Pomegranate

• How It Works

   protective effects in prostate cancer patients are mixed. More definitive research is needed.

  Pomegranate is a small fruit-bearing tree native to Asia. Juice from the seed pulp contains compounds known as polyphenols that may contribute to its activity. A few studies suggest pomegranate juice can benefit patients with heart disease and can lower cholesterol and blood pressure, but the evidence is limited. Pomegranate juice had some benefit in patients with prostate cancer, but more clinical trials are needed to confirm such effects.

• Purported Uses
  • Cancer prevention
    Data on whether pomegranate can exert protective effects in prostate cancer patients are mixed, although there may be some indirect benefit. More studies are needed.
  • Cardiovascular Disease
    A small short-term study suggests that pomegranate juice may benefit patients with coronary heart disease, but more studies are needed.
  • Hypercholesterolemia
    There is evidence from a few studies that pomegranate lowers cholesterol levels.
  • Hypertension
    A few small-scale studies suggest that drinking pomegranate juice may reduce hypertension. More studies are needed to verify this effect.
• Patient Warnings
  • In patients on statin therapy, pomegranate juice may increase the risk of rhabdomyolysis, a breakdown and release of muscle fibers into the bloodstream.
  • Diabetic patients should be careful because of the sugar content in pomegranate.
• Do Not Take If
  • You are taking medications that interact with grapefruit juice: Pomegranate may have effects similar to grapefruit juice.
  • You are taking warfarin: Pomegranate juice may interact with warfarin.
  • You are taking metformin: In an animal study, pomegranate juice reduced the effectiveness of metformin. Whether similar effects occur in humans is not yet known.
• Side Effects

  No significant side effects were reported with use of pomegranate juice. In studies of prostate cancer patients, there were a few occurrences of mild to moderate nausea, constipation, and decreased appetite. Diarrhea occurred with higher doses in some patients.

• Special Point

  Patients should be aware that pomegranate is not an approved cancer treatment.

• Scientific Name

  Punica granatum

• Clinical Summary

  Pomegranate is a small fruit-bearing tree native to Asia, but it is also cultivated in many parts of the world including the United States. The fruit juice extracted from the arils of the seeds is used in drinks and as a dietary supplement. Several studies have shown that pomegranate has antioxidant and antiatherosclerotic properties which are attributed to the presence of multiple polyphenols such as tannins, flavonols, anthocyanins, and ellagic acid ^(1) (2).

  Consumption of pomegranate juice was found to benefit patients with carotid artery stenosis ⁽⁶⁾, hypertension ⁽⁷⁾, hyperlipidemia ⁽²¹⁾, or mild to moderate erectile dysfunction ⁽¹⁹⁾, as well as patients with coronary heart disease ⁽⁸⁾, but had no effect in patients with chronic obstructive pulmonary disease (COPD) ⁽⁹⁾. A systematic review determined the evidence on pomegranate supplementation for blood pressure management is limited ⁽³⁴⁾. In a study of postmenopausal women, intake of pomegranate seed oil did not reduce hot flashes ⁽²²⁾.

  In preclinical studies, pomegranate juice suppressed inflammatory cell signaling ⁽¹⁾, inhibited prostate tumor growth, and lowered serum PSA levels ^(3) (4). It also inhibited aromatase activity, endogenous estrogen biosynthesis, and breast cancer cell proliferation ⁽⁵⁾. A pomegranate seed extract alleviated ciplatin-induced hepatotoxicity in animal studies ⁽²³⁾.

  In prostate cancer patients, the safety and utility of pomegranate has been studied neoadjuvantly, during active surveillance or with biochemical recurrence, and in those with advanced cancer. Pomegranate extract before surgery resulted in pomegranate metabolite accumulation in prostate tissue, but did not significantly lower 8-OHdG levels, a measure of oxidative damage ⁽³⁵⁾. Although pomegranate juice slowed the rate of prostate-specific antigen (PSA) increase in men with high PSA levels, data are conflicting ^(2) (24). A planned subset analysis suggests that those with the manganese superoxide dismutase (MnSOD) AA genotype might benefit ⁽³⁶⁾. Supplementation with a blend of green tea, pomegranate, broccoli, and curcumin resulted in lower rates of PSA increase among men with prostate cancer following a PSA relapse post-radical treatment ⁽²⁵⁾. An adjunctive intervention with pomegranate juice in men with advanced prostate cancer did not produce significant PSA reductions versus placebo ⁽³⁷⁾.

  Recent investigations suggest pomegranate extract can modulate gene expression for both osteoclastic and osteogenic processes in postmenopausal women, suggesting a possible role in bone health ⁽²⁶⁾, but there was no overall association between pomegranate juice intake and hormonal biomarkers for breast cancer risk ⁽³⁸⁾. Pomegranate extract influenced changes in gene expression in colon tissues from colorectal patients ⁽²⁷⁾. In newly-diagnosed CRC patients, pomegranate consumption may lower plasma LPS-binding protein levels, a marker for endotoxemia ⁽³³⁾. More studies are needed to determine the implications of such changes.

  Although animal studies suggested pomegranate may inhibit cytochrome P450 3A and 2C9 ^{(10) (11) (18)}, humans studies have not shown clinically relevant interactions ^{(12) (39) (40) (41)}.

• Food Sources

  Whole fruit, juice

• Purported Uses
  • Cancer treatment and prevention
  • Atherosclerosis
  • Coronary heart Disease
  • Hypercholesterolemia
  • Hyperlipidemia
  • Hypertension
• Mechanism of Action

  Several studies have indicated that pomegranate juice has antioxidant and antiatherosclerotic properties due to the presence of multiple polyphenols such as tannins, flavonols, anthocyanins and ellagic acid. Punicalagin, an ellagitannin, is the most abundant polyphenol that accounts for >50% of antioxidant activity ^(1) (2).

  Animal models indicate that constituents such as ellagic acid and luteolin inhibit metastasis of ovarian cancer by downregulating matrix metalloproteinases MMP2 and MMP9 ⁽²⁸⁾. In prostate cancer cells, a pomegranate extract induced apoptosis and impaired metastasis, also by downregulating MMP2/MMP9 along with upregulating tissue inhibitor of metalloproteinase TIMP2 ⁽²⁹⁾. Prevention of chemically-induced mammary carcinogenesis by another extract likely involved anti-inflammatory mechanisms such as differential regulation of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) signaling ⁽³⁰⁾. A pomegranate extract suppressed breast cancer stem cell characteristics by inhibiting the epithelial to mesenchymal transition (EMT) ⁽³¹⁾. However, pomegranate extract can also inhibit aromatase activity and decrease the endogenous synthesis of estrogen ⁽⁵⁾.

  Some commercial pomegranate juices are marketed with claims of higher antioxidant activity than green tea and red wine ⁽¹³⁾. However such effects could be due to colonic microflora metabolites and not the polyphenols present in the juice ⁽¹⁴⁾. Recent interest in the link between gut microbiota and cancer explores possible mechanisms. In one RCT, consumption of pomegranate was found to decrease plasma lipopolysaccharide binding protein (LBP) levels, which is a known marker that is associated with the onset and development of colorectal cancer ⁽³³⁾.

• Warnings
  • Pomegranate juice may increase the risk of rhabdomyolysis for patients on statin therapy ⁽¹⁷⁾.
  • Diabetic patients should be careful because of the sugar content of pomegranate.
• Adverse Reactions

  Generally well tolerated ^(25) (42). No significant adverse effects were observed in men following daily consumption of 8 ounces of pomegranate juice for over 2 years ⁽²⁾. In a study of prostate cancer patients, few related adverse events occurred, including mild to moderate nausea, constipation, and decreased appetite ⁽³⁶⁾. Diarrhea occurred with higher doses in some patients ⁽²⁴⁾.

• Herb-Drug Interactions
  • Cytochrome P4503A substrates: Although studies in rats suggest that pomegranate juice may inhibit cytochrome P450 3A (CYP3A) activity similar to grapefruit juice ^(10) (11), studies in humans did not show clinically relevant inhibition ^{(12) (39) (40)}.
  • CYP 2C9 substrates: A study in rats showed that pomegranate juice inhibited CYP2C9 activity and increased tolbutamide bioavailability ⁽¹⁸⁾, but pomegranate juice and extract had no effect on CYP2C9 activity in humans ⁽⁴¹⁾.
  • Warfarin: According to a case report, pomegranate juice may interact with warfarin ⁽²⁰⁾.
  • Metformin: In a rat model, pre-administration of pomegranate juice reduced metformin efficacy ⁽³²⁾. The clinical relevance in humans has yet to be determined.
• References

  1. Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem. Feb 8 2006;54(3):980-985.

  2. Pantuck AJ, Leppert JT, Zomorodian N, 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. Jul 1 2006;12(13):4018-4026.

  3. Lansky EP, Jiang W, Mo H, et al. Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs. Jan 2005;23(1):11-20.

  4. Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H. Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A. Oct 11 2005;102(41):14813-14818.

  5. Kim ND, Mehta R, Yu W, et al. Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat. Feb 2002;71(3):203-217.

  6. Aviram M, Rosenblat M, Gaitini D, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. Jun 2004;23(3):423-433.

  7. Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure.Atherosclerosis. Sep 2001;158(1):195-198.

  8. Sumner MD, Elliott-Eller M, Weidner G, et al. Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease. Am J Cardiol. Sep 15 2005;96(6):810-814.

  9. Cerda B, Soto C, Albaladejo MD, et al. Pomegranate juice supplementation in chronic obstructive pulmonary disease: a 5-week randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr. Feb 2006;60(2):245-253.

  10. Summers KM. Potential drug-food interactions with pomegranate juice. Ann Pharmacother. Jul-Aug 2006;40(7-8):1472-1473.

  11. Hidaka M, Okumura M, Fujita K, et al. Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats. Drug Metab Dispos. May 2005;33(5):644-648.

  12. Farkas D, Oleson LE, Zhao Y, et al. Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice. J Clin Pharmacol. Mar 2007;47(3):286-294.

  13. Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem. Oct 2000;48(10):4581-4589.

  14. Cerda B, Espin JC, Parra S, Martinez P, Tomas-Barberan FA. 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. Aug 2004;43(4):205-220.

  15. Cerda B, Llorach R, Ceron JJ, Espin JC, Tomas-Barberan FA. Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice. Eur J Nutr. Jan 2003;42(1):18-28.

  16. 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. Oct 2004;348(1-2):63-68.

  17. Sorokin AV, Duncan B, Panetta R, Thompson PD. Rhabdomyolysis associated with pomegranate juice consumption. Am J Cardiol. Sep 1 2006;98(5):705-706.

  18. Nagata M, Hidaka M, Sekiya H, et al. Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats. Drug Metab Dispos. Feb 2007;35(2):302-305.

  19. Forest CP, Padma-Nathan H, Liker HR. Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study. Int J Impot Res. 2007 Nov-Dec;19(6):564-7.

  20. Komperda KE. Potential interaction between pomegranate juice and warfarin. Pharmacotherapy. 2009 Aug;29(8):1002-6.

  21. Mirmiran P, Fazeli MR, Asghari G, Shafiee A, Azizi F. Effect of pomegranate seed oil on hyperlipidaemic subjects: a double-blind placebo-controlled clinical trial. Br J Nutr. 2010 Aug;104(3):402-6.

  22. Auerbach L, Rakus J, Bauer C, et al.Pomegranate seed oil in women with menopausal symptoms: a prospective randomized, placebo-controlled, double-blinded trial. Menopause. 2012 Apr;19(4):426-32.

  23. Yildirim NC, Kandemir FM, Ceribasi S, Ozkaraca M, Benzer F. Pomegranate seed extract attenuates chemotherapy-induced liver damage in an experimental model of rabbits.Cell Mol Biol (Noisy-le-grand). 2013 Feb 2;59 Suppl:OL1842-7.

  24. Paller CJ, Ye X, Wozniak PJ, 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. 2013 Mar;16(1):50-5.

  25. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer—the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014 Jun;17(2):180-6.

  26. Lin Y, Kazlova V, Ramakrishnan S, Murray MA, Fast D, Chandra A, Gellenbeck KW. Bone health nutraceuticals alter microarray mRNA gene expression: A randomized, parallel, open-label clinical study. Phytomedicine. 2016 Jan 15;23(1):18-26.

  27. Nuñez-Sánchez MA, González-Sarrías A, García-Villalba R, et al. Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial. J Nutr Biochem. 2017 Apr;42:126-133.

  28. Liu H, Zeng Z, Wang S, Li T, et al. Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biol Ther. 2017 Dec 2;18(12):990-999.

  29. Deng Y, Li Y, Yang F, et al. The extract from Punica granatum (pomegranate) peel induces apoptosis and impairs metastasis in prostate cancer cells. Biomed Pharmacother. 2017 Sep;93:976-984.

  30. Mandal A, Bhatia D, Bishayee A. Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways. Nutrients. 2017 Apr 28;9(5). pii: E436.

  31. Nallanthighal S, Elmaliki KM, Reliene R. Pomegranate Extract Alters Breast Cancer Stem Cell Properties in Association with Inhibition of Epithelial-to-Mesenchymal Transition.Nutr Cancer. 2017 Oct;69(7):1088-1098.

  32. Awad R, Mallah E, Khawaja BA, et al. Pomegranate and licorice juices modulate metformin pharmacokinetics in rats. Neuro Endocrinol Lett. 2016 Jul;37(3):202-206.

  33. González-Sarrías A, Núñez-Sánchez MA, Ávila-Gálvez MA, et al. Consumption of pomegranate decreases plasma lipopolysaccharide-binding protein levels, a marker of metabolic endotoxemia, in patients with newly diagnosed colorectal cancer: a randomized controlled clinical trial. Food Funct. 2018 May 23;9(5):2617-2622.

  34. Gbinigie OA, Onakpoya IJ, Spencer EA. Evidence for the effectiveness of pomegranate supplementation for blood pressure management is weak: A systematic review of randomized clinical trials. Nutr Res. Oct 2017;46:38-48.

  35. Freedland SJ, Carducci M, Kroeger N, et al. A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. Cancer Prev Res (Phila). Oct 2013;6(10):1120-1127.

  36. Pantuck AJ, Pettaway CA, Dreicer R, et al. A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis. Sep 2015;18(3):242-248.

  37. Stenner-Liewen F, Liewen H, Cathomas R, et al. Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer – Results of a Phase IIb Randomized Controlled Trial. J Cancer. 2013;4(7):597-605.

  38. Kapoor R, Ronnenberg A, Puleo E, et al. Effects of Pomegranate Juice on Hormonal Biomarkers of Breast Cancer Risk. Nutr Cancer. 2015;67(7):1113-1119.

  39. Misaka S, Nakamura R, Uchida S, et al. Effect of 2 weeks’ consumption of pomegranate juice on the pharmacokinetics of a single dose of midazolam: an open-label, randomized, single-center, 2-period crossover study in healthy Japanese volunteers. Clin Ther. Feb 2011;33(2):246-252.

  40. Park SJ, Yeo CW, Shim EJ, et al. Pomegranate juice does not affect the disposition of simvastatin in healthy subjects. Eur J Drug Metab Pharmacokinet. Aug 2016;41(4):339-344.

  41. Hanley MJ, Masse G, Harmatz JS, et al. Pomegranate juice and pomegranate extract do not impair oral clearance of flurbiprofen in human volunteers: divergence from in vitro results. Clin Pharmacol Ther. Nov 2012;92(5):651-657.

  42. Paller CJ, Pantuck A, Carducci MA. A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis. Sep 2017;20(3):265-270.