodyweight or orally at 50-150mg/kg.[25][26] Although these effects are seen vicariously through anti-oxidation (and thus punicalagins suspect)[27], the seed extract may be more potent overall as Pomegranate contains a bioactive fatty acid called Punicic Acid, which also aids the liver.[28]

General liver protection, but by relatively unspectacular means and unknown potency relative to other compounds

One study has noted that the anti-inflammatory effects of pomegranate extract (mediated via Nrf2 induction and NF-kB inhibition) was effective at oral doses of 1-10g/kg in rats to suppress cancerous growth in the liver.[29]

4.4. Kidneys

Pomegranate seed extract, at a dose of 300mg/kg bodyweight in rats, is effective in protecting the kidney from injury induced by Cisplatin.[24]

5Effects on Oxidation

Punicalagins, in in vitro assays (ABTS, DPPH, DMPD, and FRAP) shows more potent anti-oxidative capabilities than does green tea (1g brewed in water) and red wine (1997 Cabernet Sauvignon). Fresh pomegranate juice from arils is approximately twice as potent as green tea and red wine in these assays, with commercial juices about thrice as high.[1]

Due to excessive colonic fermentation of punicalagins[8] and the derivatives having much less oxidative capacity, as well as 3-6% punicalagins circulating in serum, it is unlikely that pomegranate has much more biological significance than these standards.

In vivo studies attribute most anti-oxidative effects to various polyphenols, and note a 2.55, 1.62, and 1.43-fold increases at 30, 60, and 120 minutes post consumption of 318mg punicalagins + 21.6mg ellagic acid, respectively.[3] A second spike comparable to the first was seen at 6 hours, but it is not certain whether this is due to food ingestion in the subjects or slower absorbing compounds in pomegranate.[3] Since ellagic acid's Tmax is one hour, it cannot solely explain the 30 minute measurement. Studies using 180mL juice that attained a serum value of 18.5ng/mL failed to find changes in anti-oxidants capacity in the blood.[11]

6Interactions with Blood Dynamics

6.1. Nitric Oxide

Punicalagins have been found to induce Nitric Oxide Synthase in vitro[30] in vacular endothelial cells, although more potent effects have been seen with the whole juice.[31]

An animal model looking at pomegranate juice's effects on pre-loading when a cell is subject to shear stress, nitric oxide levels are augmented slightly with Pomegranate juice extracts and cyclic cGMP increased.[31]

6.2. Angiotension-Renin System

Pomegranate Juice, at 50mL with 150mmol polyphenols (using the molar mass of punicalagin, about 150mg), was able to reduce systolic blood pressure by 5% and reduce ACE levels by 36% over 2 weeks, in persons on blood pressure medication.[32] This study notes that the drop in blood pressure was not solely due to ACE inhibition due to lack of correlation[32] and citing an anti-oxidant's ability to aid the endothelium directly[33] and/or dietary polyphenolic ability to increase Nitric Oxide Expression.[34]

Blood pressure reductions have also been seen more dramatically in rats subject to larger dosages.[35]

7Interactions with Cancer

7.1. Prostate

In vitro, pomegranate extract appears to induce apoptosis in prostatic cancer cells (PC3 cell line).[36]

Puunicalagins may have preventative potential for Prostate cancer, as one study spanning 33 months of therapy with POMx (a pomegranate extract supplement) at 8oz daily was able to suppress Prostate Specific Antigen doubling time (time it takes for PSA to double) from 15.6 months in control to 54.7 months in experimental.[37] Later, a follow-up study spanning 18 months using 1-3g POMx supplements found increases in PSA doubling time from 11.9-12.2 months at baseline to 17.5-18.8 months after 18 months of treatment, with no significant difference between 1000mg and 3000mg of POMx.[38] Both studies recieved grants from and are involved with POMx.[38][37]

7.2. Breast

Pomegranate extract has been noted to reduce proliferation and induce apoptosis of MCF-7 breast cancer cells via reducing DNA replication rates and inducing DNA strand breaks.[39]

8Interactions with Bacteria

8.1. Dental Health

Pomegranate juices, when processed into a gel, was able to enhance the anti-gingivitis efficacy of standard treatment when applied afterwards.[40]

8.2. Urinary Health

Pomegranate peel extract has been shown to reduce the motility of uropathogenic Escherichia coli, a common bacteria implicated in urinary tract infections.[41] This may be a mechanistic explanation for Pomegranate's benefits with urinary tract health.

9Nutrient-Nutrient Interactions

9.1. Viagra

A report of three case studies that shared the common link of pairing pomegranate juice (source of punicalagins) and Viagra at 50mg can be found here, where all subjects reported low-flow Priapisms, with erections ranging from 5-8 hours.[42] This increased efficacy of Viagra under the influence of pomegranate juice may be mediated through pomegranate juice inhibiting CYP2C9[43] which accounts for about 21% of Viagra metabolism (the other 79% being attributed to CYP3A4) and causing higher than normal levels of Viagra to circulate in the blood.[44]

Pomegranate juice has been associated with priapism induced by Viagra, and may be classified as an 'Adverse Drug-Herb reaction'

10Safety and Toxicity

An oral toxicity test in humans found no adverse effects at a dosage of 4269-4330mg/kg bodyweight Pomegranate Seed Oil; a dose of thrice that (13,710-14,214 mg/kg) was found to increase size of the liver, but may have been transiently due to punicic acid and was deemed not toxicologically relevant.[45] Thus, Pomegranate seed oil up to 4.3g/kg bodyweight is seen as free from harm.

Studies on the actual fruit extract, no adverse effects have been seen in rats with a gastric dose of 1.2mg/kg bodyweight[46] and oral intakes of up to 5g/kg bodyweight Pomegranate Fruit Extract (standardized to 30% punicalagins) has been deemed non-toxic acutely, with 600mg/kg bodyweight showing no toxic effects over 90 days.[47]

Scientific Support & Reference Citations


  1. Gil MI, et al Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing . J Agric Food Chem. (2000)
  2. Lee JH, Talcott ST Ellagic acid and ellagitannins affect on sedimentation in muscadine juice and wine . J Agric Food Chem. (2002)
  3. Mertens-Talcott SU, et al Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum l.) polyphenols after ingestion of a standardized extract in healthy human volunteers . J Agric Food Chem. (2006)
  4. Marzouk MS, et al Pharmacologically active ellagitannins from Terminalia myriocarpa . Planta Med. (2002)
  5. Cerdá B, et al Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice . Eur J Nutr. (2003)
  6. Larrosa M, et al Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities . J Agric Food Chem. (2006)
  7. Saruwatari A, et al Pomegranate juice inhibits sulfoconjugation in Caco-2 human colon carcinoma cells . J Med Food. (2008)
  8. Cerdá B, et al The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans . Eur J Nutr. (2004)
  9. Cerdá B, Tomás-Barberán FA, Espín JC Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability . J Agric Food Chem. (2005)
  10. Seeram NP, Lee R, Heber D Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice . Clin Chim Acta. (2004)
  11. Seeram NP, et al Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours . J Nutr. (2006)
  12. Cerdá B, et al Identification of urolithin a as a metabolite produced by human colon microflora from ellagic acid and related compounds . J Agric Food Chem. (2005)
  13. Bekir J, et al Assessment of antioxidant, anti-inflammatory, anti-cholinesterase and cytotoxic activities of pomegranate (Punica granatum) leaves . Food Chem Toxicol. (2013)
  14. Lai S, et al Effects of pomegranate tannins on experimental gastric damages . Zhongguo Zhong Yao Za Zhi. (2009)
  15. Ajaikumar KB, et al The inhibition of gastric mucosal injury by Punicagranatum L. (pomegranate) methanolic extract . J Ethnopharmacol. (2005)
  16. Pérez-Vicente A, Gil-Izquierdo A, García-Viguera C In vitro gastrointestinal digestion study of pomegranate juice phenolic compounds, anthocyanins, and vitamin C . J Agric Food Chem. (2002)
  17. Larrosa M, et al Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism . J Nutr Biochem. (2010)
  18. Bialonska D, et al The influence of pomegranate by-product and punicalagins on selected groups of human intestinal microbiota . Int J Food Microbiol. (2010)
  19. Rosillo MA, et al Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease . Biochem Pharmacol. (2011)
  20. Hollebeeck S, et al Anti-inflammatory effects of pomegranate (Punica granatum L.) husk ellagitannins in Caco-2 cells, an in vitro model of human intestine . Food Funct. (2012)
  21. González-Sarrías A, et al NF-kappaB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts . Br J Nutr. (2010)
  22. Kim HK, Baek SS, Cho HY Inhibitory effect of pomegranate on intestinal sodium dependent glucose uptake . Am J Chin Med. (2011)
  23. Rodríguez-Fragoso L, et al Potential Risks Resulting from Fruit/Vegetable-Drug Interactions: Effects on Drug-Metabolizing Enzymes and Drug Transporters . J Food Sci. (2011)
  24. Cayır K, et al Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats . J Med Food. (2011)
  25. Xu KZ, et al Pomegranate flower ameliorates fatty liver in an animal model of type 2 diabetes and obesity . J Ethnopharmacol. (2009)
  26. Kaur G, et al Punica granatum (pomegranate) flower extract possesses potent antioxidant activity and abrogates Fe-NTA induced hepatotoxicity in mice . Food Chem Toxicol. (2006)
  27. Bishayee A, et al Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms . Carcinogenesis. (2011)
  28. Vroegrijk IO, et al Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice . Food Chem Toxicol. (2011)
  29. Bishayee A, et al Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis . J Nutr Biochem. (2012)
  30. Chen LG, et al Tannin 1-alpha-O-galloylpunicalagin induces the calcium-dependent activation of endothelial nitric-oxide synthase via the phosphatidylinositol 3-kinase/Akt pathway in endothelial cells . Mol Nutr Food Res. (2008)
  31. de Nigris F, et al Effects of a pomegranate fruit extract rich in punicalagin on oxidation-sensitive genes and eNOS activity at sites of perturbed shear stress and atherogenesis . Cardiovasc Res. (2007)
  32. Aviram M, Dornfeld L Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure . Atherosclerosis. (2001)
  33. Kitiyakara C, Wilcox CS Antioxidants for hypertension . Curr Opin Nephrol Hypertens. (1998)
  34. Galley HF, et al Combination oral antioxidant supplementation reduces blood pressure . Clin Sci (Lond). (1997)
  35. Mohan M, Waghulde H, Kasture S Effect of pomegranate juice on Angiotensin II-induced hypertension in diabetic Wistar rats . Phytother Res. (2010)
  36. Sineh Sepehr K, et al Studies on the Cytotoxic Activities of Punica granatum L. var. spinosa (Apple Punice) Extract on Prostate Cell Line by Induction of Apoptosis . ISRN Pharm. (2012)
  37. Pantuck AJ, et al Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer . Clin Cancer Res. (2006)
  38. Paller CJ, et al A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer . Prostate Cancer Prostatic Dis. (2012)
  39. Shirode AB, et al Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks . Mol Carcinog. (2013)
  40. Somu CA, et al Efficacy of a herbal extract gel in the treatment of gingivitis: A clinical study . J Ayurveda Integr Med. (2012)
  41. Asadishad B, Hidalgo G, Tufenkji N Pomegranate materials inhibit flagellin gene expression and flagellar-propelled motility of uropathogenic Escherichia coli strain CFT073 . FEMS Microbiol Lett. (2012)
  42. Senthilkumaran S, et al Priapism, pomegranate juice, and sildenafil: Is there a connection . Urol Ann. (2012)
  43. Nagata M, et al Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats . Drug Metab Dispos. (2007)
  44. Warrington JS, et al In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions . Drug Metab Dispos. (2000)
  45. Meerts IA, et al Toxicological evaluation of pomegranate seed oil . Food Chem Toxicol. (2009)
  46. Vidal A, et al Studies on the toxicity of Punica granatum L. (Punicaceae) whole fruit extracts . J Ethnopharmacol. (2003)
  47. Patel C, et al Safety assessment of pomegranate fruit extract: acute and subchronic toxicity studies . Food Chem Toxicol. (2008)

(Common misspellings for Punicalagins include punicagalin, punicaligin, punicalagan, punicalagin)