Dose-dependent hepatoprotective and nephroprotective effects of Opuntia ficus-indica fruit extract against acetaminophen-induced oxidative injury in rats

Year 2026, Volume: 5 Issue: 1 , 25 - 34 , 01.05.2026

Sinem Ilgın , Büşra Korkut Çelikateş , Başak Özlem Perk , İpek Ertorun , Hale Gamze Ağalar , İ. Özkan Alataş

https://doi.org/10.55971/EJLS.1801161

https://izlik.org/JA29KF72DN

Abstract

Acetaminophen (APAP) overdose is a major cause of acute hepatic and renal injury, primarily driven by excessive formation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), glutathione depletion, and oxidative/nitrosative stress. Opuntia ficus-indica (L.) Mill. (OFI) fruit contains antioxidant and anti-inflammatory phytochemicals that may protect against xenobiotic-induced organ damage. This study investigated the hepatoprotective and nephroprotective effects of an aqueous OFI fruit extract against APAP-induced toxicity in rats, with emphasis on oxidative stress mechanisms. Adult male rats were pre-treated with OFI extract (100, 200, or 400 mg/kg, orally) for seven days, followed by a single APAP dose (3 g/kg) on day eight. After 24 h, serum biomarkers of hepatic and renal function (ALT, AST, ALP, total bilirubin, total protein, CREA, BUN, Na⁺, K⁺) and tissue oxidative stress indices (CAT, SOD, NO, and MDA) were evaluated. APAP administration caused substantial elevations in serum ALT, AST, ALP, CREA, and BUN, together with decreased antioxidant enzyme activities and increased lipid peroxidation in liver and kidney tissues. Pre-treatment with OFI at 100 and 200 mg/kg markedly ameliorated these alterations, improving biochemical markers and restoring antioxidant defence. In contrast, the 400 mg/kg dose failed to provide significant protection and exacerbated some parameters, indicating a biphasic, dose-dependent response. These findings demonstrate that low and moderate doses of OFI fruit aqueous extract exert significant hepatoprotective and nephroprotective effects against APAP-induced oxidative injury, likely through enhancement of antioxidant defence and attenuation of oxidative and nitrosative stress.

Keywords

acetaminophen , oxidative stress , hepatotoxicity , nephrotoxicity , Opuntia ficus-indica

References

• Lanuzza F, Occhiuto F, Monforte MT, Tripodo MM, D’Angelo V, Galati EM. Antioxidant Phytochemicals of Opuntia ficus-indica (L.) Mill. Cladodes with Potential Anti-spasmodic Activity. Pharmacogn Mag. (2017);13(3):424–429. https://doi.org/10.4103/pm.pm_495_16
• Dormousoglou M, Efthimiou I, Antonopoulou M, Dailianis S, Herbst G, Vlastos D. Phytochemical Analysis and Genotoxicological Evaluation of Prickly Pear Peel Extracts. Plants. (2023);12(7):1537. https://doi.org/10.3390/plants12071537
• Tesoriere L, Fazzari M, Allegra M, Livrea MA. Biothiols, taurine, and lipid-soluble antioxidants in the edible pulp of Sicilian cactus pear (Opuntia ficus-indica) fruits and changes of bioactive juice components upon industrial processing. J Agric Food Chem. (2005);53(20):7851–7855. https://doi.org/10.1021/jf050636f
• Antunes-Ricardo M, Gutiérrez-Uribe JA, Martínez-Vitela C, Serna-Saldívar SO. Topical anti-inflammatory effects of isorhamnetin glycosides isolated from Opuntia ficus-indica. Biomed Res Int. (2015);847320. https://doi.org/10.1155/2015/847320
• El Kharrassi Y, Mazri MA, Benyahia H, Benaouda H, Nasser B. Fruit and juice characteristics of 30 accessions of two cactus Pear species (Opuntia ficus indica and Opuntia megacantha) from different regions of Morocco. LWT-Food Sci. (2016);610–617. https://doi.org/10.1016/j.lwt.2015.08.044
• Semenya SS, Maroyi A. Plants Used by Bapedi Traditional Healers to Treat Asthma and Related Symptoms in Limpopo Province, South Africa. J Evid Based Complementary Altern Med. (2018);2183705. https://doi.org/10.1155/2018/2183705
• Karabagias VK, Riganakos KA, Karabagias IK, Gatzias I. Characterization of prickly Pear juice by means of shelf life, sensory notes, physicochemical parameters and bio-functional properties. J Food Sci Tecnhol. (2019);56(8):3646–3659. https://doi.org/10.1007/s13197-019-03797-4
• Tunç Y, Yaman M, Yılmaz KU, Khadivi A, Mishra DS. Biochemical, nutritional, and nutraceutical properties of cactus pear accessions. Sci Rep. (2025);15(1):1–19. https://doi.org/10.1038/s41598-025-04726-6
• Naqeb G, Fiori L, Ciolli M, Aprea E. Prickly Pear Seed Oil Extraction, Chemical Characterization and Potential Health Benefits. Molecules. (2021);26(16):5018. https://doi.org/10.3390/molecules26165018
• Silva MA, Albuquerque TG, Pereira P, Ramalho R, Vicente F, Oliveira MBPP, Costa, HS. Opuntia ficus-indica (L.) Mill.: A Multi-Benefit Potential to Be Exploited. Molecules. (2021);26(4):951. https://doi.org/10.3390/molecules26040951
• Guedes BN, Fathi F, Silva AM, Santini A, Oliveira MBP, Souto EB. Biopharmaceutical applications of Opuntia ficus-indica: bibliometric map, bioactivities and extraction techniques. Eur Food Res Technol. (2023);249(10):2457–2469. https://doi.org/10.1007/s00217-023-04314-w
• Benramdane E, Chougui N, Ramos PA, Makhloufi N, Tamendjari A, Silvestre AJ, Santos SA. Lipophilic compounds and antibacterial activity of Opuntia ficus-indica root extracts from Algeria. Int J Mol Sci. (2022);23(19):11161. https://doi.org/10.3390/ijms231911161
• Balali MR, Abdul Kareem R, Naji Sameer H, Yseen A, H Athab Z, Adil M, Amiri MRJ, Vahdati S. Antibacterial activity of four edible cactus extracts (Opuntia ficus-indica) on Drug-Resistant urinary tract infections bacteria. Microbes Infect Dis. (2025). https://doi.org/10.21608/mid.2025.336424.2346
• Bargougui A, Pape PL, Triki S. Antiplasmodial Efficacy of Fruit Extracts and Cladodes of Opuntia ficus-indica. J Nat Sci Res. (2013);3(6):31–37.
• Farag MA, Sallam IE, Fekry MI, Zaghloul SS, El-Dine RS. Metabolite profiling of three Opuntia ficus-indica fruit cultivars using UPLC-QTOF-MS in relation to their antioxidant potential. Food Biosci. (2020);36(2):100673. https://doi.org/10.1016/j.fbio.2020.100673
• Gómez-Maqueo A, Antunes-Ricardo M, Welti-Chanes J, Cano MP. Digestive stability and bioaccessibility of antioxidants in prickly pear fruits from the Canary Islands: healthy foods and ingredients. Antioxidants. (2020);9(2):164. https://doi.org/10.3390/antiox9020164
• Butterweck V, Semlin L, Feistel B, Pischel I, Bauer K, Verspohl EJ. Comparative evaluation of two different Opuntia ficus-indica extracts for blood sugar lowering effects in rats. Phytother Res. (2011);25(3):370–375. https://doi.org/10.1002/ptr.3271
• Rtibi K, Selmi S, Saidani K, Grami D, Amri M, Sebai H, Marzouki L. Reverse Effect of Opuntia ficus-indica L. Juice and Seeds Aqueous Extract on Gastric Emptying and Small-Bowel Motility in Rat. J Food Sci. (2018);83(1):205–211. https://doi.org/10.1111/1750-3841.13990
• Allegra M, Ianaro A, Tersigni M, Panza E, Tesoriere L, Livrea MA. Indicaxanthin from cactus pear fruit exerts anti-inflammatory effects in carrageenin-induced rat pleurisy. J Nutr. (2014);144(2):185–192. https://doi.org/10.3945/jn.113.183657
• Galati EM, Tripodo MM, Trovato A, Miceli N, Monforte MT. Biological effect of Opuntia ficus indica (L.) Mill. (Cactaceae) waste matter. Note I: diuretic activity. J Ethnopharmacol. (2002);79(1):17–21. https://doi.org/10.1016/s0378-8741(01)00337-3
• Bisson JF, Daubié S, Hidalgo S, Guillemet D, Linarés E. Diuretic and antioxidant effects of Cacti-Nea, a dehydrated water extract from prickly pear fruit, in rats. Phytother Res. (2010);24(4):587–594. https://doi.org/10.1002/ptr.2996
• Galati EM, Mondello MR, Lauriano ER, Taviano MF, Galluzzo M, Miceli N. Opuntia ficus indica (L.) Mill. fruit juice protects liver from carbon tetrachloride-induced injury. PTR. (2005);19(9):796–800. https://doi.org/10.1002/ptr.1741
• Alimi H, Hfaeidh N, Mbarki S, Bouoni Z, Sakly M, Ben Rouma K. Evaluation of Opuntia ficus indica f. inermis fruit juice hepatoprotective effect upon ethanol toxicity in rats. Gen Physiol Biophys. (2012);31(3):335–342. https://doi.org/10.4149/gpb_2012_038
• Kim JW, Kim TB, Kim HW, Park SW, Kim HP, Sung SH. Hepatoprotective Flavonoids in Opuntia ficus-indica Fruits by Reducing Oxidative Stress in Primary Rat Hepatocytes. Pharmacogn Mag. (2017);13(51):472–476. https://doi.org/10.4103/pm.pm_232_16
• Partovi N, Ebadzadeh MR, Fatemi SJ, Khaksari M. Effect of fruit extract on renal stone formation and kidney injury in rats. Nat Prod Res. (2018);32(10):1180–1183. https://doi.org/10.1080/14786419.2017.1320790
• Iqubala A, Iqubalb MK, Haque SE. Experimental hepatotoxicity agent: A review. International J Pharmacol Res. (2016);6(11):325–335. https://doi.org/10.7439/ijpr.v6i11.3700
• Gulati K, Reshi MR, Rai N, Ray A. Hepatotoxicity: Its Mechanisms, Experimental Evaluation and Protective Strategies. Am J Pharmacol. (2018);1(1):1–9. https://doi.org/10.18311/jnr/2024/43880
• Luster MI, Simeonova PP, Gallucci RM, Bruccoleri A, Blazka ME, Yucesoy B. Role of inflammation in chemical-induced hepatotoxicity. Toxicol Lett. (2001);120(1-3):317–321. https://doi.org/10.1016/s0378-4274(01)00284-3
• Kshirsagar A, Vetal Y, Ashok P, Bhosle P, Ingawale D. Drug Induced Hepatotoxicity: A Comprehensive Review. Internet J Pharmacol. (2008);7(1). https://doi.org/10.18231/j.ijcaap.2020.033
• McGill MR, Williams CD, Xie Y, Ramachandran A, Jaeschke H. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol Appl Pharmacol. (2012);264(3):387–394. https://doi.org/10.1016/j.taap.2012.08.015
• Jaeschke H, Xie Y, McGill MR. Acetaminophen-induced Liver Injury: from Animal Models to Humans. J Clin Transl Hepatol. (2014);2(3):153–161. https://doi.org/10.14218/JCTH.2014.00014
• Bhakuni GS, Bedi O, Bariwal J, Deshmukh R, Kumar P. Animal models of hepatotoxicity. Inflamm Res. (2016);65(1):13–24. https://doi.org/10.1007/s00011-015-0883-0
• Khan KNM, Hard GC, Alden CL. Chapter 47 - Kidney. In: Bolon B, Haschek WM, Ochoa R, Rousseaux CG, Wallig MA, editors. Haschek and Rousseaux’s Handbook of Toxicologic Pathology. California: Academic Press; (2013). p.1667–1773. ISBN:978–0–1241–5759–0
• Shin JY, Han JH, Ko JW, Park SH, Shin NR, Jung TY, Kim HA, Kim SH, Shin IS, Kim JC. Diallyl disulfide attenuates acetaminophen-induced renal injury in rats. Lab Anim Res. (2016);32(4):200–207. https://doi.org/10.5625/lar.2016.32.4.200
• Ściskalska M, Śliwińska-Mossoń M, Podawacz M, Sajewicz W, Milnerowicz H. Mechanisms of interaction of the N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity. Drug Chem Toxicol. (2015);38(2):121–125. https://doi.org/10.3109/01480545.2014.928722
• Reshi MS, Shrivastava S, Jaswal A, Sinha N, Uthra C, Shukla S. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats. Exp Toxicol Pathol. (2017);69(4):231–240. https://doi.org/10.1016/j.etp.2017.01.009
• Singh AP, Junemann A, Muthuraman A, Jaggi AS, Singh N, Grover K, Dhawan R. Animal models of acute renal failure. Pharmacol Rep. (2012);64(1):31–44. https://doi.org/10.1016/s1734-1140(12)70728-4
• Felicia FA, Muthulingam M. Renal Antioxidant and Lipid Peroxidative Role of Indigofera Tinctoria (Linn.) Against Paracetamol Induced Hepatotoxicity in Rats. Int J Pure Appl Zool. (2013);1(1):37–42
• El-Shafey MM, Abd-Allah GM, Mohamadin AM, Harisa GI, Mariee AD. Quercetin protects against acetaminophen-induced hepatorenal toxicity by reducing reactive oxygen and nitrogen species. Pathophysiology. (2015);22(1):49–55. https://doi.org/10.1016/j.pathophys.2014.12.002
• Ismail AFM, Salem AAM. Renoprotective effect of curcumin on acetaminophen-induced nephrotoxicity in rats. JOCPR. (2016);8(2):773–779.
• Akacha A, Badraoui R, Rebai T, Zourgui L. Effect of Opuntia ficus indica extract on methotrexate-induced testicular injury: a biochemical, docking and histological study. J Biomol Struct Dyn. (2022);40(10):4341–4351. https://doi:10.1080/07391102.2020.1856187
• Akacha A, Rebai T, Zourgui L, Amri M. Preventive effect of ethanolic extract of cactus (Opuntia ficus-indica) cladodes on methotrexate-induced oxidative damage of the small intestine in Wistar rats. J Cancer Res Ther. 2018;14(Supplement):779–784. https://doi:10.4103/0973-1482.174555
• Hfaiedh M, Brahmi D, Zourgui MN, Zourgui L. Phytochemical analysis and nephroprotective effect of cactus (Opuntia ficus-indica) cladodes on sodium dichromate-induced kidney injury in rats. Appl Physiol Nutr Metab. (2019);44(3):239–247. https://doi:10.1139/apnm-2018-0184
• Saad AB, Rjeibi I, Ncib S, Zouari N, Zourgui L. Ameliorative Effect of Cactus (Opuntia ficus indica) Extract on Lithium-Induced Nephrocardiotoxicity: A Biochemical and Histopathological Study. Biomed Res Int. (2017);2017:8215392. https://doi:10.1155/2017/8215392
• Lee EB, Hyun JE, Li DW, Moon YI. Effects of Opuntia ficus-indica var. Saboten stem on gastric damages in rats. Arch Pharm Res. (2002);25(1):67–70. https://doi:10.1007/BF02975264
• Giraldo-Silva L, Ferreira B, Rosa E, Dias ACP. Opuntia ficus-indica Fruit: A Systematic Review of Its Phytochemicals and Pharmacological Activities. Plants (Basel). (2023);25;12(3):543. https://doi: 10.3390/plants12030543.
• Attanzio A, Restivo I, Tutone M, Tesoriere L, Allegra M, Livrea MA. Redox Properties, Bioactivity and Health Effects of Indicaxanthin, a Bioavailable Phytochemical from Opuntia ficus indica, L.: A Critical Review of Accumulated Evidence and Perspectives. Antioxidants (Basel). (2022);29;11(12):2364. https://doi: 10.3390/antiox11122364.
• Babich H, Schuck AG, Weisburg JH, Zuckerbraun HL. Research strategies in the study of the pro-oxidant nature of polyphenol nutraceuticals. Toxicol Appl Pharmacol. (2011);254(2):136–145.
• Andrés CMC, Pérez de la Lastra JM, Juan CA, Plou FJ, Pérez-Lebeña E. Polyphenols as antioxidant/pro-oxidant compounds and donors of reducing species: Relationship with human antioxidant metabolism. Processes. (2023);11(9), 2771.
• Kehrer JP. The Haber-Weiss reaction and mechanisms of toxicity. Toxicology. (2000);4;149(1):43–50. https://doi: 10.1016/s0300-483x(00)00231-6.
• Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose (−)-epigallocatechin-3-gallate in mice. Food Chem Toxicol. (2010);48(1), 409–416.
• Chedea VS, Drăghici O, Mocan A, Vodnar DC. Antioxidant/Pro-Oxidant Actions of Polyphenols from Grapevine and Wine By-Products. FCMRCE. (2021);8, 750508.
• Rudrapal M, Khairnar SJ, Khan J, Dukhyil AB, Ansari MA, Alomary MN, Alshabrmi FM, Palai S, Deb PK, Devi R. Dietary polyphenols and their role in oxidative stress-induced human diseases. Front pharmacol. (2022);13, 806470.
• Bhosale P. Chemistry and biology of carotenoids. Int J Mol Sci. (2021);22(24):13294. https://doi.org/10.3390/ijms222413294
• Liu J, Wu Z, Yang M, Wang X. Prooxidant activities of flavonoids and their impact on cellular oxidative stress. Food Chem. (2022);368:130788. https://doi.org/10.1016/j.foodchem.2021.130788
• Allegra M, D’Acquisto F, Tesoriere L, Attanzio A, Livrea MA. Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. Redox Biol. (2014);2:892–900. https://doi.org/10.1016/j.redox.2014.07.004
• Alvarez-Suarez JM, Giampieri F, Battino M. Flavonoids as antioxidants: Mechanisms and roles in disease prevention. Antioxidants. (2020);9(9):813. https://doi.org/10.3390/antiox9090813