The protective effect of pomegranate extract against cisplatin toxicity in rat liver and kidney tissue

Abstract

The purpose of this study was to perform a histopathological investigation, at the light microscopy level, of the protective effects of pomegranate extract in cisplatin-induced liver and kidney damage in rats.
Twenty-eight adult male Wistar albino rats were randomly divided into four groups of seven animals: Group 1: Control; Group 2: Treated for 10 consecutive days by gavage with pomegranate juice (2 ml/kg/day); Group 3: Injected intraperitoneally with cisplatin (8 mg/kg body weight, single dose) onset of the day 5, and Group 4: Treated by gavage with pomegranate juice 10 days before and after a single injection of cisplatin onset of the day 5. After 10 days, the animals were sacrificed and their kidneys and liver tissue samples were removed from each animal after experimental procedures. Cisplatin-induced renal and hepatic toxicity and the effect of pomegranate juice were evaluated by histopatological examinations.
In the kidney tissue, pomegranate juice significantly ameliorated cisplatin-induced structural alterations when compared with the cisplatin alone group. But in the liver tissue, although pomegranate juice attenuated the cisplatin-induced toxicity only in two rats, significant improvement was not observed.
In conclusion, these results demonstrate that the anti-oxidant pomegranate juice might have a protective effect against cisplatin-induced toxicity in rat kidney, but not in liver. Pomegranate juice could be beneficial as a dietary supplement in patients receiving chemotherapy medications.

Full text

http://informahealthcare.com/arp
ISSN: 1381-3455 (print), 1744-4160 (electronic)
Arch Physiol Biochem, Early Online: 1–5
!2015 Informa UK Ltd. DOI: 10.3109/13813455.2015.1068336
ORIGINAL ARTICLE
The protective effect of pomegranate extract against cisplatin toxicity in
rat liver and kidney tissue
Salih Bakır
1
,U
¨mit Can Yazgan
2
,_
Ibrahim _
Ibilog
˘lu
3
, Bilal Elbey
4
, Murat Kızıl
5
, and Mustafa Kelle
1
1
Dicle University, School of Medicine, Department of Physiology, Diyarbakır, Turkey,
2
Zirve University, School of Medicine, Department of
Physiology, Gaziantep, Turkey,
3
Dicle University, School of Medicine, Department of Pathology, Diyarbakır, Turkey,
4
Dicle University, School
of Medicine, Department of Immunology, Diyarbakır, Turkey, and
5
Dicle University, Faculty of Science, Chemistry Department, Diyarbakır,
Turkey
Abstract
Objectives: The purpose of this study was to perform a histopathological investigation, at the
light microscopy level, of the protective effects of pomegranate extract in cisplatin-induced
liver and kidney damage in rats. Material and methods: Twenty-eight adult male Wistar albino
rats were randomly divided into four groups of seven animals: Group 1: Control; Group 2:
Treated for 10 consecutive days by gavage with pomegranate juice (2 ml/kg/day); Group 3:
Injected intraperitoneally with cisplatin (8 mg/kg body weight, single dose) onset of the day 5,
and Group 4: Treated by gavage with pomegranate juice 10 days before and after a single
injection of cisplatin onset of the day 5. After 10 days, the animals were sacrificed and their
kidneys and liver tissue samples were removed from each animal after experimental
procedures. Cisplatin-induced renal and hepatic toxicity and the effect of pomegranate juice
were evaluated by histopatological examinations. Results: In the kidney tissue, pomegranate
juice significantly ameliorated cisplatin-induced structural alterations when compared with
the cisplatin alone group. But in the liver tissue, although pomegranate juice attenuated the
cisplatin-induced toxicity only in two rats, significant improvement was not observed.
Conclusion: In conclusion, these results demonstrate that the anti-oxidant pomegranate juice
might have a protective effect against cisplatin-induced toxicity in rat kidney, but not in liver.
Pomegranate juice could be beneficial as a dietary supplement in patients receiving
chemotherapy medications.
Keywords
Cisplatin toxicity, kidney, liver, pomegranate
extract
History
Received 16 April 2015
Revised 23 June 2015
Accepted 26 June 2015
Published online 6 August 2015
Introduction
Several studies have shown that due to phenolic compounds
such as phenolic acid and flavonoids, pomegranates possess
anti-oxidant (Heber et al., 2006), anti-carcinogenic (Khan,
2009), anti-inflammatory properties (Hollebeeck et al., 2012),
as well as therapeutic efficacy (Jurenka, 2008; Zarfeshany
et al., 2014). Studies investigating the protective effect of
pomegranate against the nephrotoxic and hepatotoxic char-
acteristics of cisplatin have examined that protection using
materials prepared from pomegranate flower extract
(Motamedi et al., 2014) and pomegranate seed extract
(C¸ayır et al., 2011; Yildirim et al., 2013), have shown
positive results.
However, no studies have investigated the protective effect
of fresh pomegranate extract against cisplatin-related nephro-
toxicity or hepatotoxicity. Pomegranate was used in one study
with carbon tetrachloride (CCl
4
) induced nephrotoxicity and
hepatotoxicity (Moneim & El-Khadragy, 2013) and in another
with cisplatin-induced ototoxicity (Akdag
˘et al., 2014).
Positive results were reported in both studies. Cisplatin
interacts with DNA in liver and kidney, which results in DNA
damage-induced apoptosis (Jordan & Carmo-Fonseca, 2000).
Cisplatin is a heavy metal alkylating agent and acts by
damage to DNA. Metabolites released as a result of hydration
of cisplatin (monokloromonoakuadiaminplat or diakuodia-
minplat) alkylates purine and pyrimidine nucleotides that are
essential for nuclear materials. It disrupts DNA replication
and transcription and arrests the cell cycle in the G2 phase
(Erkurt et al., 2009).
The purpose of this study was to perform a histopatho-
logical investigation, at the light microscopy level, of the
protective effects of pomegranate extract in cisplatin-induced
liver and kidney damage in rats.
Materials and methods
This prospective study was performed from 14 July to 24
July at the Dicle University Animal Laboratory, Turkey.
Twenty-eight healthy adult male Wistar albino rats weighing
mean 260 ± 35 grams were used. Experimental procedures
Correspondence: U
¨mit Can Yazgan, Assistant Professor, Zirve
University, School of Medicine, Department of Physiology, Gaziantep,
27260, Turkey. Tel: +90 342 2116666-7584. Gsm: +90 532 7664528.
E-mail: umitcanyazgan@gmail.com
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were performed in compliance with the conditions for the
care and use of laboratory animals. Rats were housed in
steel cages with sufficient room to move around freely
(40 60 cm). Chippings were used as flooring, and cages
were cleaned daily. Animals were given standard rat pellet
chow with no dietary restriction and daily fresh spring water
ad libitum. Rats were kept under standard laboratory
conditions (12 h light/dark cycle, 22 C ±2 room tempera-
ture, relative humidity rate 50% ± 10 and with appropriate
ventilation).
Experimental animals were randomly assigned into one of
four groups, each containing seven rats:
Group 1: Control.
Group 2: Pomegranate extract.
Group 3: Cisplatin.
Group 4: Cisplatin + pomegranate extract.
The planned study duration was 10 days.
To result in hepatotoxicity, the dose of cisplatin (Cisplatin
DBL 10 ml 10 mg vial, Orna _
Ilac¸ Sanayi, Turkey) with a
single injection should be at least 7.5 mg/kg (Zicca et al.,
2002; Mansour et al., 2006). Cisplatin was administered in a
single 8 mg/kg intraperitoneal (i.p.) dose on the fifth day of
the study. Pomegranate extract was administered at a dose of
2 cc/kg per day by gavage using an orogastric tube. General
anaesthesia was performed i.p. using a combination of
5 mg/kg xylazine (alphazyne 2%, Alfasan International BV,
Woerden, Holland) and 50 mg/kg ketamine hydrochloride
(Ketalar, Eczacıba¸sı Pharmaceutical Industry, Lu
¨leburgaz,
Turkey).
Cisplatin administration in the third group was performed
i.p. on the fifth day using a single 8 mg/kg dose. In the fourth
group, cisplatin and pomegranate extract, administration
of 2 cc/kg dissolved pomegranate extract commenced 4 days
before administration of cisplatin, continued for 5 days
thereafter, and was concluded on the tenth day. In the
second group, receiving only pomegranate without cisplatin,
pomegranate extract was again administered for 10 days. No
allergy or mortality associated with cisplatin or pomegranate
extract was observed. The control group (Group 1) received
a single i.p. dose of sodium chloride solution on the fifth
day in a volume equal to that of the cisplatin given to the
other groups.
Fresh pomegranate extract was obtained by pressing one
pomegranate, including the shell and part of the section
membranes and seeds, and was given to the subjects on
every day of the study. The pomegranates were all of the
same type. Total phenolic contents of the filtered extract
were analysed using the Folin-Ciocalteu method (FCR)
(Motamedi et al., 2014); 0.5 ml of pomegranate juice was
diluted with 1.58 ml deionized water and was mixed 100ml
Folin-Ciocalteu re-agent; 30 seconds later 30 mlNa
2
CO
3
was added to the mixture. The mixture was incubated
at 20 C for 2 h and then absorbance was measured at
765 nm with a spectrophotometer. Results were expressed
with gallic acid equivalents (GAE) (mg GAE/0.5 ml). The
total flavonoid content in pomegranate juice was deter-
mined with colorimetric method based on flavonoid
aluminium complex formation. Results were expressed in
quercetin equivalent (QUE ug/0.5 ml) (Motamedi et al.,
2014).
On the tenth day of the study animals in all groups were
administered general anesthesia after 12-h fasting with an i.p.
combination of 10 mg/kg xylazine and 50 mg/kg ketamine
hydrochloride. Animals were then sacrificed with cardiac
puncture. The abdomens were then opened and liver and
kidney tissues extracted.
For examination under light microscope, the kidney and
liver tissues were fixed in 10% formalin for 48 h and subjected
to routine processing and embedded in paraffin blocks.
Sections 5 mm in thickness were taken using a microtome
(Leica RM2125RTS). Sections were stained with hematoxylin
and eosin and covered with entellan. Sections were examined
under a light microscope (Olympus BX53) and photographs
were taken using a digital camera (Olympus Camera DP26).
At histopathological examination, injury in kidney tissues
from all groups was investigated on the basis of tubular
swelling, brush-like margin loss, nuclear condensation and
loss of tubular nuclei. Each section was scored between 0 and
3 (no injury ¼0; slight injury ¼1; moderate injury ¼2; severe
injury ¼3) (Motamedi et al., 2014).
Injury in liver sections from all groups was assessed on
the basis of cytoplasmic vacuolization in hepatocytes, focal
nuclear pyknosis, parenchymal necrosis, cytoplasmic eosino-
philia, sinusoidal dilation, loss of tissue structure in hepatic
cords and congestion-thrombosis. Each section was scored
between 0 and 4 (no injury ¼0; slight injury ¼1; moderate
injury ¼2; severe injury ¼3; very severe injury ¼4) (C¸ayır
et al., 2011).
The results were analysed using the chi-square test on
SPSS for Windows 15.0 software. pvalue50.05 was regarded
as significant.
Ethical approval for the study was obtained from the Dicle
University Ethical Committee under protocol No. 2014/33
dated 10.06.2014.
Results
Total phenolic content of pomegranate extract was deter-
mined at 26.25 mg GAE/0.5 ml and f lavonoid content at
31.50 mg/0.5 ml. Histological analysis results are shown in
Table 1.
Light microscopic examination of kidney tissues from
Groups 1 and 2 revealed normal morphological characteristics
in terms of renal organelles (glomerular clusters with a
normal appearance, normal thickness in the parietal basement
membrane and glomerular basement membrane), proximal
tubules (structure consisting of prismatic cells with brush-like
margins and regular periodicity) and distal tubules (located on
Table 1. The results of the histopathological analysis of the groups’
kidney tissues.
Groups (n,%)
Kidney
tissue Control
Pomegranate
extract Cisplatin
Cisplatin +
pomegranate
extract
Grade 0 7 (100%) 7 (100%) – 3 (42.9%)
Grade 1 – – 2 (28.6%) 4 (57.1%)
Grade 2 – – 5 (71.4%) –
Grade 3 – – – –
2S. Bakır et al. Arch Physiol Biochem, Early Online: 1–5
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basement membranes of normal thickness, structure consist-
ing of isoprismatic cells).
Results from Group 3 revealed significantly greater
injury compared with the control group (p50.001).
Histopathological examination revealed swelling in some
tubular cells, brush-like margin loss, nuclear condensation
and losses at levels between one third and two thirds in
tubular epithelium cell nuclei (Figure 1).
Examination of preparates from Group 4 subjects (the
cisplatin + pomegranate extract group) revealed less tubular
cell injury compared with Group 3, less cytoplasmic trans-
parency and an improvement in tubular epithelium cell losses
(Figure 2).
The cisplatin + pomegranate extract group exhibited sig-
nificantly greater decreases in injury compared to the cisplatin
group (p¼0.003).
The results of the histopathological analysis of the groups’
liver tissues are shown in Table 2.
Light microscopic examination of liver tissues from
Group 1 (control group) and Group 2 (pomegranate extract
group) revealed a regular lobule structure. Hepatocytes,
hepatic parenchymal cells, formed hepatocyte cords in a
linear and radial arrangement around the central veins
(V. centrolobularis) and were sited parallel to the sinusoids.
Hepatocytes had large, round centrally located single or
occasionally double nuclei and contained glycogen granules
distributed in such a way as to bestow a granular appearance.
The portal vein (V. porta) and hepatic artery (A. hepatica)
branches and gallbladder canals had a normal appearance.
No findings such as sinusoidal dilatation, congestion, vacu-
olar changes in hepatocyte cytoplasm, cytoplasmic eosino-
philia, nuclear pyknosis, inflammatory inflammation or
parenchymal necrosis were observed.
Light microscopic examination of liver tissues from
subjects in Group 3 (cisplatin group) revealed vacuolization
in hepatocyte cytoplasm in all animals and more severe
compromise including areas of coagulative necrosis, hyper-
eosinophilia in cytoplasm, and dense sinusoidal dilatation and
congestion in one animal. The findings revealed significantly
greater liver damage compared to the control group
(p50.001) (Figure 3).
Light microscopic examination of liver tissues from
subjects in Group 4 (cisplatin and pomegranate extract
group) revealed improvement in cytoplasmic vacuolization
in two rats in the cisplatin group and no change in the others
(p¼0.204) (Figure 4).
No significant improvement in injury was observed
compared with the group receiving cisplatin.
Figure 3. The histological liver section of Group 3 (Cisplatin).
Figure 2. The histological kidney section of Group 4
(Cisplatin+pomegranate extract).
Figure 1. The histological kidney section of Group 3 (Cisplatin).
Table 2. The results of the histopathological analysis of the groups’ liver
tissues.
Groups (n,%)
Liver
tissue Control
Pomegranate
extract Cisplatin
Cisplatin +
pomegranate
extract
Grade 0 7 (100%) 7 (100.0%) – 2 (28.6%)
Grade 1 – – 6 (85.7%) 4 (57.1%)
Grade 2 – – – –
Grade 3 – – 1 (14.3%) 1 (14.3%)
DOI: 10.3109/13813455.2015.1068336 The protective effect of pomegranate extract against cisplatin toxicity in rat liver and kidney tissue 3
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Discussion
Several studies have shown that pomegranate exhibits high
anti-oxidant activity. Pomegranate extracts have been shown
to exhibit a 2–3-fold greater anti-oxidant effect than red wine
and green tea (Gil et al., 2000) and a 6–8-fold greater effect
than grape, grapefruit and orange juice (Tzulker et al., 2007).
Garcia-Alanso et al. (2004) investigated polyphenols in 28
types of fruit and reported the highest levels of polyphenols in
pomegranate, grape, and blackberry (Guo et al., 2003).
Another study investigating the amount of phenolic com-
pounds in pomegranate extract reported that pomegranate
extract contains approximately twice as many phenolic
compounds than the phenolic compound-rich green tea
(1029 mg/L) (Gil et al., 2000). In a study employing five
different methods, Seeram et al. (2004) reported the highest
level of anti-oxidant capacity in pomegranate extract. This
was followed, in order, by red wine, concord grape juice,
blueberry juice, sour cherry juice, cornelian cherry juice,
orange juice, ice tea and apple juice (Seeram et al., 2004). We
administered fresh pomegranate extract prepared with a fruit
press in a laboratory environment to the experimental animals
in this study.
Cisplatin produces reactive oxygen species such as
hydroxyl radicals, hydrogen peroxide and singlet oxygen
and superoxide ions, compromises natural anti-oxidant
defence by inhibiting anti-oxidant enzymes and increasing
reactive oxygen species, and also leads to lipid peroxidation in
membranes and a decrease in protective enzyme activities
against peroxidation. This increased oxidative stress, which
results in DNA injury, is responsible for the resulting
nephrotoxicity (Nazırog
˘lu et al., 2004). Cisplatin primarily
targets distal convoluted tubules and proximal smooth
tubules, which are rich in mitochondria organelles
(Mainccia-Bozzo et al., 1990). Acute tubular necrosis has
been reported in 30% of patients after even the first course of
cisplatin therapy (Erkurt et al., 2009; dos Santos et al., 2012).
There has been an increase in recent years in the number of
studies investigating the efficacy of various anti-oxidants
against cisplatin nephrotoxicity. Many fruit and vegetables are
well-known for their powerful anti-oxidant activities. For that
reason, various anti-oxidant agents have been investigated in
red pepper (Shimeda et al., 2005), ginkgo biloba extract
(Gulec et al., 2006), melatonin (Kilic et al., 2013), vitamin E
(Kanter et al., 2007), vitamin C (Chen et al., 2014), lycopene
(Atessahin et al., 2005), thymol (thyme oil) (Hosseinimehr
et al., 2015), black tea (tannic acid) (Ahmed & Sultana,
2012), turmeric (curcumin, Indian saffron) (Sahin et al.,
2014) and green tea (Ahn et al., 2014) for their protective
effects against nephrotoxicity.
Antimicrobial (Heber et al., 2006), anti-fungal (Heber
et al., 2006), anti-inflammatory (Hollebeeck et al., 2012) and
anti-oxidant (Heber et al., 2006) effects of pomegranate
extracts have been reported. The main phenolic compound in
pomegranate flower extract is gallic acid, which is well
known for its anti-oxidant activity (Aruoma et al., 1993;
Li et al., 2005). Protective effects of aqueous extract of
pomegranate have been shown in nephrotoxicity models
(Cekmen et al., 2013; Motamedi et al., 2014).
Tubular injury such as dilated tubules containing cystic
formations, especially in the corticomedullary region, vacuo-
lization in the tubular epithelium and tubular epithelium cell
loss, as well as deposition in tubules in some cases were
observed in rats receiving cisplatin injection. These findings,
suggestive of focal acute tubular necrosis, were compatible
with the results of previous studies involving kidney damage
induced with cisplatin (Ate¸s¸sahı
´net al., 2005, 2007; C¸ayır,
2011; Ahn et al., 2014).
In our study, damage was significantly greater, in terms of
all parameters, in the group administered cisplatin compared
to the control group (p50.001). A significant improvement
was observed in all injury parameters in the cisplatin + pom-
egranate extract group compared to the cisplatin group
(p¼0.003).
The hepatobiliary system and the kidneys, are important in
excreting the toxic metabolites of cisplatin from the body.
After the kidneys, cisplatin is mostly metabolized in the liver
(Maniccia-Bozzo et al., 1990). Maniccia-Bozzo et al. (1990)
compared mitochondria in hepatocytes with platinum con-
centrations in nuclear regions and reported greater platinum
metabolite concentration in mitochondria.
In an immunohistochemical investigation of the effective-
ness of pomegranate seed extract, C¸ayıret al. (2011) reported
sinusoidal dilatation, congestion, hepatocyte degeneration,
inflammation in the portal region and increased apoptotic
activity, particularly around the central vein, in rats receiving
cisplatin. Pomegranate seed extract administered for 15 days
following cisplatin injection significantly reduced these
findings. In other words, pomegranate seed extract was
effective in the repair of cisplatin-related injury. Comparison
of the cisplatin + pomegranate extract group and the group
receiving cisplatin alone in our study, revealed that the
hepatotoxic changes were not statistically significant
(p¼0.204). Pomegranate extract, identified as beneficial in
the kidney, had no effect against cisplatin-induced
hepatotoxicity.
In conclusion, we think that administration of a substance
with powerful anti-oxidant activity such as pomegranate
extract before cisplatin and with a subsequent maintenance
dose completely prevented injury in the kidney and partly
prevented damage in liver tissue. We think that pomegranate
extract is an inexpensive, easily available, and easy to use
Figure 4. The histological liver section of Group 4 (Cisplatin +
pomegranate extract).
4S. Bakır et al. Arch Physiol Biochem, Early Online: 1–5
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alternative in the elimination or reduction of damaging side-
effects of cisplatin on the kidney and liver.
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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