Pomegranate seed oil protects against tacrolimus-induced toxicity in the heart and kidney by modulation of oxidative stress in rats

Document Type : Original Research Article


1 Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran. Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Cancer Molecular Pathology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Objective: The clinical use of tacrolimus is limited due to its side effects. This research investigated the protective activities of pomegranate seed oil (PSO) against TAC toxicity.
Materials and Methods: The groups are included normal (1 ml of corn oil), TAC (2 mg/kg), and co-treatment of PSO (0.4 and 0.8 ml/kg) and TAC. All administrations were carried out intraperitoneally for 14 days. After the last injection, blood was collected from the heart.
Results: TAC increased creatinine and urea. Increased malondialdehyde, reduced thiol content and superoxide dismutase. The elevation of lactate dehydrogenase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine kinase-MB and creatinine phosphokinase that confirmed cardiac toxicity. PSO reduced TAC toxicity. PSO decreased TAC-induced pathology injury.
Conclusion: PSO reduced TAC toxicity in renal and heart via scavenging free radicals.


Afsar T, Razak S, Batoo KM, Khan MR. 2017.
Acacia hydaspica R. Parker prevents
doxorubicin-induced cardiac injury by
attenuation of oxidative stress and
structural Cardiomyocyte alterations in rats.
BMC Complement Altern Med, 17: 1-14.
Ahmed O, Ashour M, Fahim H, AbouZid S,
Ahmed R, Abdel Gaid M. 2016.
Ameliorative effects of Punica Granatum
juice and extracts against 7, 12-
Dimethylbenz (a) Anthracene and carbon
tetrachloride-induced Cardiorenal toxicity
in albino rats. SM J Biol, 2: 1011.
Al-Harbi NO, Imam F, Al-Harbi MM, Iqbal
M, Nadeem A, Al-Shahrah OA, Korashy
HM, Al-Hosaini KA, Ahmed M,
Bahashwar S. 2015. Treatment with
aliskiren ameliorates tacrolimus-induced
nephrotoxicity in rats. J Renin Angiotensin
Aldosterone Syst, 16: 1329-1336.
Al-Harbi NO, Imam F, Nadeem A, Al-Harbi
MM, Iqbal M, Rahman S, Al-Hosaini KA,
Bahashwan S. 2014. Protection against
tacrolimus-induced cardiotoxicity in rats by
olmesartan and aliskiren. Toxicol Mech
Methods, 24: 697-702.
Al-Kuraishy HM, Al-Gareeb A, Al-Naimi
MSS. 2019. Pomegranate attenuates acute
gentamicin-induced nephrotoxicity in
Sprague-Dawley rats: The potential
antioxidant and anti-inflammatory effects.
Asian J Pharm Clin Res, 12: 484-486.
Al-Kuraishy HM, Al-Gareeb AI. 2016.
Potential effects of pomegranate on lipid
peroxidation and pro-inflammatory changes
in daunorubicin-induced cardiotoxicity in
rats. Int J Prev Med, 7: 85.
Alkuraishy HM, Al-Gareeb AI, Al-Naimi MS.
2019. Pomegranate protects renal proximal
tubules during gentamicin inducednephrotoxicity in rats. J Contemp Med Sci,
5: 35-40.
Asgary S, Keshvari M, Sahebkar A, Hashemi
M, Rafieian-Kopaei M. 2013. Clinical
investigation of the acute effects of
pomegranate juice on blood pressure and
endothelial function in hypertensive
individuals. ARYA Atheroscler, 9: 326-
Atkison P, Joubert G, Barron A, Grant D, Wall
W, Rosenberg H, Howard J, Williams S,
Stiller C, Paradis K. 1995. Hypertrophic
cardiomyopathy associated with tacrolimus
in paediatric transplant patients. Lancet,
345: 894-896.
Atkison PR, Joubert GI, Guiraudon C,
Armstrong R, Wall W, Asfar S, Grant D.
1997. Arteritis and increased intracellular
calcium as a possible mechanism for
tacrolimus-related cardiac toxicity in a
pediatric transplant recipient.
Transplantation, 64: 773-775.
Basu A, Penugonda K. 2009. Pomegranate
juice: a heart-healthy fruit juice. Nutr Rev,
67: 49-56.
Bechstein WO. 2000. Neurotoxicity of
calcineurin inhibitors: impact and clinical
management. Transpl Int, 13: 313-326.
Bihamta M, Hosseini A, Ghorbani A,
Boroushaki MT. 2017. Protective effect of
pomegranate seed oil against H2O2-
induced oxidative stress in cardiomyocytes.
Avicenna J Phytomed, 7: 46-53.
Boroushaki MT, Arshadi D, Jalili-Rasti H,
Asadpour E, Hosseini A. 2013. Protective
effect of pomegranate seed oil against acute
toxicity of diazinon in rat kidney. Iran J
Pharm Res, 12: 821-827.
Boroushaki MT, Asadpour E, Sadeghnia HR,
Dolati K. 2014a. Effect of pomegranate
seed oil against gentamicin-induced
nephrotoxicity in rat. J Food Sci Technol,
51: 3510-3514.
Boroushaki MT, Mollazadeh H, Afshari AR.
2016. Pomegranate seed oil: A
comprehensive review on its therapeutic
effects. Int J Pharm Sci Res, 7: 430-442.
Boroushaki MT, Mollazadeh H, Rajabian A,
Dolati K, Hoseini A, Paseban M, Farzadnia
M. 2014b. Protective effect of pomegranate
seed oil against mercuric chloride-induced
nephrotoxicity in rat. Ren Fail, 36: 1581-
Boroushaki MT, Rajabian A, Farzadnia M,
Hoseini A, Poorlashkari M, Taghavi A,
Dolati K, Bazmandegan G. 2015.
Protective effect of pomegranate seed oil
against cisplatin-induced nephrotoxicity in
rat. Ren Fail, 37: 1338-1343.
Bouroshaki MT, Sadeghnia HR, Banihasan M,
Yavari S. 2010. Protective effect of
pomegranate seed oil on
PSO against tacrolimus-induced toxicity
AJP, Vol. 12, No. 4, Jul-Aug 2022 447
nephrotoxicity in rat kidneys. Ren Fail, 32:
Butani L, Afshinnik A, Johnson J, Javaheri D,
Peck S, German JB, Perez RV. 2003.
Amelioration of tacrolimus-induced
nephrotoxicity in rats using juniper oil.
Transplantation, 76: 306-311.
Długosz A, Średnicka D, Boratyński J. 2007.
The influence of tacrolimus on oxidative
stress and free-radical processes. Postepy
Hig Med Dosw.(online), 61: 466-471.
El-Habibi E. 2013. Renoprotective effects of
Punica granatum (pomegranate) against
adenine-induced chronic renal failure in
male rats. Life Sci J, 10: 2059-2069.
Ferjani H, El Arem A, Bouraoui A, Achour A,
Abid S, Bacha H, Boussema-Ayed I. 2016.
Protective effect of mycophenolate mofetil
against nephrotoxicity and hepatotoxicity
induced by tacrolimus in Wistar rats. J
Physiol Biochem, 72: 133-144.
Ferjani H, Timoumi R, Amara I, Abid S,
Achour A, Bacha H, Boussema-Ayed I.
2017. Beneficial effects of mycophenolate
mofetil on cardiotoxicity induced by
tacrolimus in wistar rats. Exp Biol Med,
242: 448-455.
Fernandes MB, Caldas HC, Toloni LD,
Baptista M, Fernandes I, Abbud-Filho M.
2014. Supplementation with omega-3
polyunsaturated fatty acids and
experimental tacrolimus-induced
nephrotoxicity. Exp Clin Transplant, 12:
Gil MI, Tomás-Barberán FA, Hess-Pierce B,
Holcroft DM, Kader AA. 2000.
Antioxidant activity of pomegranate juice
and its relationship with phenolic
composition and processing. J Agric Food
Chem, 48: 4581-4589.
Han S, Mun K, Choi H, Kwak C, Bae J, Suh S,
Park S, Kim H, Chang E. 2006. Effects of
cyclosporine and tacrolimus on the
oxidative stress in cultured mesangial cells.
Transplant Proc, 38: 2240-2241.
Hartman RE, Shah A, Fagan AM, Schwetye
KE, Parsadanian M, Schulman RN, Finn
MB, Holtzman DM. 2006. Pomegranate
juice decreases amyloid load and improves
behavior in a mouse model of Alzheimer's
disease. Neurobiol Dis, 24: 506-515.
Hosseinzadeh H, Sadeghnia HR, Ziaee T,
Danaee A. 2005. Protective effect of
aqueous saffron extract (Crocus sativus L.)
and crocin, its active constituent, on renal
ischemia-reperfusion-induced oxidative
damage in rats. J Pharm Pharm Sci, 8: 387-
Jalilov AS, Zhang C, Samuel EL, Sikkema
WK, Wu G, Berka V, Kent TA, Tsai A-L,
Tour JM. 2016. Mechanistic study of the
conversion of superoxide to oxygen and
hydrogen peroxide in carbon nanoparticles.
ACS Appl Mater Interfaces, 8: 15086-
Junge W, Wilke B, Halabi A, Klein G. 2004.
Determination of reference intervals for
serum creatinine, creatinine excretion and
creatinine clearance with an enzymatic and
a modified Jaffe method. Clin Chim Acta,
344: 137-148.
Kandeil MA, Hassanin KM, Arafa MM,
Abdulgawad HA, Safwat GM. 2019.
Pomegranate peels ameliorate renal nitric
oxide synthase, interleukin-1β, and kidney
injury molecule-1 in nephrotoxicity
induced by acrylamide in rats. Egypt
Pharmaceut J, 18: 368-376.
Khalil EA. 2004. A hepatoprotective effect of
an aqueous extract of pomegranate (Punica
granatum L.) rind against acetaminop hen
treated rats. Egypt J Hosp Med, 16: 112-
Kidokoro K, Satoh M, Nagasu H, Sakuta T,
Kuwabara A, Yorimitsu D, Nishi Y,
Tomita N, Sasaki T, Kashihara N. 2012.
Tacrolimus induces glomerular injury via
endothelial dysfunction caused by reactive
oxygen species and inflammatory change.
Kidney Blood Press Res, 35: 549-557.
Lansky EP, Newman RA. 2007. Punica
granatum (pomegranate) and its potential
for prevention and treatment of
inflammation and cancer. J
Ethnopharmacol, 109: 177-206.
Lee D, Lee D-S, Jung K, Hwang GS, Lee HL,
Yamabe N, Lee H-J, Eom D-W, Kim KH,
Kang KS. 2018. Protective effect of
ginsenoside Rb1 against tacrolimusinduced apoptosis in renal proximal tubular
LLC-PK1 cells. J Ginseng Res, 42: 75-80.
Lloberas N, Torras J, Alperovich G, Cruzado
JM, Giménez-Bonafé P, Herrero-Fresneda
I, Franquesa Ml, Rama I, Grinyó JM. 2008.
Different renal toxicity profiles in the
association of cyclosporine and tacrolimus
with sirolimus in rats. Nephrol Dial
Transplant, 23: 3111-3119.
Hosseini et al.
AJP, Vol. 12, No. 4, Jul-Aug 2022 448
Luo K, Lim SW, Jin J, Jin L, Gil HW, Hwang
HS, Yang CW. 2019. Cilastatin protects
against tacrolimus-induced nephrotoxicity
via anti-oxidative and anti-apoptotic
properties. BMC Nephrol, 20: 1-11.
Madesh M, Balasubramanian K. 1998.
Microtiter plate assay for superoxide
dismutase using MTT reduction by
superoxide. Indian J Biochem Biophys, 35:
McLeod J, Wu S, Grazette L, Sarcon A. 2017.
Tacrolimus-associated dilated
cardiomyopathy in adult patient after
orthotopic liver transplant. J Investig Med
High Impact Case Rep, 5:
Meerts I, Verspeek-Rip C, Buskens C, Keizer
H, Bassaganya-Riera J, Jouni Z, Van
Huygevoort A, Van Otterdijk F, Van de
Waart E. 2009. Toxicological evaluation of
pomegranate seed oil. Food Chem Toxicol,
47: 1085-1092.
Mena P, Gironés-Vilaplana A, Moreno DA,
García-Viguera C. 2011. Pomegranate fruit
for health promotion: Myths and realities.
Funct Plant Sci Biotechnol, 5: 33-42.
Mollazadeh H, Boroushaki MT, Soukhtanloo
M, Afshari AR, Vahedi MM. 2017. Effects
of pomegranate seed oil on
oxidant/antioxidant balance in heart and
kidney homogenates and mitochondria of
diabetic rats and high glucose-treated H9c2
cell line. Avicenna J phytomed, 7: 317-333.
Mollazadeh H, Sadeghnia HR, Hoseini A,
Farzadnia M, Boroushaki MT. 2016.
Effects of pomegranate seed oil on
oxidative stress markers, serum
biochemical parameters and pathological
findings in kidney and heart of
streptozotocin-induced diabetic rats. Ren
Fail, 38: 1256-1266.
Park C, Jang H, Lee J, Oh M, Kim H. 2018.
Tetrahydrocurcumin ameliorates
Tacrolimus-induced nephrotoxicity via
inhibiting apoptosis. Transplant Proc, 50:
Patel C, Dadhaniya P, Hingorani L, Soni M.
2008. Safety assessment of pomegranate
fruit extract: acute and subchronic toxicity
studies. Food Chem Toxicol, 46: 2728-
Peterka TR, Hren J, Bastarda A, Bergles J,
Urleb U. 2015. Solid state compatibility
study and characterization of a novel
degradation product of tacrolimus in
formulation. J Pharm Biomed Anal, 110:
Roberts CA, Stern DL, Radio SJ. 2002.
Asymmetric cardiac hypertrophy at autopsy
in patients who received FK506
(tacrolimus) or cyclosporine A after liver
transplant1. Transplantation, 74: 817-821.
Scalea JR, Levi ST, Ally W, Brayman KL.
2016. Tacrolimus for the prevention and
treatment of rejection of solid organ
transplants. Expert Rev Clin Immunol, 12:
Taylor J, Rabe T, McGaw L, Jäger A, Van
Staden J. 2001. Towards the scientific
validation of traditional medicinal plants.
Plant Growth Regul, 34: 23-37.
Thomson A, Bonham C, Zeevi A. 1995. Mode
of action of tacrolimus (FK506): molecular
and cellular mechanisms. Ther Drug Monit,
17: 584-591.
Tiwari SC, Husain N. 2017. Biological
activities and role of flavonoids in human
health–A. Indian J Sci Res, 12: 193-196.
Zhong Z, Connor HD, Li X, Mason RP,
Forman DT, Lemasters JJ, Thurman RG.
2006. Reduction of ciclosporin and
tacrolimus nephrotoxicity by plant
polyphenols. J Pharm Pharmacol, 58: 1533-