The pharmacological use of ellagic acid-rich pomegranate fruit

Abstract

Abstract In recent years, the therapeutic use of non-drug substances such as herbal and medicinal foods is increasing progressively. Of these substances, Punica granatum L., which is an ancient and highly distinctive fruit, has been proposed for treatment of several different illnesses. Ellagic acid (EA) is one of those biological molecules found in pomegranate and may have therapeutic potential in many diseases. EA has been detected not only in pomegranate but also in a wide variety of fruits and nuts such as raspberries, strawberries, walnuts, grapes and black currants, and is becoming an increasingly popular dietary supplement over recent years. Similar to other ellagitannins (ETs), EA is quite stable under physiological conditions in the stomach. EA and ETs as active agents induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-inflammatory and anti-carcinogenic activities in various animal preparations call an attention to the need for designing adequate tests in humans to assess these potentially useful properties in diseased states.

Full text

2013
http://informahealthcare.com/ijf
ISSN: 0963-7486 (print), 1465-3478 (electronic)
Int J Food Sci Nutr, 2013; 64(7): 907–913
!2013 Informa UK Ltd. DOI: 10.3109/09637486.2013.798268
COMPREHENSIVE REVIEW
The pharmacological use of ellagic acid-rich pomegranate fruit
Coskun Usta
1
, Semir Ozdemir
2
, Michele Schiariti
3
, and Paolo Emilio Puddu
3
1
Department of Pharmacology,
2
Department of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey, and
3
Department of
Cardiovascular, Respiratory, Nephrological and Geriatrical Sciences, Laboratory of Biotechnologies Applied to Cardiovascular Medicine, Sapienza,
University of Rome, Rome, Italy
Abstract
In recent years, the therapeutic use of non-drug substances such as herbal and medicinal foods
is increasing progressively. Of these substances, Punica granatum L., which is an ancient and
highly distinctive fruit, has been proposed for treatment of several different illnesses. Ellagic
acid (EA) is one of those biological molecules found in pomegranate and may have therapeutic
potential in many diseases. EA has been detected not only in pomegranate but also in a wide
variety of fruits and nuts such as raspberries, strawberries, walnuts, grapes and black currants,
and is becoming an increasingly popular dietary supplement over recent years. Similar to other
ellagitannins (ETs), EA is quite stable under physiological conditions in the stomach. EA and ETs
as active agents induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-
inflammatory and anti-carcinogenic activities in various animal preparations call an attention to
the need for designing adequate tests in humans to assess these potentially useful properties in
diseased states.
Keywords
Ellagic acid, ellagitannins, polyphenols, Punica
granatum L
History
Received 24 January 2013
Revised 8 April 2013
Accepted 15 April 2013
Published online 23 May 2013
Introduction
Throughout the past decades, there has been a significantly
increased use of dietary supplements such as vitamins, herbals
and medicinal foods in the general population. From 1990 to
1997, more than 15 million adults in the United States reported
using herbal supplements in conjunction with prescribed medica-
tions (Eisenberg et al., 1998). In addition, from 1997 to 2002,
there was a further increase of more than 50% in the consumption
of dietary supplements (Tindle et al., 2005).
The pomegranate, Punica granatum L., is an ancient, mystical
and highly distinctive fruit. In addition to its historical uses,
pomegranate is found in several medicinal systems for a variety of
ailments. Over the past decade, significant progress has been
made in establishing the pharmacological mechanisms of pom-
egranate and its individual responsible constituents.
Current research seems to indicate that the most therapeutic-
ally beneficial pomegranate constituents are ellagitannins (ETs;
including ellagic acid (EA)), punicic acid, f lavonoids, anthocya-
nidins, anthocyanins and estrogenic flavonols and flavones (Espı
´n
et al., 2007; Quideau & Feldman, 1996). Pomegranate’s con-
sumption has been associated with cardiovascular health benefits,
since it contains relevant amounts of phenolic anti-oxidants, and
particularly ETs, considered responsible, at least in part, for these
physiological properties (Larrosa et al., 2010). These polyphenols
contained in pomegranate and different fruits and nuts are
described in the category of hydrolysable tannins, phytochemicals
of the non-flavonoid polyphenol group, including ETs, which
release EA upon hydrolysis and under the physiological
conditions of the gastrointestinal tract (Falsaperla et al., 2005).
EA content of several food products can be quite high.
EA, a polyphenol compound found in a wide variety of fruits
and nuts, such as raspberries, strawberries, walnuts, grapes, and
black currants, is becoming an increasingly popular dietary
supplement over the recent years because it can be easily
extracted and used (Devipriya et al., 2007b). There is a relatively
high content of EA in raspberries (1500 mg/g dry weight),
strawberries (630 mg/g dr y weight), cranber ries (120 mg/g dry
weight), walnuts (590 mg/g dry weight), pecans (330 mg/g dry
weight) and other plant foods (Figure 1; Bala et al., 2006).
Although several functions of EA are described, the mechanism
of its biological functionality is not very well-understood.
Commonly found in many plants, EA exhibits powerful anti-
carcinogenic and anti-oxidant properties, propelling it to the
forefront of pomegranate research (Hassoun et al., 2004;
Priyadarsini et al., 2002; Rukkumani et al., 2004).
There are promising results showing that phytochemicals may
exert their benefits in the prevention and therapy of many diseases
including cancer, atherosclerosis and alcoholism, partially based
on their ability to quench reactive oxygen species and thereby
protecting critical cellular targets (i.e. DNA, proteins and lipids)
from oxidative insult (Mertens-Talcott & Percival, 2005;
Murakami et al., 2002). Recently, ETs and EA appear among
the topics of interest in medicine and food science. This review
will concentrate on the EA and aims at pointing to the important
potential characteristics of EA and ETs in pomegranate
(P. granatum L.) and other fruits and nuts, from a large body of
evidence in animal preparations and clinical investigations, to
foster interest in pharmacological and nutritional properties that
may have indeed application to human disease states. To
accomplish this, Medline English literature was searched, without
restrictions, for EA both in animal and human investigations.
Correspondence: Coskun Usta, MD, Department of Pharmacology,
Faculty of Medicine, Akdeniz University, Antalya, Turkey. Tel: +90
242-2496921. E-mail: fcusta@akdeniz.edu.tr
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Bioavailability and metabolism
ETs have been claimed to possess stable structural properties
under physiological conditions in the stomach. EA, however,
following its absorption in digestive tract, is methyl conjugated by
the action of catechol O-methyltransferase quickly (Larrosa et al.,
2010, 2012). The pharmacokinetic profile of this absorption has
poor characteristics, and only a part of this absorption takes place
in the stomach (Lei et al., 2003). The metabolism of EA proceeds
by conversion of EA to dimethyl-EA-glucuronide, which is the
most abundant metabolite detected up to date via a two-step
reaction (Whitley et al., 2003).
Bioavailability and metabolism of EA and ET have also been
assessed extensively in animal studies. In these studies, Urolithin
A (Uro-A) and Urolithin B (Uro-B) were detected as the
predominant metabolites of EA in urine and feces (Doyle &
Griffiths, 1980).
In humans, 1 h after 180 ml of pomegranate juice consumption,
the maximum EA blood concentration was 31.9 ng/ml, which was
rapidly metabolized in the next 4 h (Seeram et al., 2004). In
another study, the concentration time profile of EA was evaluated,
and the maximum concentration of EA in plasma was 213 ng/ml,
approximately 1 h after oral administration of 0.8 g/kg of pom-
egranate leaf extract (Lei et al., 2003).
In conclusion, ETs are generally not absorbed. Released EA at
gut level is also poorly absorbed in the stomach and small
intestine and largely metabolized by unidentified bacteria in the
intestinal lumen to produce urolithins. Microbial metabolism
primarily starts in the small intestine, and the first metabolites
produced retain four phenolic hydroxyls. The latters are further
metabolized along the intestinal tract to remove hydroxyl units
leading to Uro-A and Uro-B in the distal parts of the colon
(Devipriya et al., 2007b).
Anti-oxidative effects of EA
The phenolic phytochemicals such as EA can aid in the cellular
anti-oxidant defense response by activating the expression of
enzymes involved in anti-oxidant defense and repressing the
expression of oxidative stress producing pathways, such as
nicotinamide adenine dinucleotide phosphate-oxidase, and CYP
dependent phase-I enzymes (Mazumder et al., 1997). Devipriya
et al. have shown in an animal model that EA, at the concentration
of 60 mg/kg of body weight, decreases the intensity of alcohol-
induced toxicity and could be developed as a potential drug for
alcohol abuse (Devipriya et al., 2007a). They also showed the
anti-oxidant and cytoprotective properties of EA against oxidative
stress induced by alcohol (Cozzi et al., 1995). EA protected from
damage induced by mitomycin-C and hydrogen peroxide in
Chinese hamster ovary cells, probably by a scavenger mechanism
of oxygen species produced by H
2
O
2
treatment, and protected
DNA double helix from alkylating agent injury (Iino et al., 2001).
Iino et al. suggested that whisky is less irritating to the rat gastric
mucosa, as compared with pure ethanol, and this property of
whisky may be explained by EA contained in whisky and the
radical scavenging action of EA (Iino et al., 2002). In addition,
Figure 1. Plant ellagitannins and transformation to ellagic acid.
908 C. Usta et al. Int J Food Sci Nutr, 2013; 64(7): 907–913
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EA was shown to exhibit gastric protective action against gastric
lesions induced by ammonium hydroxide or reperfusion in the
ischemic stomach, probably due to its anti-oxidative activity.
Finally, it was found that oral administration of EA can
circumvent the carbon tetrachloride toxicity and subsequent
liver fibrosis (Thresiamma & Kuttan, 1996).
Anti-inflammatory effects of EA
Although the anti-inflammatory and anti-nociceptive effects of
EA were present in several animal models, little information
exists on the exact mechanism related to EA (Corbett et al., 2010;
Gainok et al., 2011; Rogerio et al., 2006). Rogerio et al.
demonstrated that EA significantly decreases paw edema as
measured by calipers after an injection of 1% carrageenan and
decreases the number of acid-induced writhing periods in mice
(Rogerio et al., 2006). A possible involvement in the inflamma-
tory cascade was observed through inhibition of cyclooxygenase
(COX) protein expression, resulting in anti-inflammatory effects.
If EA was a COX inhibitor, then it might be a potent anti-
inflammatory and anti-nociceptive agent. Accordingly, this
reduction in writhing periods may stem from COX inhibition or
another anti-nociceptive pathway (Afaq et al., 2005). These latter
findings were congruent with those of Rogerio et al. (2006). There
are several additional studies suggesting that different plants
containing EA may significantly reduce paw edema in rats
(Corbett et al., 2010; Feresin et al., 2002; Ojewole, 2006).
EA was shown to inhibit Interleukin (IL)-1beta- and tumor
necrosis factor (TNF)-alpha induced activation of activator
protein-1 and mitogen-activated protein kinases in activated
pancreatic stellate cells in vitro (Masamune et al., 2005). EA
exhibits anti-inflammatory properties by inducible nitric oxide
synthase (iNOS), COX-2, TNF-alpha and IL-6 down-regulation
due to nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-kB) repression and exerts its chemopreventive effect on
colon carcinogenesis in rats (Umesalma & Sudhandiran, 2010).
Similarly, pomegranate extract and EA drastically decreased COX-
2 and iNOS overexpression, reduced mitogen-activated protein
kinases phosphorylation and prevented the nuclear NF-kB trans-
location in a murine chronic model of Chron’s disease (Rosillo
et al., 2012). Recently, Gime
´nez-Bastida et al. (2012b) have tested
several metabolites of ET and observed that anti-inflammatory
effects of Uro-A is predominant in colon fibroblasts, which
implicates potential beneficial effects of ET-containing foods on
gut inflammatory diseases. Inhibition of monocyte adhesion and
endothelial cell migration in human aortic endothelial cells were
also detected after exposure to ET metabolites including Uro-A
glucuronide, Uro-B glucuronide or their corresponding aglycones,
which may underlie the beneficial effects against cardiovascular
diseases (Gime
´nez-Bastida et al., 2012a).
Anti-carcinogenic activities
EA was shown as a potent anti-carcinogenic agent in human
studies and animal models, and one of the main mechanisms is by
modulating the metabolism of environmental toxins and therefore
preventing the initiation of carcinogenesis induced by these
chemicals (Zhang et al., 1993). EA is reported to possess
significant anti-mutagenic activity. Teel (1986) suggested that one
of the mechanisms by which EA inhibits mutagenesis and
carcinogenesis is by forming adducts with DNA, thus masking
binding sites to be occupied by the mutagen or carcinogen.
However, this assumption has never been proved directly and still
remains to be elucidated. Soni et al. (1997) showed that EA may
inhibit the mutagenesis induced by aflatoxin B1 in Salmonella
tester strains TA98 and TA100. Another set of experiments
suggested that EA may lead to G
1
phase arrest within 48 h, able to
inhibit overall cell growth and to induce apoptosis in CaSki cells
after 72 h of treatment. Fur thermore, EA was suggested to have a
role in cell cycle regulation of cancer cells via activation of the
cyclin-dependent kinase (CDK) inhibitory protein p21
(Narayanan et al., 1999) and to prevent the cancer progression
by down-regulation of protein kinase C signaling pathway leading
to cell proliferation in lymphoma (Mishra & Vinayak, 2013).
EA was also found to significantly reduce the number of bone
marrow cells with chromosomal aberrations and chromosomal
fragments (Thresiamma et al., 1998). Chen et al. suggested that the
anti-tumor-promoting action of EA and of other related phenolics
may be mediated, in part, by inducing a redox modification of
protein kinase C, which serves as a receptor for tumor promoters
(Chen et al., 2000). Other studies have shown that EA is a potent
inhibitor of DNA topoisomerases, which are involved in carcino-
genesis. By using specific in vitro assays, structure–function
activity studies identified the 3,3-hydroxyl groups and the lactone
groups as the most essential elements for the topoisomerase
inhibitory actions of plant phenolics (Constantinou et al., 1995).
Furthermore, EA and polyhydroxylated urolithins were suggested
to act as adenosine triphosphate (ATP)-competitive inhibitors of
human topoisomerase II (Furlanetto et al., 2012).
Khanduja et al. looked into the anti-carcinogenic potential of
plant polyphenols such as EA and quercetin against N-
nitrosodiethylamine-induced lung tumorigenesis in mice. EA
was effective in decreasing the lipid peroxidation and increasing
the glutathione levels. This impact was suggested as one of the
factors responsible for higher anti-carcinogenic properties as
compared to quercetin in mice (Khanduja et al., 1999). However,
combined quercetin and EA treatment increased the activation of
p53 and p21cip1/waf1 and the MAP kinases, JNK1,2 and p38, in a
more than additive manner, suggesting a mechanism by which
quercetin and EA synergistically induce apoptosis in cancer cells
(Mertens-Talcott et al., 2005).
Losso et al. suggested that EA exhibit a selective cytotoxicity
and anti-proliferative activity and induced apoptosis in Caco-2,
MCF-7, Hs 578T and DU 145 cancer cells without any toxic
effect on the viability of normal human lung fibroblast cells. It
was also observed that the mechanism of apoptosis induction in
EA-treated cancer cells was associated with decreased
ATP production, which is crucial for the viability of cancer
cells (Losso et al., 2004). EA significantly reduced the viable
cells, induced G
0
/G
1
-phase arrest of the cell cycle and apoptosis.
It also increased p53 and p21 and decreased CDK2 gene
expression that may lead to the G
0
/G
1
arrest of T24 cells and
promoted caspase-3 activity after exposure for 1, 3, 6, 12 and 24 h,
which led to induction of apoptosis. Furthermore, the EA-induced
apoptosis on T24 cells was blocked by the broad-spectrum
caspase inhibitor (carbobenzoxy-valyl-alanyl-aspartyl-[O-
methyl]-fluoromethylketone; Li et al., 2005). In a study,
EA application resulted in remarkable stimulation of apoptosis
through inhibition of the prosurvival transcription factor NF-kB
(Edderkaoui et al., 2008). Additionally, Malik et al. evaluated
a crude pomegranate fruit extract containing EA for its
anti-proliferative and pro-apoptotic properties and found that it
can cause both cell growth inhibition and apoptosis in a
dose-dependent manner in androgen-insensitive PC3 cells
via modulation of the cyclin kinase inhibitor–cyclin–CDK
machinery (Malik et al., 2005). It was also shown that the potential
of EA to down-regulate the 17b-estradiol-induced human
telomerase reverse transcriptase aþbþmRNA expression may
be a mechanism via which, at least in part, chemopreventive
effects in breast cancer are obtained (Strati et al., 2009).
In a recent study, the involvement of phosphatidylinositol
30-kinase(PI3K)-Akt signaling was also suggested as molecular
pathway by which EA may induce apoptosis and subsequently
DOI: 10.3109/09637486.2013.798268 Ellagic acid pharmacology 909
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suppress colon cancer during 1,2-dimethylhydrazine-induced rat
colon carcinogenesis (Umesalma & Sudhandiran, 2011). Taken
all these evidences together, interest in EA has increased so much
that the American Cancer Society maintains an information link
on its Web site (www.cancer.org).
However, despite these clinical and experimental studies that
ascribed beneficial effects of pomegranate to EA, anti-carcino-
genic effect of pomegranate juice consumption can not only be
due only to EA but also other phytochemicals (Mena, 2011). A
clinical trial in patients with rising PSA values after surgery or
radiotherapy begun in January, 2003. During this study, patients
were treated with 8 oz of pomegranate juice daily for 2 years.
Interestingly, mean PSA doubling time following treatment, from
15 months at baseline to 54 months post-treatment increased
significantly (Pantuck et al., 2006). In an ex vivo mitogenic
bioassay, serum obtained from these pomegranate juice-treated
patients inhibited proliferation and stimulated apoptosis of
prostate cancer cell line prostate cancer cells in vitro (Pantuck
et al., 2006; Schubert et al., 1999). Moreover, pomegranate juice
components may also be effective in the treatment of metastasis of
other cancers, since the mechanisms of metastasis are similar for
most cancers (Wang et al., 2012). Accordingly, Rocha et al.
showed that pomegranate juice exert inhibitory effect on meta-
static processes in breast cancer cells in addition to prostate
cancer cells (Rocha et al., 2012). Another randomized, double
blind, controlled clinical trial investigated the effects of pom-
egranate tablets on symptoms of benign prostatic hyperplasia is
now being conducted and was not completed yet (Table 1). In a
phase II ongoing study, pomegranate juice is evaluated in patients
with recurrent adenocarcinoma of the prostate. Table 1 condenses
all the information that may be obtained at present on running
clinical trials with pomegranate juice.
Anti-hyperlipidemic effects of EA
Consumption of pomegranate juice has been suggested to reduce
oxidation of low-density lipoprotein (LDL) cholesterol (LDL-c)
and leading to the elimination of arterial plaques both in human
and animal studies (Aviram, 2012; Aviram & Rosenblat, 2012).
However, despite the findings showing striking reduction in blood
pressure, LDL oxidation and carotid intimal-media thickness,
serum glucose and lipid profiles have not been altered by
pomegranate juice consumption (Aviram et al., 2004; Sumner
et al., 2005). Similarly, pomegranate seed oil was also unable to
change serum cholesterol and LDL levels in Obese Zucker rats
(de Nigris et al., 2007). This beneficial effect of pomegranate
juice in atherosclerotic disease in animal models was ascribed to
the presence of EA (Yu et al., 2005). Pomegranate juice and
extracts, rich in EA and ETs, have been shown to exert multiple
anti-atherogenic effects. Pomegranate juice protected lipoproteins
from oxidation by up-regulating the expression and activity of
paraoxonase (PON)1 and PON2 in hepatic cells and in macro-
phages and inducing the association of PON1 to high-density
lipoprotein (HDL) (Fuhrman et al., 2010; Khateeb et al., 2010;
Shiner et al., 2007). On the other hand, anti-oxidative properties
of pomegranate juice on mouse macrophages have been sug-
gested to act via pomegranate juice-induced stimulation of
macrophage PON2 expression, while serum PON1 stimulation
by pomegranate juice consumption were not implicated in this
effect (Rosenblat et al., 2010). PONs are lactonases that prevent
Table 1. Clinical trials with pomegranate juice.
Clinical trials
GOV identifier Study focus Sponsor Study start date Status
NCT00413530 Rising PSA levels in men with previous
prostate cancer
M.D. Anderson Cancer
Center
December 2006 Currently recruiting
NCT00719030 A study of the effectiveness of pomegranate
pills in men with prostate cancer before
prostatectomy
University of California,
Los Angeles
October 2009 Currently recruiting
NCT00668954 Antioxidant effects of pomegranate juice
versus placebo in adults with type 2
diabetes mellitus
University of Colorado,
Denver
April 25, 2008 Unknown
NCT00727519 The Effect of pomegranate juice on oxidative
stress in hemodialysis patients
Western Galilee Hospital-
Nahariya
July 27, 2008 Completed but unknown
NCT00060086 Pomegranate juice in treating patients with
recurrent prostate cancer
University of California,
Los Angeles
May 6, 2003 This study is ongoing, but
not recruiting
participants
NCT00428532 The effect of licorice root extract and pom-
egranate juice on atherosclerotic param-
eters in diabetic patients
HaEmek Medical Center,
Israel
January 2007 Unknown
NCT01220206 POMx in the treatment of erectile
dysfunction
POM Wonderful LLC June 2011 Ongoing
NCT01220817 Safety and efficacy of POMx capsules in men
with recurrent prostate cancer: an 18-
month study
POM Wonderful LLC October 8, 2010 Completed
NCT00682149 Effects of polyphenol containing antioxidants
on oxidative stress in diabetic patients
Yeditepe University
Hospital
May 2008 Unknown
NCT00455416 Dietary intervention in follicular lymphoma
(KLYMF)
Oslo University Hospital April 2007 Ongoing
NCT01100866 Study of POMELLAÔextract to treat pros-
tate cancer
Vancouver Coastal Health December 2009 Currently recruiting
NCT00470808 The effect of a natural polyphenolic extract
From pomegranate (POMX) on the
development of atherosclerosis in diabetic
patients
HaEmek Medical Center,
Israel
April 2007 Unknown
NCT00728299 The effects of consumption of pomegranate
juice on carotid intima-media thickness
Radiant Research July 31, 2008 Completed
NCT00381108 Study of the effects of pomegranate tablets on
enlarged prostates
University of California,
Irvine
September 26, 2006 Ongoing
910 C. Usta et al. Int J Food Sci Nutr, 2013; 64(7): 907–913
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LDL-c from peroxidation, thereby preventing atherosclerosis.
Pomegranate extracts also reduced the levels of cholesterol in
macrophages by inhibiting the uptake of native and oxidized LDL
(ox-LDL) and stimulating HDL efflux and protected monocytes
and endothelial cells from peroxide and ox-LDL damage (Aviram
et al., 2008; Sestili et al., 2007).
In addition to the prevention of lipoproteins oxidation, the anti-
atherogenic properties of pomegranate also include its capacity to
induce the expression of endothelial nitric oxide synthase in
human and rat artery endothelial cells and to inhibit activated
platelets aggregation as well as to reduce the production of the
circulating platelet activating agent thromboxane A2 (de Nigris
et al., 2007; Mattiello et al., 2009). Other extracts rich in EA and
ETs, such as walnut extracts, were also able to delay LDL
oxidation and to decrease the levels of intercellular adhesion
molecule 1 (ICAM-1) and vascular cell adhesion molecule 1
(VCAM 1) in human endothelial cells (Anderson et al., 2001;
Karlsson et al., 2010; Papoutsi et al., 2008).
EA has been reported to have anti-inflammatory effects by
reducing the levels of prostaglandin synthases and by decreasing
the expression levels of adhesion molecules such as ICAM-1,
VCAM-1 and E-selectin (Huang et al., 2011; Yu et al., 2007).
In addition, EA also induces anti-angiogenic responses by
decreasing the levels of the metalloproteinase matrix metallopro-
teinase-12 and inhibiting vascular endothelial growth
factor-induced endothelial and vascular smooth muscle cells
migration (Labrecque et al., 2005; Takahashi et al., 2010).
Recently (Kannan & Quine, 2013) showed that oral pre-
treatment with EA was safe and effective in cardioprotection
against isoproterenol-induced arrhythmias, hypertrophy and myo-
cardial necrosis. Anti-lipid peroxidation property and anti hyper-
lipidemic activity through 3-hydroxy-3 methyl glutaryl CoA
reductase inhibition by EA may be the reasons for the beneficial
action of EA against experimentally induced myocardial
infarction.
Other effects
Pomegranate extracts have been reported to exhibit hypotensive
and anti-diabetic effects in Wistar rats (Mohan et al., 2010). The
administration of 100–300 mg/kg/d for 4 weeks of pomegranate
juice extract to animals treated with angiotensin II decreased
mean arterial blood pressure and the biochemical changes induced
by diabetes and angiotensin II (Huang et al., 2005b). The
consumption of pomegranate flower extract and punicic acid
increases oral glucose tolerance and decreases the fasting glucose
plasma levels in experimental diabetes (Bagri et al., 2009;
Hontecillas et al., 2009). The mechanisms that may be involved in
these anti-diabetic effects include an increase in peroxisome
proliferator-activated receptor-gamma expression in cardiac,
skeletal muscle and adipose tissue (Huang et al., 2005a;
Yoshimura et al., 2005). Yoshimura et al. (2005) demonstrated
that an oral administration of EA-rich pomegranate extract
effectively whitened the pigmented skin of guinea pigs. This
effect was probably due to inhibition of the proliferation of
melanocytes and melanin synthesis by tyrosinase in melanocytes.
We have a preliminary experience showing that in rat thoracic
aorta, EA administration causes vasorelaxation, which is, in part,
modulated via endothelium-dependent mechanisms and through
inhibition of calcium influx (Yilmaz & Usta, 2013).
Conclusions
In an era where supplementations to ailments became so popular to
see a tremendous growth over the past 20 years, it may be timing to
make studies using pomegranate, a fruit used as a medicinal food
for centuries. It is, however, important to stress that data obtained
until now from humans are limited, thus indicating that EA, the
main active compound of pomegranate juice, and its potential
health protective effects are mostly derived from animal or in vitro
studies. In addition, it is not clearly established whether all
protective effects are attributed to EA per se, or to other food
components as well included in the same foods like quercetin,
which is reported to act synergistically with EA, or to the presence
in pomegranate juice of a high amount of anthocyanins, already
found to exert anti-carcinogenic properties. Moreover, the bene-
ficial effects of EA have been mostly attributed to its active
metabolites such as Uro-A and Uro-B. Therefore, further investi-
gations are needed to clarify these issues unequivocally.
Poor absorption from the gut may limit the bioavailability and
clinical usefulness of EA. Therefore more pharmacokinetic
research, especially in humans, is required before the real
usefulness of EA is determined. Nevertheless, the evidence
pointing to two main constituents of pomegranate, EA and ETs,
as active agents to induce in various animal preparations, both
in vitro and in vivo, vasorelaxation, oxygen scavenging, hypolipi-
demic, anti-inflammatory and anti-carcinogenic activities, call
attention to the need for designing adequate tests in humans to
assess these potentially useful properties in diseased states. It will
be essential to assess whether health protective effects of EA and/or
ETs are seen at plasma concentrations (around 50 nM) obtained
after ordinary quantity of pomegranate juice (5200 ml).
Unfortunately, the large majority of current clinical trials in man
are ongoing and for those completed, yet, little information exists.
Acknowledgements
This study was supported by Akdeniz University Scientific Research Unit
grant (No: 2010.01.0103.003).
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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