Therapeutic Applications of Pomegranate
Authors: Prof. P. T. Yeole*, S. A. Belge,
Email : ptyeole@kkwagh.edu.in
(Assistant Professor, K. K.Wagh College of Agricultural Biotechnology, Nashik.)
Email : ptyeole@kkwagh.edu.in
R. Kamble, Sapana Wagh

Abstract

The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, 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 addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ilments. The pomegranate, Punica granatum L., is an ancient, mystical unique fruit borne on a small, 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. Other potential applications include infant brain ischemia, male infertility, Alzheimer’s disease, arthritis, and obesity.

Introduction

Functional foods act as antioxidant nutrients and protect against many human chronic diseases by combating reactive oxygen species (ROS) generation. Fruit concentrates consumption protect against oxidative stress-mediated human diseases; including cancer. In experimental animal models; azoxymethane (AOM) increases oxidative injury to colon cells and it is believed that this process play a role in the etiology of colon cancer in rats. Phytotherapy is considered as a complementary approach for preventing and treating simple disease, although well grounded in medical tradition, it often lacks proper scientific validation.

The edible part of the fruits contains acids, sugars, vitamins, polysaccharides, polyphenols and minerals, however, several factors may contribute to the chemical changes, including cultivars, environmental conditions, ripening, storage and postharvest treatments.

The pomegranate tree typically grows 12-16 feet, has many spiny branches, and can be extremely long lived, as evidenced by trees at Versailles, France, known to be over 200 years old. The leaves are glossy and lance shaped, and the bark of the tree turns gray as the tree ages. The flowers are large, red, white, or variegated and have a tubular calyx that eventually becomes the fruit. The current explosion of interest in pomegranate as a medicinal and nutritional product is evidenced by a MedLine search from 2000 to present, revealing over 130 new scientific papers pertaining to its health effects.

Constituent Standardization



The goal of many pomegranate studies has been to identify the therapeutic constituents. Commonly found in many plants, ellagic acid exhibits powerful Anticarcinogenic and antioxidant , properties, propelling it to the forefront of pomegranate research. Many commercially available pomegranate extracts are being standardized to contain 40-percent (or more) ellagic acid; however, Lansky, a prominent researcher on the medicinal properties of pomegranate, cautions against focusing on ellagic acid standardization to the exclusion of other therapeutically important pomegranate constituents. Research on ellagic acid with other flavonoids such as quercetin supports his contention.

Biochemistry/Pharmacokinetics

Although little is known about the metabolism and bioavailability of ellagitannins from food sources, three small human trials and one case study have investigated the bioavailability, absorption, metabolism, and in vivo antioxidant effects of pomegranate. This was the first direct evidence that ellagic acid consumed from food was absorbed in humans.

Mechanisms of Action

Although pomegranate’s wide-ranging therapeutic benefits may be attributable to several mechanisms, most research has focused on its antioxidant, anticarcinogenic, and anti-inflammatory properties.

Antioxidant Mechanisms


An in vitro assay using four separate testing methods demonstrated pomegranate juice and seed extracts have 2-3 times the antioxidant capacity of either red wine or green tea. Pomegranate extracts have been shown to scavenge free radicals and decrease macrophage oxidative stress and lipid peroxidation in animals and increase plasma antioxidant capacity in elderly humans. Pomegranate could be expected be suitable for food processing in which thermal devices are used, because of their heat resistance.

Using pomegranate rind powders in cooked goat meat patties in a hot air oven until the internal temperature reached 80°C (approximately 15 min at 170°C) and then packaged in low density polyethylene bags and stored at 4°C, for 12 days obtained good results. pomegranate rind power revealed also to be also a good antioxidant on the preservation of raw ground goat meat during refrigerated storage (4°C), aerobically packaged in low density polyethylene bags for 6 days, even in the presence of salt which generally promotes lipid oxidation.

Antioxidant properties of pomegranate samples, independent on the antioxidant method performed. They have chosen this method because it reflects bioavailability of the test compound to the cells, and the antioxidant activity is evaluated in the cellular environment and in terms of inhibition of intracellular generation of reactive oxygen species. They found that urolithins exhibited a significant antioxidant activity correlated with the number of hydroxyl groups as well as lipophilicity of the molecules.

Antimicrobial activity

The combination of pomegranate juice and pomegranate polyphenols was also effective against food-borne viral infectivity. pomegranate purified polyphenol extract inhibited influenza virus having also a synergistic effect with oseltamivir.

Anticarcinogenic Mechanisms

Ethnobotanical study of medicinal plants in Chandauli District, one of the less studied regions of India, using semi-structured interviews, field observations, preference and direct matrix ranking with traditional medicine practitioners.

They were able to document 40 medicinal plants belonging to 27 families. P. granatum was found to be an ingredient of a powder along with whole plant of Vernonia cinerea Less. (AS38) and leaves of Crataeva nurvala that after heated with castor and coconut oils was used in the Miguel et al. 2841 external treatment of breast cancer. In addition to that ethnobotanical study in India, pomegranate has been target of studies in laboratories and cancer centres that have showed its properties against diverse types of cancers.

Two recent review articles reported the laboratory and clinical evidence of cancer chemoprevention or treatment of pomegranate pomegranate fruit, pomegranate juice, pomegranate seed and seed oil act in prostate, breast, skin, colon, lung, oral and leukaemia cancers, through antioxidant, antiproliferation (growth inhibition, cell cycle disruption and apoptosis), antiangiogenisis and anti-inflammatory mechanisms of action. Ellagic acid, one of the constituents of pomegranate juice and seed oils are reported as acting against cancer of skin, pancreas, breast, prostate, colon, intestine, oesophagus, bladder, oral, leukaemia, liver and neuroblastoma, which mechanisms of action are similar to those described for pomegranate.

Several animal studies have elucidated pomegranate’s potential anticancer mechanisms. Two studies in mice implanted with the prostate cancer PC-3 cell line demonstrated pomegranate fruit extract (PFE; edible parts of the fruit, excluding the peel) inhibits cell growth and induces apoptosis via modulation of proteins regulating apoptosis.

Anti-inflammatory Mechanisms

Cold pressed pomegranate seed oil has been shown to inhibit both cyclooxygenase and lipoxygenase enzymes in vitro. Cyclooxygenase, a key enzyme in the conversion of arachidonic acid to prostaglandins (important inflammatory mediators), was inhibited by 37 percent by a CPSO extract. Lipoxygenase, which catalyzes the conversion of arachidonic acid to leukotrienes, also key mediators of inflammation, was inhibited by 75 percent by a CPSO extract. By comparison, an FPJ extract resulted in a 23.8-percent inhibition of lipoxygenase in vitro. in vitro study that may have far-reaching implications for those suffering from osteoarthritis (OA) demonstrated PFE has a significant and broad inhibitory effect on matrix metalloproteinases (MMPs), a subgroup of collagenase enzymes expressed in high levels in arthritic joints and involved in the turnover, degradation, and catabolism of extracellular joint matrix.

In pretreated human femoral OA chondrocytes, PFE inhibited IL-1betainduced destruction of proteoglycan, expression of MMPs at the cellular level, and phosphorylation and activation of mitogen-activated protein kinases (signal transduction molecules involved in MMP expression). The suppression of MMP expression in OA chondrocyte cultures by PFE suggests pomegranate constituents prevent collagen degradation and may inhibit joint destruction in OA patients. At the same time, the authors using a column chromatography combined with in vitro bioassay-guided fractionation found that punicalagin, punicalin, strictinin A, and granatin B were able to inhibit NO production as well as iNOS expression in RAW 264.7 cells. Granatin B was that showed the strongest iNOS and COX-2 inhibitory effects, and exhibited these effects in the inhibition of paw swelling and PGE2 level in carrageenan-induced mice. According to these results, the authors proposed that granatin B could be used as a standard marker for the anti-inflammatory effect of pomegranate

Other biological activities

In addition to the biological activities of pomegranate reported so far in the present work, others were also found during our database research. They include for example, the reversible inhibition of human plasma thrombin at physiological pH values by the pomegranate extracts (endocarp and mesocarp) which were mainly constituted by catechin along with gallic acid, epicatechin and ellagic acid The hyperbolic nature of the inhibition curves also revealed that the polyphenol-thrombin complex behaves as a noncooperative reversible system.

The effect of pomegranate juice and the polyphenolrich extracts from pomegranate fruit on platelet aggregation, calcium mobilisation production of thromboxan A2 induced by collagen and arachidonic acid revealed that both types of samples were able to reduce all platelet responses studied; polyphenol-rich extracts from pomegranate fruits showed a strong action in reducing platelet activation, being active at concentrations similar to those after ingested Other study using isoproterenol that induces cardiac necrosis in rats demonstrated for the first time that a pre-supplementation with pomegranate juice for 30 consecutive days before administration of isoproterenol on days 29 and 30^th showed lesser increase in heart weight, infarct size, plasma marker enzymes, lipid peroxidation, Ca2+ ATPase and a significant protective effect in endogenous enzymatic and non-enzymatic antioxidants when compared to those animals only treated with isoproterenol.

A pilot study in type 2 diabetic patients with hyperlipidemia found concentrated PJ decreased cholesterol absorption, increased fecal excretion of cholesterol, had a beneficial effect on enzymes involved in cholesterol metabolism, significantly reduced total and LDL cholesterol, and improved total/HDL and LDL/HDL cholesterol ratios. PJ consumption by hypertensive patients inhibits serum angiotensin converting enzyme (ACE; a catalyst for the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor) activity, thereby reducing systolic blood pressure44 and potentially protecting against cardiovascular disease. Numerous in vitro studies3,47,48 and two human trials49,50 demonstrate the antimicrobial activity of pomegranate extracts. The growth ofStaphylococcus aureus, Streptococcus pyogenes,Diplococcus pneumoniae, Escherichia coli O157:H7, and Candida albicans was inhibited via direct bacteriocidal or fungicidal activity.

Potential Drug Interactions

Based on pomegranate’s current popularity and research suggesting its therapeutic benefit in cancer, cardiovascular disease, and other diseases treated with prescription medications, it has been of interest to determine whether pomegranate extracts have any effect on cytochrome P450-3A, the hepatic enzyme system responsible for metabolism of many prescription medications. A randomized, single-dose, crossover study in 13 healthy human volunteers emonstrated PJ pretreatment did not affect elimination half-life or distribution of intravenous midazolam (a benzodiazepine derivative with anxiolytic, amnestic, hypnotic, anticonvulsant, and muscle relaxant properties), nor did it affect the Cmax or clearance of oral midazolam.89 This human study contradicts a rat study showing PJ has an inhibitory effect on carbamazepine pharmacokinetics, an anticonvulsant medication also metabolized by cytochrome P450- 3A.

Safety of Pomegranate Extracts

Pomegranate and its constituents have safely been consumed for centuries without adverse effects. Studies of pomegranate constituents in animals at concentrations and levels commonly used in folk and traditional medicine note no toxic effects. Toxicity of the polyphenol antioxidant punicalagin, abundant in pomegranate juice, was evaluated in rats. No toxic effects or significant differences were observed in the treatment group compared to controls, which was confirmed via histopathological analysis of rat organs. Overweight human volunteers demonstrated the safety of a tableted PFE in amounts up to 1,420 mg/day (870 mg gallic acid equivalents) for 28 days, with no adverse events reported or adverse changes in blood or urine laboratory values observed. Another study in 10 patients with carotid artery stenosis demonstrated PJ consumption (121 mg/L EA equivalents) for up to three years had no toxic effect on blood chemistry analysis for kidney, liver, and heart function.

References:

1. 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 2005;33:644-648.

2. Vidal A, Fallarero A, Pena BR, et al. Studies on the toxicity of Punica granatum L. (Punicaceae) whole fruit extracts. J Ethnopharmacol 2003;89:295-300.

3. Cerda B, Ceron JJ, Tomas-Barberan FA, Espin JC. Repeated oral administration of high doses of the pomegranate ellagitannin punicalagin to rats for 37 days is not toxic. J Agric Food Chem 2003;51:3493-3501.

4. Juice does not impair clearance of oral or intravenous idazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice. J Clin Pharmacol 2007;47:286-294.

5.Lansky EP. Beware of pomegranates bearing 40%ellagic acid. J Med Food 2006;9:119-122. Mertens-Talcott SU, Bomser JA, Romero C, et al.



About Author / Additional Info:
I am currently working as Asssistant Professor at K. K. Wagh college of Agril. Biotech., Sarswatinagar, Nashik