Abstract
Cyclophosphamide (CP) is a common chemotherapeutic agent that is effective against a wide variety of tumors. The associated hepatotoxicity and nephrotoxicity, however, limit its therapeutic use. Naringin (NG) is a natural flavanone glycoside that has pharmacological and therapeutic activities, such as anti-inflammation, anti-apoptotic, and antioxidant properties. Therefore, the present study was undertaken to evaluate the protective effect of NG against CP-induced hepatotoxicity and nephrotoxicity in rats. Rats were pre-treated with NG (50 and 100 mg/kg b.w.) for 7 days before administering a single dose of CP (200 mg/kg b.w.) on the seventh day. CP-induced hepatotoxicity and nephrotoxicity were associated with an increase in serum toxicity markers and a decrease in antioxidant enzyme activities. CP also induced inflammatory responses by increasing the levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it activated the apoptotic and autophagic pathway by increasing cysteine aspartate-specific protease-3 (caspase-3) expression and light chain 3B (LC3B) level and also increased the expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), which is the marker of oxidative DNA damage. Pre-treatment with NG (50 and 100 mg/kg), however, significantly decreased serum toxicity markers, increased antioxidant enzyme activities, and regulated inflammation, apoptosis, autophagy, and oxidative DNA damage in hepatic and renal tissues. These results indicated that NG was an effective protectant against CP-induced hepatotoxicity and nephrotoxicity.
Similar content being viewed by others
References
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126. https://doi.org/10.1016/S0076-6879(84)05016-3.
Alak G, Yeltekin AÇ, Tas IH, Ucar A, Parlak V, Topal A, Kocaman EM, Atamanalp M (2017) Investigation of 8-OHdG, CYP1A, HSP70 and transcriptional analyses of antioxidant defence system in liver tissues of rainbow trout exposed to eprinomectin. Fish Shellfish Immunol 65:136–144. https://doi.org/10.1016/j.fsi.2017.04.004.
Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, Sarker SD (2014) Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr 5:404–417. https://doi.org/10.3945/an.113.005603
Alqahtani S, Mahmoud AM (2016) Gamma-Glutamylcysteine ethyl Ester protects against cyclophosphamide-induced liver injury and hematologic alterations via upregulation of PPARγ and attenuation of oxidative stress, inflammation, and apoptosis. Oxidative Med Cell Longev 2016:1–14. https://doi.org/10.1155/2016/4016209
Al-Yahya AA, Al-Majed AA, Gado AM, Daba MH, Al-Shabanah OA, El-Azab AS, Abd-Allah AR (2009) Acacia Senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity. Oxidative Med Cell Longev 2:207–213. https://doi.org/10.4161/oxim.2.4.8878
Basu A, Bhattacharjee A, Samanta A, Bhattacharya S (2015) Prevention of cyclophosphamide-induced hepatotoxicity and genotoxicity: effect of an l-cysteine based oxovanadium (IV) complex on oxidative stress and DNA damage. Environ Toxicol Pharmacol 40:747–757. https://doi.org/10.1016/j.etap.2015.08.035
Benzer F, Kandemir FM, Ozkaraca M, Kucukler S, Caglayan C (2018a) Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. J Biochem Mol Toxicol 32:e22030. https://doi.org/10.1002/jbt.22030
Benzer F, Kandemir FM, Kucukler S, Comaklı S, Caglayan C (2018b) Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem. https://doi.org/10.1080/13813455.2017.1422766
Bhattacharjee A, Basu A, Biswas J, Bhattacharya S (2015) Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice. Mol Cell Biochem 405:243–256. https://doi.org/10.1007/s11010-015-2415-1
Chtourou Y, Aouey B, Kebieche M, Fetoui H (2015) Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-κB and P53 signaling pathways. Chem Biol Interact 239:76–86. https://doi.org/10.1016/j.cbi.2015.06.036.
Chtourou Y, Aouey B, Aroui S, Kebieche M, Fetoui H (2016) Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat. Chem Biol Interact 243:1–9. https://doi.org/10.1016/j.cbi.2015.11.019
Chung SS, Kim M, Youn BS, Lee NS, Park JW, Lee IK, Lee YS, Kim JB, Cho YM, Lee HK, Park KS (2009) Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor γ in human skeletal muscle cells. Mol Cell Biol 29:20–30
Cuce G, Çetinkaya S, Koc T, Esen HH, Limandal C, Balcı T, Akoz M (2015) Chemoprotective effect of vitamin E in cyclophosphamide-induced hepatotoxicity in rats. Chem Biol Interact 232:7–11. https://doi.org/10.1016/j.cbi.2015.02.016
Dong D, Xu L, Yin L, Qi Y, Peng J (2015) Naringin prevents carbon tetrachloride-induced acute liver injury in mice. J Funct Foods 12:179–191. https://doi.org/10.1016/j.jff.2014.11.020
Eldutar E, Kandemir FM, Kucukler S, Caglayan C (2017) Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol-induced hepatotoxicity in rats: an experimental and biochemical study. J Biochem Mol Toxicol 31:e21960. https://doi.org/10.1002/jbt.21960
El-Kholy AA, Elkablawy MA, El-Agamy DS (2017) Lutein mitigates cyclophosphamide induced lung and liver injury via NF-κB/MAPK dependent mechanism. Biomed Pharmacother 92:519–527. https://doi.org/10.1016/j.biopha.2017.05.103
Farombi EO, Shrotriya S, Surh YJ (2009) Kolaviron inhibits dimethyl nitrosamine-induced liver injury by suppressing COX-2 and iNOS expression via NF-κB and AP-1. Life Sci 84:149–155. https://doi.org/10.1016/j.lfs.2008.11.012
Fouad AA, Qutub HO, Al-Melhim WN (2016) Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environ Toxicol Pharmacol 45:158–162. https://doi.org/10.1016/j.etap.2016.05.031
Fraiser LH, Kanekal S, Kehrer JP (1991) Cyclophosphamide toxicity. Drugs 42:781–795
Galati EM, Monforte MT, d’Aquino A, Miceli N, Di Mauro D, Sanogo R (1998) Effects of naringin on experimental ulcer in rats. Phytomedicine 5:361–366. https://doi.org/10.1016/S0944-7113(98)80018-4
Germoush MO, Mahmoud AM (2014) Berberine mitigates cyclophosphamide-induced hepatotoxicity by modulating antioxidant status and inflammatory cytokines. J Cancer Res Clin Oncol 140:1103–1109. https://doi.org/10.1007/s00432-014-1665-8.
Girnun GD, Domann FE, Moore SA, Robbins ME (2002) Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter. Mol Endocrinol 16:2793–2801. https://doi.org/10.1210/me.2002-0020
Habibi E, Shokrzadeh M, Chabra A, Naghshvar F, Keshavarz-Maleki R, Ahmadi A (2015) Protective effects of Origanum vulgare ethanol extract against cyclophosphamide-induced liver toxicity in mice. Pharm Biol 53:10–15. https://doi.org/10.3109/13880209.2014.908399.
Haenen GR, Vermeulen NP, Tsoi JNTT, Ragetli HM, Timmerman H, Bast A (1988) Activation of the microsomal glutathione-S-transferase and reduction of the glutathione dependent protection against lipid peroxidation by acrolein. Biochem Pharmacol 37:1933–1938. https://doi.org/10.1016/0006-2952(88)90539-4
Hassan MH, Ghobara M, Abd-Allah GM (2014) Modulator effects of meloxicam against doxorubicin-induced nephrotoxicity in mice. J Biochem Mol Toxicol 28:337–346. https://doi.org/10.1002/jbt.21570.
Jeon SM, Bok SH, Jang MK, Lee MK, Nam KT, Park YB, Choi MS (2001) Antioxidative activity of naringin and lovastatin in high cholesterol-fed rabbits. Life Sci 69:2855–2866. https://doi.org/10.1016/S0024-3205(01)01363-7.
Jnaneshwari S, Hemshekhar M, Santhosh MS, Sunitha K, Thushara R, Thirunavukkarasu C, Girish KS (2013) Crocin, a dietary colorant mitigates cyclophosphamide-induced organ toxicity by modulating antioxidant status and inflammatory cytokines. J Pharm Pharmacol 65:604–614. https://doi.org/10.1111/jphp.12016.
Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ (2017a) Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem 41(5). https://doi.org/10.1111/jfbc.12398
Kandemir FM, Küçükler S, Çağlayan C (2017b) Beneficial effects of silymarin and naringin against methotrexate-induced hepatotoxicity in rats. Atatürk Üniv Vet Bil Derg 12:167–177. https://doi.org/10.17094/ataunivbd.347970
Kandemir FM, Ozkaraca M, Küçükler S, Caglayan C, Hanedan B (2017c) Preventive effects of hesperidin on diabetic nephropathy induced by streptozotocin via modulating TGF-β1 and oxidative DNA damage. Toxin Rev:1–7. https://doi.org/10.1080/15569543.2017.1364268
Kim SH, Lee IC, Baek HS, Shin IS, Moon C, Bae CS, Kim HC (2014) Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats. Food Chem Toxicol 64:110–118. https://doi.org/10.1016/j.fct.2013.11.023
Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293. https://doi.org/10.1016/j.molcel.2010.09.023.
Lameire N, Kruse VIBEKE, Rottey S (2011) Nephrotoxicity of anticancer drugs—an underestimated problem? Acta Clin Belg 66:337–345
Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:1–19. https://doi.org/10.1155/2014/149185
Laudet V, Hanni C, Coll J, Catzeflis F, Stehelin D (1992) Evolution of the nuclear receptor gene superfamily. EMBO J 11:1003–1013. https://doi.org/10.1002/j.1460-2075.1992.tb05139.x.
Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 7:952–958
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Mahmoud AM (2012) Influence of rutin on biochemical alterations in hyperammonemia in rats. Exp Toxicol Pathol 64:783–789. https://doi.org/10.1016/j.etp.2011.01.016
Mahmoud AM (2014) Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation. Can J Physiol Pharmacol 92:717–724. https://doi.org/10.1139/cjpp-2014-0204
Mahmoud AM, Al Dera HS (2015) 18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARγ and Nrf2 upregulation. Genes Nutr 10:41. https://doi.org/10.1007/s12263-015-0491-1
Mahmoud AM, Mohammed HM, Khadrawy SM, Galaly SR (2017) Hesperidin protects against chemically induced hepatocarcinogenesis via modulation of Nrf2/ARE/HO-1, PPARγ and TGF-β1/Smad3 signaling, and amelioration of oxidative stress and inflammation. Chem Biol Interact 277:146–158. https://doi.org/10.1016/j.cbi.2017.09.015
Mansour DF, Salama AA, Hegazy RR, Omara EA, Nada SA (2017) Whey protein isolate protects against cyclophosphamide-induced acute liver and kidney damage in rats. J Appl Pharm Sci 7:111–120. https://doi.org/10.7324/JAPS.2017.70615
Mantawy EM, El-Bakly WM, Esmat A, Badr AM, El-Demerdash E (2014) Chrysin alleviates acute doxorubicin cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Eur J Pharmacol 728:107–118. https://doi.org/10.1016/j.ejphar.2014.01.065
McKim SE, Gäbele E, Isayama F, Lambert JC, Tucker LM, Wheeler MD, Arteel GE (2003) Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice. Gastroenterology 125:1834–1844. https://doi.org/10.1053/j.gastro.2003.08.030
Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140:313–326. https://doi.org/10.1016/j.cell.2010.01.028
Moon DO, Kim MO, Kang SH, Choi YH, Kim GY (2009) Sulforaphane suppresses TNF-α-mediated activation of NF-κB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3. Cancer Lett 274:132–142. https://doi.org/10.1016/j.canlet.2008.09.013
Motawi TM, Sadik NA, Refaat A (2010) Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: an experimental study on rat myocardium, testicles and urinary bladder. Food Chem Toxicol 48:2326–2336. https://doi.org/10.1016/j.fct.2010.05.067
Nafees S, Rashid S, Ali N, Hasan SK, Sultana S (2015) Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact 231:98–107. https://doi.org/10.1016/j.cbi.2015.02.021
Placer ZA, Cushmanni LL, Johnson BC (1966) Estimation of products of lipid peroxidation (as malondialdehyde) in biochemical systems. Anal Biochem 16:359–364. https://doi.org/10.1016/0003-2697(66)90167-9
Rehman MU, Tahir M, Ali F, Qamar W, Lateef A, Khan R, Sultana S (2012) Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: the protective effect of Ellagic acid. Mol Cell Biochem 365:119–127. https://doi.org/10.1007/s11010-012-1250-x
Sahu BD, Tatireddy S, Koneru M, Borkar RM, Kumar JM, Kuncha M, Sistla R (2014) Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection. Toxicol Appl Pharmacol 277:8–20. https://doi.org/10.1016/j.taap.2014.02.022
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205. https://doi.org/10.1016/0003-2697(68)90092-4
Sinanoglu O, Yener AN, Ekici S, Midi A, Aksungar FB (2012) The protective effects of spirulina in cyclophosphamide induced nephrotoxicity and urotoxicity in rats. Urology 80:1392–13e1. https://doi.org/10.1016/j.urology.2012.06.053
Singh M, Kumar N, Shuaib M, Garg VK, Sharma A (2014) A review on renal protective agents for cyclophosphamide induced nephrotoxicity. World J Pharm Pharmaceut Sci 3:737–747
Sun YI, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500
Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3:768–780. https://doi.org/10.1038/nrc1189
Taslimi P, Caglayan C, Gulcin İ (2017) The impact of some natural phenolic compounds on carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes: an antidiabetic, anticholinergic, and antiepileptic study. J Biochem Mol Toxicol 31:e21995. https://doi.org/10.1002/jbt.21995
Topal A, Alak G, Ozkaraca M, Yeltekin AC, Comaklı S, Acıl G, Kokturk M, Atamanalp M (2017) Neurotoxic responses in brain tissues of rainbow trout exposed to imidacloprid pesticide: assessment of 8-hydroxy-2-deoxyguanosine activity, oxidative stress and acetylcholinesterase activity. Chemosphere 175:186–191. https://doi.org/10.1016/j.chemosphere.2017.02.047
Vandewalle B, Moerman E, Lefebvre B, Defrance F, Gmyr V, Lukowiak B, Conte JK, Pattou F (2008) PPARγ-dependent and-independent effects of rosiglitazone on lipotoxic human pancreatic islets. Biochem Biophys Res Commun 366:1096–1101. https://doi.org/10.1016/j.bbrc.2007.12.088
Zarei M, Shivanandappa T (2013) Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food Chem Toxicol 57:179–184. https://doi.org/10.1016/j.fct.2013.03.028
Zhu H, Long MH, Wu J, Wang MM, Li XY, Shen H, Li SL (2015) Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid. Sci Rep 5:17536. https://doi.org/10.1038/srep17536
Acknowledgements
This study was supported by Scientific Research Projects Coordination Unit of Bingol University (Project number BAP-SSHMYO.2016.00.001). Therefore, we are grateful to Bingol University, Turkey.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The study was designed and conducted according to ethical norms approved by the Animal Experimentation Ethics Committee of the Bingol University (Bingol, Turkey) (Protocol No. 2016-4/5).
Conflict of interest
The authors declare that there is no conflict of interest.
Additional information
Responsible editor: Philippe Garrigues
Rights and permissions
About this article
Cite this article
Caglayan, C., Temel, Y., Kandemir, F.M. et al. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res 25, 20968–20984 (2018). https://doi.org/10.1007/s11356-018-2242-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-018-2242-5