Impact of vitamin C supplementation on lipid peroxidation and reduced glutathione levels in the liver tissue of mice with cyclophosphamide-induced immunosuppression
Keywords:
Ascorbic acid, Cyclophosphamide, Oxidative stress, Glutathione, LipidperoxidationAbstract
Objective
To investigate the effects of vitamin C supplementation on the levels of lipid peroxidation and reduced glutathione in the liver tissue of mice immunosuppressed with cyclophosphamide.
Methods
Thirty-two 45-day-old female Swiss mice were divided into four groups of eight animals each as follows: control (distilled water); vitamin C (50 mg/kg); cyclophosphamide (100 + 150 mg/kg); and treatment (vitamin C 50 mg/kg + cyclophosphamide 100 +150 mg/kg). The substances were provided intraperitoneally for six days, and on the seventh day, the mice were euthanized. The biochemical analyses of lipid peroxidation (quantification of thiobarbituric acid-reactive substances) and reduced glutathione (estimate of non-protein thiols) were performed on liver tissue.
Results
Cyclophosphamide increased the levels of lipid peroxidation (p<0.0001). Significant changes were not found in the groups treated with vitamin C. Cyclophosphamide alone did not affect the levels of reduced glutathione. Compared with the control group, vitamin C reduced the levels of reduced glutathione in animals that received or not cyclophosphamide. Vitamin C interacted with cyclophosphamide, that is, the chemotherapeutic agent further decreased the lower levels of reduced glutathione secondary to vitamin C intake.
Conclusion
Cyclophosphamide, in the study dosage and duration, was capable of inducing oxidative damage, verified by increased lipid peroxidation. A vitamin C dosage of 50mg/kg of body weight did not protect against the oxidative damage caused by the chemotherapeutic agent.
References
Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, et al. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007; 109(11):2291-8.
CapelID, Jenner M, Dorrell HM, Williams DC. Hepatic function assessed (in rats) during chemotherapy with some anti-cancer drugs. Clin Chem. 1979; 25(8):1381-3.
Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs.1991; 42(5):781-95.
Kern JC, Kehrer JP. Acrolein-induced cell death: Acaspase-influenced decision between apoptosis and oncosis/necrosis. Chem Biol Interact. 2002; 139(1):79-95.
Honjo I, Suou T, Hirayama C. Hepatotoxicity of cyclophosphamide in man: Pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol. 1988; 61(2):149-65.
Bhattacharya A, Lawrence RA, Krishnan A, Zaman K, Sun D, Fernandes G. Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune prone NZB/W female mice. J Am Coll Nutr. 2003; 22(5):288-99.
Stankiewicz A, Skrzydlewska E, Makiela M. Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metabol Drug Interact. 2002; 19(2):67-82.
Hershko C. Mechanism of iron toxicity and its possible role in red cell membrane damage. Semin Hematol. 1989; 26(4):277-85.
Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004; 134(3):489-92.
El-Sheikh AAK, Rifaai RA. Peroxisome Proliferator Activator Receptor (PPAR)-gamma ligand, but not ppar-alpha, ameliorates cyclophosphamide induced oxidative stress and inflammation in rat liver. PPAR Res., 2014; 2014. [ID 626319]. http:// dx.doi.org/10.1155/2014/626319
Fox N, Freifeld AG. The neutropenic diet reviewed: Moving toward a safe food handling approach. Oncology. 2012; 26(6):580-82.
Lee WJ. The prospects of vitamin C in cancer therapy. Immune Netw. 2009; 9(5):147-52. http:// dx.doi.org/10.4110/in.2009.9.5.147
Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med. 1986; 314(14):892-902.
Lane DJ, Richardson DR. The active role of vitamin C in mammalian iron metabolism: Much more than just enhanced iron absorption! Free Radic Biol Med. 2014; 75:69-83.http://dx.doi.org/10.1016/j. freeradbiomed.2014.07.007
Campbell EJ, Dachs GU. Current limitations of murine models in oncology for ascorbate research. Front Oncol. 2014; 4:282.http://dx.doi.org/10. 3389/fonc.2014.00282
Gren A, Barbasz A, Kreczmer B, Sieprawska A, Rudolphi-Skorska E, Filek M. Protective effect of ascorbic acid after single and repetitive administration of cadmium in Swiss mice. Toxicol Mech Methods. 2012; 22(8):597-604. http://dx. doi.org/10.3109/15376516.2012.704957
Guo X, Li W, Xin Q, Ding H, Zhang C, Chang Y, et al. Vitamin C protective role for alcoholic liver disease in mice through regulating iron metabolism. Toxicol Ind Health. 2011; 27(4):341-8. http://dx.doi. org/10.1177/0748233710387007
Zuluaga AF, Salazar BE, Rodriguez CA, Zapata AX, Agudelo M, Vesga O. Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: Characterization and applicability to diverse experimental models of infectious diseases. BMC Infect Dis. 2006; 6:55.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem.1979; 95(2):351-8.
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 959; 82(1):70-7.
Lowry OH, Rosebrough NJ, Farr Al, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75.
Wei X, Su F, Su X, Hu T, Hu S. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia. 2012; 83(4):636-42. http://dx.doi.org/ 10.1016/j.fitote.2012.01.006
Ergul Y, Erkan T, Uzun H, Genc H, Altug T, Erginoz E. Effect of vitamin C on oxidative liver injury due to isoniazid in rats. Pediatr Int. 2010; 52(1):69-74. http://dx.doi.org/10.1111/j.1442-200X.2009.0 2891.x
Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009; 30(1-2):42-59. http://dx.doi. org/10.1016/j.mam.2008.05.005
Lei XG. In vivo antioxidant role of glutathione peroxidase: Evidence from knockout mice. Methods Enzymol. 2002; 347:213-25.
Banhegyi G, Braun L, Csala M, Puskas F, Mandl J. Ascorbate metabolism and its regulation in animals. Free Radic Biol Med. 1997; 23(5):793-803.
Prasad SB, Rosangkima G, Nicol BM. Cyclophosphamide and ascorbic acid-mediated ultrastructural and biochemical changes in Dalton’s lymphoma cells in vivo. Eur J Pharmacol. 2010; 645(1):47-54. http://dx.doi.org/10.1016/j.ejphar. 2010.07.020
Khynriam D, Prasad SB. Changes in endogenous tissue glutathione level in relation to murine ascites tumor growth and the anticancer activity of cisplatin. Braz J Med Biol Res. 2003; 36(1):53-63.
Navarro J, Obrador E, Carretero J, Petschen I, Avino J, Perez P, et al. Changes in glutathione status and the antioxidant system in blood and in cancer cells g ^ g ^ associate with tumour growth in vivo. Free Radic Biol Med. 1999; 26(3/4):410-8.
Gürgen SG, Erdo´ an D, Elmas Ç, Kaplano ´lu GT, Özer Ç. Chemoprotective effect of ascorbic acid, α-tocopherol, and selenium on cyclophosphamide induced toxicity in the rat ovarium. Nutrition. 2013; 29(5):777-84. http://dx.doi.org/10.1016/j.nut.20 12.11.004
Veskoukis AS, Tsatsakis Am, Kouretas D. Dietary oxidative stress and antioxidant defense with an emphasis on plant extract administration. Cell Stress Chaperotones. 2012; 17(1):11-21. http://dx.doi. org/10.1007/s12192-011-0293-3
Halliwell B. The antioxidant paradox. Lancet. 2000; 355(9210):1179-80.
Park S. The effects of high concentrations of vitamin C on cancer cells. Nutrients. 2013; 5(9):3496-505. http://dx.doi.org/10.3390/nu5093496
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