Pomegranate Juice for the Prevention of Cardiac Disease and Cancer

Dónal P. O'Mathúna. Dr. O'Mathúna is a lecturer in Health Care Ethics, School of Nursing, Dublin City University, Ireland; he reports no financial relationship relevant to this field of study.

Pomegranates have not been well known in the west, except for those encountering references to them in the Bible and other ancient literature. Native to Iran, the small tree Punica granatum is cultivated in parts of the Mediterranean, the Middle East, Russia, India, China, and Japan.1 The tree is now being grown in parts of the United States, in particular Arizona and California.2 The edible fruit is relatively small, sometimes viewed as no more than a large berry.3 It has a leathery orange skin when ripe, toped by a crown and the remains of its red flower. When the fruit is opened, many shiny ruby-shaped seeds spill forth in the midst of its intense red juice. For this reason, pomegranates have long been seen as a symbol of human fertility.4 In many cultures, different parts of the fruit and tree have long been used in traditional medicine. Since scientists from Israel published data in 2000 showing pomegranate's beneficial effects on cardiovascular health,5 interest in the exotic fruit has been growing. The interest has primarily centered on its possible beneficial effects on cardiovascular health and in cancer prevention and treatment.

Table 1

Health Benefits of Pomegranate

Providing 16% of an adult's daily vitamin C requirement per 100 mL serving, pomegranate juice is also a good source of vitamin B, pantothenic acid, potassium, and antioxidant polyphenols. Overall, however, pomegranate is not a significant source of nutrients.1

The most abundant polyphenols in pomegranate juice are the hydrolyzable tannins called punicalagins, shown, in 39 peer-reviewed research publications over 1990-2007 (August), to have potent free-radical scavenging ability in laboratory studies.2 The antioxidant punicalagins absorb into the human body after consumption of pomegranate extracts,3 and an ex vivo study of human plasma after consumption of a pomegranate extract standardized to punicalagins indicated an average 32% increase in plasma antioxidant capacity.4

Many food and dietary supplement makers have found the advantages of using pomegranate extracts (which have no sugar, calories, or additives), instead of the juice, as healthy ingredients in their products. Many pomegranate extracts are essentially ellagic acid, which may only be absorbed into the body after consumption of punicalagins.5

In preliminary laboratory research and human pilot studies, juice of the pomegranate has been found effective in reducing heart disease risk factors, including LDL oxidation, macrophage oxidative status, and foam cell formation, all of which are steps in atherosclerosis and cardiovascular disease. Tannins such as punicalagins have been identified as the primary components responsible for the reduction of oxidative stress which led to these risk factors.2 Pomegranate has been shown to reduce systolic blood pressure by inhibiting serum angiotensin-converting enzyme (ACE).3

Metabolites of pomegranate juice ellagitannins have been shown to localize specifically in the prostate gland, colon and intestinal tissues of mice4 Other research indicates that pomegranate juice may be effective against prostate cancer6,7 and osteoarthritis.8

In 2007, six clinical trials in the United States, Israel and Norway have been approved to examine the effects of pomegranate juice consumption on parameters of prostate cancer or prostatic hyperplasia, diabetes or lymphoma.9

The juice may also have antiviral10 and antibacterial effects against dental plaque.11

References

1. Nutrition Data. www.nutritiondata.com/facts

2. Gross PM. Pomegranate punicalagins

3. Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure Atherosclerosis. 2001;158:195–198.

4. Seeram NP et al. Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem. 2007;55:7732-7737.

5. 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;54:8956-8961.

6. Can pomegranates prevent prostate cancer? A new study offers promise 26 September 2005

7. BBC Juice 'can slow prostate cancer' 1 July 2006

8. Pomegranate Fruit Shown To Slow Cartilage Deterioration In Osteoarthritis

9. NIH-listed human clinical trials on pomegranate

10. Neurath AR, et al. Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide. BMC Infect Dis. 2004;4:41.

11. Menezes SM, et al. Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother. 2006;6:79-92.

Source: Accessed November 7, 2007 http://en.wikipedia.org/wiki/Pomegranate

Pharmacology

About 20% of a typical pomegranate fruit is made up of its seeds — a relatively large proportion. These contain about 20% pomegranate seed oil made up primarily of polyunsaturated fatty acids.2 Among these, 80% is a rare fatty acid called punicic acid. Also present in the oil is the isoflavone genistein (also found in soy), the phytoestrogen coumestrol, and the sex steroid estrone.5 This combination of compounds is unique in nature, giving testimony to the plant's unique botanical heritage. Pomegranate juice has an intense red color and is composed of 85% water, 10% sugar, and a large variety of other compounds.1 Vitamin C is present in large quantities, as are numerous minerals, with iron being particularly prevalent.2 The juice's red color arises from several anthocyanins, which are potent antioxidant flavonoids. These, along with several polyphenolics and tannins (which contribute to the juice's tart taste), contribute to pomegranate's antioxidant activity.6

Mechanism of Action

Pomegranate juice is believed to work via its significant antioxidant activity, higher than most other fruit juices, red wine, and green tea.7 Oxidative stress is associated with poor cardiac health. The body naturally seeks to neutralize various compounds that cause oxidation and can contribute to cardiac disease. Supplemental antioxidants are widely used in the belief they will lower oxidative stress and may thus prevent cardiac disease and some forms of cancer. Laboratory tests have also shown that various components of pomegranate have anti-proliferating, apoptotic (causing cell death), and anti-angiogenic (preventing growth of new blood vessels essential for cancer cell growth) activities, or can inhibit different growth factors involved in cancer cell growth.8

Clinical Studies

Cardiovascular Disease

Early tests with healthy humans found that pomegranate juice increased serum total antioxidant levels, thus reducing oxidative stress.9 Nineteen patients with 70-90% stenosis of the carotid arteries were randomized to either receive pomegranate juice (50 mL/day) or no intervention.6 Ten patients were in the pomegranate group and consumed the juice for one year, with 5 patients agreeing to continue for an additional 2 years. Outcomes were measured using echo Doppler ultrasound and blood tests. The mean intima-media thickness (IMT) of the carotid arteries in the control group increased significantly by 9% over one year (P < 0.01). In the pomegranate juice group, the mean IMT decreased significantly by 13, 22, 26, and 35% after 3, 6, 9, and 12 months, respectively. No significant changes were found in serum glucose, cholesterol (HDL or LDL), or triglyceride levels. Significant reductions in systolic blood pressure (by 12% after one year; P < 0.05), unlike diastolic blood pressure, occurred in the pomegranate group, with no changes in the control group. A number of blood tests showed significantly lowered oxidative stress in the pomegranate group. LDL oxidation was significantly reduced by samples taken from the pomegranate group (by 32% after one year; P < 0.01) compared to the control group.

Another clinical trial involved 45 patients with coronary heart disease and myocardial ischemia.10 The randomized, double-blind trial assigned people to receive either pomegranate juice (240 mL/day) or a modified sports beverage of similar color, flavor, and caloric content. Patients underwent myocardial perfusion imaging while exercising to assessed levels of stress-induced myocardial ischemia. At baseline, the two groups did not differ significantly. After 3 months, those consuming pomegranate juice had reduced stress-induced ischemia while those in the control group had increased ischemia (P < 0.05). No differences existed in the medications taken by either group and serum lipid levels did not vary between the groups.

Cancer

Naturally occurring antioxidants have been recommended as part of a general strategy in cancer prevention. Given the relatively high levels of antioxidants in pomegranate, it has been tested against several cancers. In lung cancer, an extract of pomegranate juice was tested in cell cultures and mice. The results have been better than those produced by green tea, which is also believed to have potential anti-cancer activity.8 Several pomegranate extracts, as well as juice have been tested against breast cancer cell lines, producing beneficial results. With colon cancer cells, pomegranate juice has been shown to be more potent than any pomegranate extract. Preliminary studies have found that rats fed pomegranate seed oil showed less proliferation of colon cancer. All these results warrant further research, but do not as yet demonstrate that pomegranate or any of its components will prevent or treat cancer in humans.

Anticancer studies with pomegranate have progressed furthest with prostate cancer. An open-label, single-arm phase II clinical trial was reported in 2006.11 This was conducted with men whose prostate cancer had been treated surgically and/or with radiotherapy. In spite of this treatment, the men's prostate specific antigen (PSA) levels were continuing to rise. Forty-eight patients were enrolled, with two withdrawing early in the study. Among the remaining 46 patients, pomegranate juice (8 oz/day) significantly increased the mean PSA doubling time from 15 to 54 months (P < 0.001). Controversy exists regarding the reliability of PSA levels as indicators of prostate cancer mortality, although PSA doubling time is increasingly accepted as a reliable surrogate biomarker. Although this study had limitations, these are being addressed in a randomized, double-blind, three-arm trial that began in 2006.8 This study is comparing two doses of pomegranate juice against a placebo and will evaluate the reliability of the biomarkers used in the phase II trial.

Adverse Effects

Pomegranate juice consumption (50 mL/day) for 3 years showed no adverse effects in several blood chemistry analyses of liver, heart, and kidney function.6 Among these patients, 60% were taking statin drugs for high cholesterol levels. However, a number of in vitro studies have found that pomegranate juice inhibits human cytochrome CYP450 enzyme.12 The degree of inhibition is similar to that produced by grapefruit juice, which has been demonstrated to impact metabolism of statins. Although a drug-food interaction involving pomegranate has not been demonstrated in humans, people taking statins should be carefully monitored if they start taking pomegranate juice.

Conclusion

The long history of pomegranate's medicinal use is starting to draw attention from medical researchers. Most of the research to date has been carried out in cell cultures and animals. Among the few studies conducted in humans, the results are encouraging. In spite of these positive results, caution is needed. A review published in October 2007 by researchers working in this area concluded, "Although the evidence on pomegranate is very promising, extensive studies are required to fully understand its contribution to human health, before recommending its regular consumption in human diets."8 The early excitement about vitamin E supplementation is a good example here. While preliminary research results were positive, properly controlled clinical trials did not bear out these findings.13 What is known for sure is that diets should contain a range of antioxidants from a variety of plants. Pomegranates may contribute to daily fruit intake, but the evidence that they might prevent any particular disease is preliminary at this stage.

References

1. Pomegranates for the prostate and the heart: Seeds of hope. Harv Mens Health Watch. 2007;11:4-5.

2. Syed DN, et al. Pomegranate derived products for cancer chemoprevention. Semin Cancer Biol. 2007;17:377-385.

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

4. Southgate MT. The cover. Pomegranate Jars. JAMA. 2007;297:781.

5. Longtin R. The pomegranate: Nature's power fruit? J Natl Cancer Inst. 2003;95:346-348.

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

7. Malik A, Mukhtar H. Prostate cancer prevention through pomegranate fruit. Cell Cycle. 2006;5:371-373.

8. Syed DN, et al. Pomegranate derived products for cancer chemoprevention. Semin Cancer Biol. 2007;17:377-385.

9. Aviram M, et al. Pomegranate juice consumption reduces oxidative stress, atherogenic modifications of LDL, and platelet aggregation: Studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr. 2000;71:1062-1076.

10. Sumner MD, et al. Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease. Am J Cardiol. 2005;96:810-814.

11. 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;12:4018-4026.

12. Summers KM. Potential drug-food interactions with pomegranate juice. Ann Pharmacother. 2006;40:1472-1473.

13. O'Mathúna D, Larimore W. Alternative medicine, rev. ed. Grand Rapids, MI: Zondervan; 2007.