The protective effect of hydroalcoholic Citrus aurantifolia peel extract against doxorubicin-induced nephrotoxicity

Ni Made Dwi Sandhiutami , Yesi Desmiaty , Putu Diah Utari Pitaloka, Salsabila Salsabila

Abstract


Background and purpose: Doxorubicin chemotherapy is a widely used treatment for various cancers, including breast, ovarian, and uterine cancers, among others. However, long-term use can cause nephrotoxicity side effects. Some citrus flavonoids have demonstrated nephroprotective activity; therefore, this study aimed to test the nephroprotective effectiveness of Citrus aurantifolia peel extract in protecting and reducing kidney damage caused by doxorubicin.

Experimental approach: Citrus aurantifolia peel was dried, ground, and extracted by ultrasonication                     (70% ethanol), then the extract was dried. Twenty-five female Sprague-Dawley rats were divided into 5 groups including the normal group (control), positive control (doxorubicin) group receiving doxorubicin at the repeated intraperitoneal (i.p.) dose of 4 mg/kg/day on days 2, 6, 10, and 14, and treatment groups receiving Citrus aurantifolia peel extract (CPE) with the doses of 100, 200, and 400 mg/kg/day orally for 14 days, and doxorubicin (4 mg/kg/day, i.p.) on days 2, 6, 10 and 14. On day 15, the rats were euthanized for the measurements of MDA, superoxide dismutase (SOD), catalase, kidney function (measuring blood urea nitrogen (BUN), creatinine, albumin serum levels), and renal histopathology.

Findings/Results: The CPE yield was 16.13%. CPE could significantly reduce the levels of MDA, and increase SOD and catalase activities compared with the doxorubicin-induced nephrotoxic model. CPE could increase renal function by reducing BUN and creatinine levels, increasing albumin, and improving the histopathology of the kidney.

Conclusion and implications: CPE has a potential effect as nephroprotective against doxorubicin-induced toxicity in renal through antioxidant capacities and increased renal function.

 

 


Keywords


Citrus aurantifolia peel; Doxorubicin; Nephrotoxicity; Oxidative stress.

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Bidram E, Esmaeili Y, Ranji-Burachaloo H, Al-Zaubai N, Zarrabi A, Stewart A, et al. A concise review on cancer treatment methods and delivery systems. J Drug Deliv Sci Technol. 2019;54:101350,1-28.DOI: 10.1016/j.jddst.2019.101350.

International Agency for Research on Cancer. Indonesia-Global Cancer Observatory. Globocan. 2020;858:1-2. Available: https://gco.iarc.who.int/media/globocan/factsheets/populations/360-indonesia-fact-sheet.

Fernando J, Jones R. The principles of cancer treatment by chemotherapy. Surgery (Oxford) 2015;33(3):131-135.DOI: 10.1016/j.mpsur.2015.01.005.

Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: activity, chemoresistance and its overcoming. Mol Aspects Med. 2023;93:101205,1-43.DOI: 10.1016/j.mam.2023.101205.

Sandhiutami NM, Desmiaty Y, Noviani Y. Development rat models of nephrotoxic: a pre-clinical test model to discover nephroprotective agents. Pharmacy Education. 2024;24(2):63-70.DOI: 10.46542/pe.2024.242.6370.

Kim SY, Moon A. Drug-induced nephrotoxicity and its biomarkers. Biomol Ther. 2012;20(3):268-272.DOI: 10.4062/biomolther.2012.20.3.268.

Mobaraki M, Faraji A, Zare M, Dolati P, Ataei M, Dehghan Manshadi HR. Molecular mechanisms of cardiotoxicity: a review on the major side-effects of doxorubicin. Indian J Pharm Sci. 2017;79(3): 335-344.DOI: 10.4172/pharmaceutical-sciences.1000235.

Priya LB, Baskaran R, Huang CY, Padma VV. Neferine ameliorates cardiomyoblast apoptosis induced by doxorubicin: possible role in modulating NADPH oxidase/ROS-mediated NFκB redox signaling cascade. Sci Rep. 2017;7(1): 1-13.DOI: 10.1038/s41598-017-12060-9.

Ajah O, Onyedikachi UB, Nkwocha CC. Urtica dioica extract mitigates doxorubicin-induced hepatotoxicity and nephrotoxicity by suppressing oxidative stress and modulating biochemical indices: in vivo and molecular docking study. Comp Clin Path. 2024;33:287-302.DOI: 10.1007/s00580-024-03550-0.

Isiiko J, Atwiine B, Oloro J. Prevalence and risk factors of nephrotoxicity among adult cancer patients at Mbarara Regional Referral Hospital. Cancer Manag Res. 2021;13:7677-7684.DOI: 10.2147/CMAR.S326052.

Rachman A, Shatri H, Salamat R. Correlation between higher cumulative dose of cisplatin for concurrent chemoradiation and acute kidney disease incidence among nasopharyngeal carcinoma patients: a comparative study. Int J Gen Med. 2021;14:10527-10539.DOI:10.2147/IJGM.S343644.

Kemper MJ, Gibson K, Sinha A. Nongenetic forms of steroid-resistant nephrotic syndrome. In: Emma F, Goldstein SL, Bagga A, Bates CM, Shroff R, editors. Pediatric Nephrology. 8th ed. Switzerland AG: Springer, Cham; 2022. pp. 387-410.DOI: 10.1007/978-3-030-52719-8_93.

Santos MLC, de Brito BB, da Silva FAF, dos Santos Botelho AC, de Melo FF. Nephrotoxicity in cancer treatment: an overview. World J Clin Oncol. 2020;11(4):190-204.DOI: 10.5306/wjco.v11.i4.190.

van der Zanden SY, Qiao X, Neefjes J. New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 2021;288(21): 6095-6111.DOI: 10.1111/febs.15583.

Basist P, Parveen B, Zahiruddin S, Gautam G, Parveen R, Khan MA, et al. Potential nephroprotective phytochemicals: mechanism and future prospects. J Ethnopharmacol. 2022; 283:114743.DOI: 10.1016/j.jep.2021.114743.

Patil JR, Chidambara Murthy KN, Jayaprakasha GK, Chetti MB, Patil BS. Bioactive compounds from Mexican lime (Citrus aurantifolia) juice induce apoptosis in human pancreatic cells. J Agric Food Chem. 2009;57(22):10933-10942.DOI: 10.1021/jf901718u.

Okwu DE. Citrus fruits: a rich source of phytochemicals and their roles in human health. Int J Chem Sci. 2008;6(2):451-571.

Sreedevi A, Uppuluri S, Bharathi K. Effect of hesperdin isolated from orange peels on cisplatin-induced nephrotoxicity. Int J Pharmacogn Phytochem Res. 2012;4(2):49-53.DOI: 10.22376/IJPBS.2016.7.4.P15-21.

Kamel KM, Abd El-Raouf OM, Metwally SA, Abd El-Latif HA, El-sayed ME. Hesperidin and rutin, antioxidant citrus flavonoids, attenuate cisplatin-induced nephrotoxicity in rats. J Biochem Mol Toxicol. 2014;28(7):312-319.DOI: 10.1002/jbt.21567.

Sharma P, Vishvakarma R, Gautam K, Vimal A, Gaur VK, Farooqui A, et al. Valorization of citrus peel waste for the sustainable production of value-added products. Bioresour Technol. 2022; 351:127064.DOI: 10.1016/j.biortech.2022.127064.

Singh B, Singh JP, Kaur A, Singh N. Phenolic composition, antioxidant potential and health benefits of citrus peel. Food Res Int. 2020;132:109114,1-87.DOI: 10.1016/j.foodres.2020.109114.

Hussain M, Abogresha N, Abdelkader G, Hassan R, Abdelaziz EZ, Greish SM. Antioxidant and anti-inflammatory effects of crocin ameliorate doxorubicin-induced nephrotoxicity in rats. Oxid Med Cell Longev 2021;4:1-12.DOI: 10.1155/2021/8841726.

Su Z, Ye J, Qin Z, Ding X. Protective effects of madecassoside against doxorubicin induced nephrotoxicity in vivo and in vitro. Sci Rep. 2015;5(1):1-14.DOI: 10.1038/srep18314.

Wang R, Hassan W, Ahmad FUD, Jabeen Q, Ahmed H, Iqbal O. Citrus aurantium ameliorates cisplatin-induced nephrotoxicity. Biomed Res Int. 2019;2019:1-9.DOI: 10.1155/2019/3960908.

Wu H, Kong Y, Zhao W, Wang F. Measurement of cellular MDA content through MTBE-extraction based TBA assay by eliminating cellular interferences. J Pharm Biomed Anal. 2024;248:116332.DOI: 10.1016/j.jpba.2024.116332.

Sandhiutami NMD, Desmiaty Y, Anbar A. Antioxidant effect of ethanol extract from papaya seed (Carica papaya L.) on superoxide dismutase activity and malondialdehyde level in stress oxidative mice with swimming stress method. J Ilmu Kefarmasian Indonesia. 2016;14(1):26-32.

Fan Hy, Wang XK, Li X, Ji K, Du SH, Liu Y, et al. Curcumin, as a pleiotropic agent, improves doxorubicin-induced nephrotic syndrome in rats. J Ethnopharmacol. 2020;250:112502,1-10.DOI: 10.1016/j.jep.2019.112502.

Grant MKO, Seelig DM, Sharkey LC, Choi WSV, Abdelgawad IY, Zordoky BN. Sexual dimorphism of acute doxorubicin-induced nephrotoxicity in C57Bl/6 mice. PLoS One. 2019;14(2):e0212486,1-19.DOI: 10.1371/journal.pone.0212486.

Bilgic S, Armagan I. Effects of misoprostol treatment on doxorubicin induced renal injury in rats. Biotech Histochem. 2020;95(2):113-120.DOI: 10.1080/10520295.2019.1645356.

Shafiee F, Safaeian L, Gorbani F. Protective effects of protocatechuic acid against doxorubicin- and arsenic trioxide-induced toxicity in cardiomyocytes. Res Pharm Sci. 2023;18(2):149-158.DOI: 10.4103/1735-5362.367794.

Szalay CI, Erdélyi K, Kökény G, Lajtár E, Godó M, Révész C, et al. Oxidative/nitrative stress and inflammation drive progression of doxorubicin-induced renal fibrosis in rats as revealed by comparing a normal and a fibrosis-resistant rat strain. PLoS One. 2015;10(6):e0127090,1-17.DOI: 10.1371/journal.pone.0127090.

Rajasekaran M. Nephroprotective effect of Costus pictus extract against doxorubicin-induced toxicity on wistar rat. Bangladesh J Pharmacol. 2019;14(2):93-100.DOI: 10.3329/bjp.v14i2.39992.

Shang W, Wang Z. The update of NGAL in acute kidney injury. Curr Protein Pept Sci. 2017;18(12):1211-1217.DOI: 10.2174/1389203717666160909125004.

Dhondup T, Qian Q. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.DOI: 10.1159/000452725.

Altınkaynak Y, Kural B, Akcan BA, Bodur A, Özer S, Yuluğ E, et al. Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats. Biomed Pharmacother. 2018;108: 1524-1534.DOI: 10.1016/j.biopha.2018.09.171.

El-Sheikh AAK, Morsy MA, Mahmoud MM, Rifaai RA, Abdelrahman AM. Effect of coenzyme-Q10 on doxorubicin-induced nephrotoxicity in rats. Adv Pharmacol Sci. 2012;2012,1-8.DOI: 10.1155/2012/981461.

Nourie N, Ghaleb R, Lefaucheur C, Louis K. Toward precision medicine: exploring the landscape of biomarkers in acute kidney injury. Biomolecules. 2024;14(1):82,1-18.DOI: 10.3390/biom14010082.

Rafiee Z, Zare Moaiedi M, Valizade Gorji A, Mansouri E. p-Coumaric acid mitigates doxorubicin-induced nephrotoxicity through suppression of oxidative stress, inflammation and apoptosis. Arch Med Res. 2020;51(1):32-40.DOI: 10.1016/j.arcmed.2019.12.004.

Wu Q, Li W, Zhao J, Sun W, Yang Q, Chen C, et al. Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation. Biomed Pharmacother. 2021;137: 111308,1-14.DOI: 10.1016/j.biopha.2021.111308.

Afsar T, Razak S, Almajwal A, Al-Disi D. Doxorubicin-induced alterations in kidney functioning, oxidative stress, DNA damage, and renal tissue morphology; improvement by Acacia hydaspica tannin-rich ethyl acetate fraction. Saudi J Biol Sci. 2020; 27(9):2251-2260.DOI: 10.1016/j.sjbs.2020.07.011.

Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J pharm pharmacol. 2013;65(2):157-170.DOI: 10.1111/j.2042-7158.2012.01567.x.

Injac R, Boskovic M, Perse M, Koprivec-Furlan E, Cerar A, Djordjevic A, et al. Acute doxorubicin nephrotoxicity in rats with malignant neoplasm can be successfully treated with fullerenol C60 (OH) 24 via suppression of oxidative stress. Pharmacol Rep. 2008;60(5):742-749.DOI: 10.1016/S1734-1140(09)70041-6.

Pisoschi AM, Pop A, Iordache F, Stanca L, Predoi G, Serban AI. Oxidative stress mitigation by antioxidants-an overview on their chemistry and influences on health status. Eur J Med Chem. 2021;209:112891,1-56.DOI: 10.1016/j.ejmech.2020.112891.

Abou Seif HS. Protective effect of rutin and hesperidin against doxorubicin induced nephrotoxicity. Beni-Suef Univ J App Sci. 2012;1(2):1-18.

Chaabane M, Elwej A, Ghorbel I, Boudawara T, Zeghal N, Soudani N. Citrus aurantium L. peel extract mitigates hexavalent chromium-induced oxidative stress and cardiotoxicity in adult rats. Pharm Biomed Res. 2017;3(2):8-18.DOI: 10.29252/pbr.3.2.8.

Dahal A, Mulukuri S. Flavonoids in kidney protection. World J Pharm Pharmaceut Sci. 2015;4(3):362-382.

Askaripour M, Najafipour H, Saberi S, Dabiri S, Iranpour M, Etminan A, et al. Sodium hydrogen sulfide may not protect the kidney against ischemia/reperfusion damage in male and female rats. Res Pharm Sci. 2023;18(3):262-269.DOI: 10.4103/1735-5362.371582.

Baloch WA, Sundus S, Mohioddin M, Fatmee S, Kumar A, Jaan A. Ameliorative effect of Nigella Sativa on absolute weight, relative weight, and body weight after doxorubicin induced kidney of albino rats. J Sheikh Zayed Med College. 2021; 12(4):24-28.DOI: 10.47883/jszmc.v12i4.203.

Ramalingayya GV, Cheruku SP, Nayak PG, Kishore A, Shenoy R, Rao CM, et al. Rutin protects against neuronal damage in vitro and ameliorates doxorubicin-induced memory deficits in vivo in wistar rats. Drug Des Devel Ther. 2017;11: 1011-1026.DOI: 10.2147/DDDT.S103511.

Udupa V, Prakash V. Gentamicin induced acute renal damage and its evaluation using urinary biomarkers in rats. Toxicol Rep. 2019;6:91-99.DOI: 10.1016/j.toxrep.2018.11.015.

Mohammed SA, Mohamed DS, Khalifa AS, Mohamed SM. Impact of cerium oxide nanoparticles versus quercetin on doxorubicin induced nephropathy in adult male rats: biochemical, histological and immunohistochemical study. The Egyptian Journal of Histology. 2024;47(1):565-594.DOI: 10.21608/ejh.2023.181409.1834.

Refaie MMM, Amin EF, El-Tahawy NF, Abdelrahman AM. Possible protective effect of diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol. 2016;2016:1-9.DOI: 10.1155/2016/9507563.

Levey AS, Titan SM, Powe NR, Coresh J, Inker LA. Kidney disease, race, and GFR estimation. Clin J Am Soc Nephrol. 2020;15(8):1203-1212.DOI: 10.2215/CJN.12791019.

Kumar P, Barua CC, Sulakhiya K, Sharma RK. Curcumin ameliorates cisplatin-induced nephrotoxicity and potentiates its anticancer activity in SD rats: potential role of curcumin in breast cancer chemotherapy. Front Pharmacol. 2017;8:132,1-12.DOI: 10.3389/fphar.2017.00132.

Ozbek E. Induction of oxidative stress in kidney. Int J Nephrol. 2012;2012:1-9.DOI: 10.1155/2012/465897.

Owumi SE, Lewu DO, Arunsi UO, Oyelere AK. Luteolin attenuates doxorubicin-induced derangements of liver and kidney by reducing oxidative and inflammatory stress to suppress apoptosis. Hum Exp Toxicol. 2021;40(10): 1656-1672.DOI: 10.1177/09603271211006171.

Shivakumar P, Rani MU, Reddy AG, Anjaneyulu Y. A study on the toxic effects of doxorubicin on the histology of certain organs. Toxicol Int. 2012;19(3):241-244.DOI: 10.4103/0971-6580.103656.

Alsawaf S, Alnuaimi F, Afzal S, Thomas RM, Chelakkot AL, Ramadan WS, et al. Plant flavonoids on oxidative stress-mediated kidney inflammation. Biology. 2022;11(12):1717,1-27.DOI: 10.3390/biology11121717.


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