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Licensed Unlicensed Requires Authentication Published by De Gruyter December 13, 2017

Citrullus colocynthis Linn. Fruit extract ameliorates cisplatin-induced hepato-renal toxicity in rats

Olufunmilayo O. Adeyemi, Ismail O. Ishola and Ifeoluwa D. Ajani

Abstract

Background

Cisplatin-induced acute liver and kidney injuries are serious problems in cancer patients during treatment of solid tumours.

Objective

This study sought to investigate possible protective effect of ethanolic fruit extract of Citrullus colocynthis (CC) against cisplatin-induced hepato-renal toxicity in rats.

Methods

Thirty male albino rats (150–200 g) were divided into five groups (n=6) and treated as follows: group 1: vehicle (10 mL/kg, p.o.; normal control); group 2: vehicle (10 mL/kg); groups 3–5: CC (100, 200 or 400 mg/kg, p.o.), respectively, for 10 days. Cisplatin (7.5 mg/kg; i.p.) was administered on the 7th day to animals in groups (2–5) 1 h after pretreatment. The animals were euthanized on day 10 for haematological, biochemical and histological analysis.

Results

Cisplatin induced a significant increase in the serum levels of ALT, ALP, creatinine and blood urea nitrogen indicative of hepato-renal injury. More so, cisplatin caused marked increase in granulocyte, lymphocyte and platelets counts which were ameliorated by CC (100–400 mg/kg) treatment. In addition, cisplatin induced marked increase in MDA and nitrite levels coupled with deficits in glutathione, catalase and superoxide dismutase activities which were attenuated by CC administration. In vitro assay showed that CC scavenged DPPH and nitrite radicals (69.50 and 64.50 µg/mL, respectively). Total antioxidant capacity, phenolic and flavonoid contents are 24.27±0.09 mg QUE/g, 17.14±0.12 mg GAE/g and 10.20±0.09 mg QUE/g, respectively. CC preserved the liver and kidney histoarchitecture.

Conclusions

This study showed that C. colocynthis possesses hepatoprotective and nephroprotective actions possibly through enhancement of antioxidant defence system. Thus, it could be a potential adjuvant in cisplatin-based chemotherapy.

Acknowledgements

The authors are grateful to Mr. C. Micah of the Department of Pharmacology, Therapeutics and Toxicology, and Mr. S.A. Adenekan both in the Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Nigeria for their technical assistance.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

[1] Ries F, Klastersky J. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis. 1986;8:368–79.10.1016/S0272-6386(86)80112-3Search in Google Scholar PubMed

[2] Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discovery. 2005;4:307–20.10.1038/nrd1691Search in Google Scholar

[3] Palipoch S, Punsawad C. Biochemical and histological study of rat liver and kidney injury induced by cisplatin. J Toxicol Pathol. 2013;26:293–99.10.1293/tox.26.293Search in Google Scholar PubMed

[4] Lu Y, Cederbaum AI. Cisplatin-induced hepatotoxicity is enhanced by elevated expression of cytochrome P450 2E1. Toxicol Sci. 2006;89:515–23.10.1093/toxsci/kfj031Search in Google Scholar PubMed

[5] Pratibha R, Sameer R, Rataboli PV, Bhiwgade DA, Dhume CY. Enzymatic studies of cisplatin-induced oxidative stress in hepatic tissue of rats. Eur J Pharmacol. 2006;532:290–93.10.1016/j.ejphar.2006.01.007Search in Google Scholar PubMed

[6] Rehman MU, Ali N, Rashid S, Jain T, Nafees S, Tahir M, et al. Alleviation of hepatic injury by chrysin in cisplatin administered rats: probable role of oxidative and inflammatory markers. Pharmacol Rep. 2012;66:1050–59.10.1016/j.pharep.2014.06.004Search in Google Scholar

[7] Sugiyama S, Hayakawa M, Kato T, Hanaki Y, Shimizu K, Ozawa T. Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: disturbances in glutathione peroxidase activity. Biochem Biophys Res Commun. 1989;159:1121–27.10.1016/0006-291X(89)92225-0Search in Google Scholar PubMed

[8] Matsushima H, Yonemura K, Ohishi K, Hishida A. The role of oxygen free radicals in cisplatin-induced acute renal failure in rats. J Lab Clin Med. 1998;131:518–26.10.1016/S0022-2143(98)90060-9Search in Google Scholar PubMed

[9] Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol. 2009;61:223–42.10.1016/j.etp.2008.09.003Search in Google Scholar PubMed

[10] Racz I, Tory K, Jr GF, Berente Z, Osz E, Jaszlits L, et al. BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity. Biochem Pharmacol. 2002;63:1099–111.10.1016/S0006-2952(01)00935-2Search in Google Scholar PubMed

[11] Omar HA, Mohamed WR, Arafa El SA, Shehata BA, El Sherbiny GA, Arab HH, et al. Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity. Pharmacol Rep. 2016;68:349–56.10.1016/j.pharep.2015.09.007Search in Google Scholar PubMed

[12] Pedraza-Chaverrí J, Barrera D, Maldonado PD, Chirino YI, Macías-Ruvalcaba NA, Medina-Campos ON, et al. S-allylmercaptocysteine scavenges hydroxyl radical and singlet oxygen in vitro and attenuates gentamicin-induced oxidative and nitrosative stress and renal damage in vivo. BMC Clin Pharmacol. 2004;4:5.10.1186/1472-6904-4-5Search in Google Scholar PubMed

[13] Burkill HM. 1985. The useful plants of west tropical Africa, Vol 1.Search in Google Scholar

[14] Gurudeeban S, Satyavani K, Ramanathan T. Bitter Apple (Citrullus colocynthis): An overview of chemical composition and biomedical potentials. Asian J Plant Sci. 2010;9:394–401.10.3923/ajps.2010.394.401Search in Google Scholar

[15] Hussain AI, Rathore HA, Sattar MZ, Chatha SA, Sarker SD, Gilani AH. Citrullus colocynthis (L.) Schrad (bitter apple fruit): a review of its phytochemistry, pharmacology, traditional uses and nutritional potential. J Ethnopharmacol. 2014;155:54–66.10.1016/j.jep.2014.06.011Search in Google Scholar

[16] Senthilkumar A, Venkatesalu V. Chemical constituents, in vitro antioxidant and antimicrobial activities of essential oil from the fruit pulp of wood apple. Ind Crops Prod. 2013;46:66–72.10.1016/j.indcrop.2013.01.018Search in Google Scholar

[17] Oyaizu M. Studies on product of browning reaction prepared from glucose amine. Jpn J Nutr. 1986;44:307–15.10.5264/eiyogakuzashi.44.307Search in Google Scholar

[18] Kumaran A, Karunakaran RJ. Nitric oxide radical scavenging active components from Phyllanthus emblica L. Plant Foods Hum Nutr. 2006;61:1–5.10.1007/s11130-006-0001-0Search in Google Scholar PubMed

[19] Sangameswaran B, Balakrishnan BR, Deshraj C, Jayakar B. In vitro antioxidant activity of roots of Thespesia lampas Dalz and Gibs. Pak J Pharm Sci. 2009;22:368–72.Search in Google Scholar PubMed

[20] Adeosun AM, Ighodaro OM, Aminu AO, Ogunlana AI. The antioxidant and phenolic profiles of five green vegetables grown in Southern Nigeria. Acta Sci Pol Technol Aliment. 2016;15:391–97.10.17306/J.AFS.2016.4.37Search in Google Scholar PubMed

[21] Singleton VL, Rossi JA. Jr. Colorimetry of total phenolics with phosphomolybdic acid- phosphotungstic acid reagents. Am J Enol Viticult. 1965;16:144–58.Search in Google Scholar

[22] OECD (Organisation for Economic Co-operation and Development) Test no. 423: Acute oral toxicity – acute toxic class method. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. Paris: OECD Publishing, 2002.Search in Google Scholar

[23] Ishola IO, Akinyede AA, Robert AK, Omilabu SA. Hepatoprotective and antioxidant activities of Hepacare®, a herbal formulation against carbon tetrachloride-induced liver injury. Drug Res (Stuttg). 2015;65:30–39.10.1055/s-0034-1371829Search in Google Scholar PubMed

[24] Cohen SM, Lippard SJ. Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol. 2001;67:93–130.10.1016/S0079-6603(01)67026-0Search in Google Scholar PubMed

[25] Sadowitz PD, Hubbard BA, Dabrowiak JC, Goodisman J, Tacka KA, Aktas MK, et al. Kinetics of cisplatin binding to cellular DNA and modulations by thiol-blocking agents and thiol drugs. Drug Metab Dispos. 2002;30:183–90.10.1124/dmd.30.2.183Search in Google Scholar PubMed

[26] Grimm T, Schäfer A, Högger P. Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol). Free Radic Biol Med. 2004;36:811–22.10.1016/j.freeradbiomed.2003.12.017Search in Google Scholar PubMed

[27] Zimmerman HJ, Seeff LB. Enzymes in hepatic disease: In Diagnostic Enzymology. Philadelphia: Lea and Febiger, 1970.Search in Google Scholar

[28] Cersosimo RJ. Hepatotoxicity associated with cisplatin chemotherapy. Ann Pharmacother. 1993;27:438–41.10.1177/106002809302700408Search in Google Scholar PubMed

[29] Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008;73:994–1007.10.1038/sj.ki.5002786Search in Google Scholar PubMed

[30] Ko JW, Lee IC, Park SH, Moon C, Kang SS, Kim SH, et al. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats. Lab Anim Res. 2014;30:174–80.10.5625/lar.2014.30.4.174Search in Google Scholar PubMed PubMed Central

[31] Waseem M, Bhardwaj M, Tabassum H, Raisuddin S, Parvez S. Cisplatin hepatotoxicity mediated by mitochondrial stress. Drug Chem Toxicol. 2015;38:452–59.10.3109/01480545.2014.992437Search in Google Scholar PubMed

[32] Liu X, Huang Z, Zou X, Yang Y, Qiu Y, Wen Y. Panax notoginseng saponins attenuates cisplatin-induced nephrotoxicity via inhibiting the mitochondrial pathway of apoptosis. Int J Clin Exp Pathol. 2014;7:8391–400.Search in Google Scholar PubMed

[33] Kumar S, Kumar D, Manjusha SK, Singh N, Vashishta B. Antioxidant and free radical scavenging potential of Citrullus colocynthis (L.) Schrad. methanolic fruit extract. Acta Pharm. 2008;58:215–20.10.2478/v10007-008-0008-1Search in Google Scholar PubMed

[34] Tannin-Spitz T, Grossman S, Dovrat S, Gottlieb HE, Bergman M. Growth inhibitory activity of cucurbitacin glucosides isolated from Citrullus colocynthis on human breast cancer cells. Biochem Pharmacol. 2007;73:56–67.10.1016/j.bcp.2006.09.012Search in Google Scholar PubMed

[35] Ayyad SE, Abdel-Lateff A, Alarif WM, Patacchioli FR, Badria FA, Ezmirly ST. In vitro and in vivo study of cucurbitacins-type triterpene glucoside from Citrullus colocynthis growing in Saudi Arabia against hepatocellular carcinoma. Environ Toxicol Pharmacol. 2012;33:245–51.10.1016/j.etap.2011.12.010Search in Google Scholar PubMed


Supplemental Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jcim-2017-0086).


Received: 2017-6-7
Accepted: 2017-10-18
Published Online: 2017-12-13

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