Prophylactic Effect of Ascorbic Acid On Certain Biochemical and Histopathological  Indices In Rats Treated With Repeated Dose of Cyclophosphamide:  doi.org/10.26538/tjnpr/v2i4.6

Tosin O. Olaoba; Olalekan A. Akinyemi

Authors

Tosin O. Olaoba Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
Olalekan A. Akinyemi Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria

Keywords:

Prophylactic,, ascorbic acid,, biochemical indices,, cyclophosphamide.

Abstract

The limited use of cyclophosphamide in cancer treatment resulted from its role in multiple organ toxicities. The present study aimed to investigate the prophylactic capacity of ascorbic acid against hepatotoxicity induced by repeated dose of cyclophosphamide in male rats. Twenty-four male Wistar rats were randomly selected into 4 groups of 6 rats each. Group 1 served as the control and received intraperitoneal injection of normal saline BP 0.9% w/v. Group 2 received freshly prepared cyclophosphamide 4 mg/kg intraperitoneally once daily throughout the period of administration. Group 3 received an oral dose of 100 mg/kg ascorbic acid and then
cyclophosphamide while Group 4 received ascorbic acid only. After 21 days of administration, the animals were sacrificed and biochemical estimation as well as histological assessment of the liver were carried out. The result showed significant (P<0.05) decrease in protein concentration, significant (P<0.05) elevation in serum alanine transaminase (ALT), alkaline phosphatase (ALP),
gamma glutamyl transpeptidase (GGT) and disrupted liver histological assembly in rats treated with repeated dose of cyclophosphamide as compared to control. Ascorbic acid showed prophylactic capacity against liver damage in cyclophosphamide treated rats. The total protein concentration was normal, the serum liver enzyme activities were not significantly affected and
there was protection of the hepatic histoarchitecture when compared with cyclophosphamide treated group. Therefore, the supplementation of ascorbic acid with the use of chemotherapeutic agent such as cyclophosphamide during cancer treatment may prevent related symptoms.

References

Ahmed AR, Hombal SM. Cyclophosphamide (Cycloxan). A review on relevant pharmacology and clinical uses. J Am Acad Dermatol. 1984; 11: 1115-1126.

Omidvar Z, Parivar K, Sanee H, Amiri-Tehranizadeh Z, Baratian A, Saberi MR, Asoodeh A, Chamani JK. Investigation with spectroscopy, Zeta potential and Molecular Modelling of the Non-cooperative behaviour between cyclophosphamide hydrochloride and aspirin upon

interaction with human serum albumin: binary and ternary systems from the view point of multi-drug therapy. J Biomol Struct Dyn. 2011; 29: 181-206.

Connors TA, Cox PJ, Farmer PB. Some studies on the active intermediate formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol. 1974; 23: 115-129.

Flowers JL, Ludeman SM, Gamcsik MP. Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemother Pharmacol. 2000; 45: 335-344.

Völker G, Dräger U, Peter G. Studien zum spontanzerfall von 4-hydroxycyclophosphamid und 4-hydroxyperoxycyclophosphamid mit hilfe der dünnschichtschromatographie. Arzneimittel-Forsch Drug Res 1974; 24: 1172-1176.

Shanmugarajan TS, Arunsunder M, Somasundaram I, Sivaraman D, Krishnakumar E, Ravichandran V. Ameliorative effect of Ficus hispida Linn leaf extract on cyclophosphamide-induced oxidative hepatic injury in rat. J Pharmacol & Toxicol. 2008; 3(5): 363-372.

Sladek NE. Metabolism of oxazaphosphorines. Pharmacol Ther. 1988; 37: 301-315.

Gurtoo HL, Hipkens JH, Sharma SD. Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide. Cancer Res. 1981; 41: 3584-3591.

Crook TR, Souhami RL, McLean AEM. Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells. Cancer Res. 1986; 46:5029-5034.

Blomgren H, Hallsröm M. Possible role of acrolein in 4-hydroxyperoxycyclophosphamide-induced cell damage in vitro. Methods Find Exp Clin Pharmacol. 1991; 13: 11-14.

Alarcon RA, Meienhofer J. Formation of the cyctotoxic aldehyde acrolein during in vitro degradation of cyclophosphamide. Nat New Biol. 1971; 233: 250-252.

Ludeman SM. The chemistry of the metabolites of cyclophosphamide. Curr Pharm Des. 1999; 5: 627-643.

King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist 2001; 6:162-176.

Bhata K, Ahmad F, Rashid H, Raisuddin S. Protective effect of S-allylcycteine against cyclophosphamide-induced bladder hemorrhagic cyctitis in mice. Food Chem Toxicol. 2008; 46:3368-3374.

Rouissil K, Kouidhil S, Hamrita B, Outerhani S, Cherif M, Elgaaied AB. Therapeutic effect of Aloe vera plant extract against cyclophosphamide and buthionine sulfoximine induced toxicities in the bladder. Biochem Pharmacol. 2012; 1: 101-107.

Zarei M, Shivanandappa T. Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food Chem Toxicol. 2013; 57: 179-184.

Senthilkumar S, Devaki T, Manohar BM, Babu MS. Effect of squalene in cyclophosphamide-induced toxicity. Clin Chim Acta. 2006; 364: 335-342.

Sheetla C, Bashir A, Rajendra C, Vinoy KS. Ameliorative role of ascorbic acid against hepatotoxicity induced by chemotherapeutic drug cyclophosphamide, in male albino rat, Rattus norvegicus. Int J Biol Pharm Res. 2014;5(11):830-842.

Ademola AO, Olutayo TO, Ebunoluwa RA, Akinrinde SA, Rachael OO, Adebowale BS. Cyclophosphamide-induced hepatotoxicity in wistar rats: the modulatory role of gallic acid as a hepatoprotective and chemopreventive phytochemical. Int J Prev Med. 2016; 7: 51-58.

Anitra CC, Margret CM, John SC. The effect of intravenous vitamin C on cancer and chemotherapy-related fatigue and quality of life. Front Oncol. 2014; 4: 283.

Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients’ health-related quality of life after high dose of vitamin C administration. J Korean Med Sci. 2007; 22(1): 7-11.

Vollbracht C, Schneider B, Leendert V, Weiss G, Aurebach L, Beuth J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemradiotherapy and after care: results of a retrospective, multicare, epidemiological cohort study in Germany. Pub

Med. 2011; 25(6): 983-990.

Ali SA. Chemoprotective effect of ascorbic acid on cyclophosphamide induced oral toxicity. J Med Sci. 2017; 21(1): 1540-1551.

Reeb C, Jones R, Beard D, Bedigam H, Myers D, Paigen B. Microenvironment in ventilated animals cages with differing ventilation rates mice population, and frequency of bedding changes. Contemp Top Lab Anim Sci 1998; 37: 43-49.

OECD. Guidelines for testing of chemicals. Repeated 28-day oral toxicity study in rodents. Guideline 407. Organization for Economic Co-operation and Development. 2008.

Coria-Avila GA, Gavrila AM, Menard S, Ismail N, Pfaus JG. Cecum location in rats and the implications for ntraperitoneal injections. Lab Anim (NY) 2007; 36: 25-30.

Lukas G, Brindle SD, Greegard P. The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther 1971; 178:562-566.

McEvoy GK. Drug Information the American Hospital Formulary Service, America Society of Health. System Pharmacists, Inc., MD. 1993.

Close B, Banister K, Baumans V, Bernoth EM, Bromage N, Bunyan J, Erhardt W, Flecknell P, Gregory N, Hackbarth H, Morton D, Warwick C. Recommendations for euthanasia of experimental animals: part 2. Lab Anim 1997; 31: 1-32.

Koller A. Total serum protein. Kaplan A. Clinical Chemistry. The C. V. Mosby Co. St Louise. Toronto. Princeton. 1984; 1316-1324, 418.

Burtis CA, Ashwood ER. Textbook of Clinical Chemistry. (3rd ed.). Saunders, Philadelphia. 1999.

Rec. GSCC (DGKC). J Clin. Chem. Clin. Biochem. 1972;10:182.

Drury RA, Wallington EA, Cancerson R. 4th ed. Oxford, London, New York: Oxford University Press; Carlton’s Histopathological Techniques. 1976.

Luna LC. Manual of histologic staining methods. Armed Forces Institute of Pathology. (3rd edn). New York, McGraw Hill Book Company. 1968.

Colleoni M, Rocca A, Sandri MT. Low dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumour activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002; 13: 73-80.

Huang Z, Roy P, Waxman DJ. Role of liver microsomal CYP 3A4 and CYP2B6 in catalysing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol.2000; 59: 961-972.

Griskevicius L, Yasar U, Sandberg H. Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes. Eur J Clin Pharmacol. 2003; 59: 103-109.

Kern JC, Kehrer JP. Acrolein-induced cell death: A caspaseinfluenced decisions between apoptosis and oncosis/necrosis. Chem Biol Interact. 2002; 139: 79-95.

Sheeja K, Kuttan G. Ameliorating effecr of Andrographis paniculata extract against cyclophosphamide-induced toxicity in mice. Asian J Cancer Prev. 2006; 7: 609-614.

Tripathi DN, Jena GB. Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: Role of Nrf2, p53, p38 and phase-II enzymes. Mutat Res. 2010; 696: 69-80.

Sabry AE, Abeer AA, Mousa OG, Kamal FE, Hassan AE. Ameliorative effect of propolis against cyclophosphamideinduced toxicity in mice. Journal Pharmaceutical Biology. 2014; 53(2): 235-241.

Kumar G, Banu GS, Kannan V, Pandian MR. Antihepatotoxic effect of beta-carotene on paracetamol induced hepatic damage in rats. Indian J Exp Biol. 2005; 43: 351-355.

Ishihara M, Itoh M, Miymoto K, Suna S, Takeuchi Y, Takenaka I, Jitsunari F. Spermatogenic disturbance by di-(2-ethylhexyl) phthalate is significantly prevented by treatment with antioxidant vitamins in the rat. Int J Androl. 2000; 23: 85-94.

Nicol BM, Prasad SB. The effects of cyclophosphamide alone and in combination with ascorbic acid against murine ascite’s Dalton’s lymphoma. Indian J. Pharmacol.2006; 38: 260-265.

Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The cuurent status serum biomarkers of hepatotoxicity. Toxicology. 2008; 245: 194-205.

Ravih SS, Rizna AC, Rozita M, Kong WY, Halim AG. Lowdose cyclophosphamide-induced acute hepatotoxicity. Am J Case Rep. 2013; 14: 345-349.

Das UB, Mallick M, Debnath JM, Ghosh D. Protective effect of ascorbic acid on cyclophosphamide-induced testicular gametogenic and androgenic disorders in male rats. Asian J Androl. 2002; 2(2): 79-86.

Ross MH, Reith EJ. Histology A Test and Atlas. (1st ed). Harper International. Harper & Row, Publishers, JB Lippincott Company New York. 1985.

Ramachandran R, Kakar S. Histological patterns in druginduced liver disease. J Clin Pathol. 2009; 62: 481-492.

Okolie NP, Iroanya CU. Some histological and biochemical evidence for mitigation of cyanide induced tissue lesions by antioxidants vitamins administration in rabbits. Food Chem Toxicol. 2003; 41(4): 465-469.