Skip to main content
SpringerLink
Log in

Seleno l-Methionine Acts on Cyclophosphamide-Induced Kidney Toxicity

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

The anticancer drug cyclophosphamide (CP) has nephrotoxic effects besides its urotoxicity, which both in turn limit its clinical utility. The nephrotoxicity of CP is less common compared to its urotoxicity, and not much importance has been given for the study of mechanism of CP-induced nephrotoxicity so far. Overproduction of reactive oxygen species (ROS) during inflammation is one of the reasons of the kidney injury. Selenoproteins play crucial roles in regulating ROS and redox status in nearly all tissues; therefore, in this study, the nephrotoxicity of CP and the possible protective effects of seleno l-methionine (SLM) on rat kidneys were investigated. Forty-two Sprague–Dawley rats were equally divided into six groups of seven rats each. The control group received saline, and other rats were injected with CP (100 mg/kg), SLM (0.5 or 1 mg/kg), or CP + SLM intraperitoneally. Malondialdehyde (MDA) and glutathione (GSH) levels in kidney homogenates of rats were measured, and kidney tissues were examined under the microscope. CP-treated rats showed a depletion of renal GSH levels (28% of control), while CP + SLM-injected rats had GSH values close to the control group. MDA levels increased 36% of control following CP administration, which were significantly decreased after SLM treatment. Furthermore, these biochemical results were supported by microscopical observations. In conclusion, the present study not only points to the therapeutic potential of SLM in CP-induced kidney toxicity but also indicates a significant role for ROS and their relation to kidney dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dollery C (1999) Cyclophosphamide. Therapeutic drugs. Churchill Livingstone, Edinburg, pp 349–353

    Google Scholar 

  2. Kopecna L (2001) Late effects of anticancer therapy on kidney function in children with acute lymphoblastic leukemia. Bratisl Lek Listy 102:357–360

    CAS  PubMed  Google Scholar 

  3. Okamura T, Garland EM, Taylor RJ, Johansson SL, Cohen SM (1992) The effect of cyclophosphamide administration on the kidney of the rat. Toxicol Lett 63:261–276

    Article  CAS  PubMed  Google Scholar 

  4. Gustafsson LL, Eriksson L, Dahl S, Eleborg L (1996) Cyclophosphamide induced acute liver failure requiring transplantation in a patient with genetically deficient debrisoquine metabolism: a causal relationship? J Int Med 240:311–314

    Article  CAS  Google Scholar 

  5. Rossi R, Godde A, Kleinebrand A, Riepenhausen M, Boos J, Ritter J (1994) Unilateral nephrectomy and cisplatin as risk factor of ifosfamide-induced nephrotoxicity: analysis of 120 patients. J Clin Oncol 12:159–165

    CAS  PubMed  Google Scholar 

  6. Sugumar E, Kanakasabapathy I, Abraham P (2007) Normal plasma creatinine level despite histological evidence of damage and increased oxidative stress in the kidneys of cyclophosphamide treated rats. Clin Chim Acta 376:244–245

    Article  CAS  PubMed  Google Scholar 

  7. Abraham P, Rabi S (2009) Nitrosative stress, protein tyrosine nitration, PARP activation and NAD depletion in the kidneys of rats after single dose of cyclophosphamide. Clin Exp Nephrol 13:281–287. doi:10.1007/s10157-009-0160-z

    Article  PubMed  Google Scholar 

  8. Kern JC, Kehrer JP (2002) Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis. Chem Biol Interact 139:79–95

    Article  CAS  PubMed  Google Scholar 

  9. Arumugam N, Sivakumar V, Thanislass J, Devaraj H (1997) Effects of acrolein on rat liver antioxidant defense system. Indian J Exp Biol 35:1373–1374

    CAS  PubMed  Google Scholar 

  10. Mythili Y, Sudharsan PT, Selvakumar E, Varalakshmi P (2004) Protective effect of dl-a-lipoic acid on cyclophosphamide induced oxidative cardiac injury. Chem Biol Interact 151:13–19

    Article  CAS  PubMed  Google Scholar 

  11. Kawanishi M, Matsuda T, Nakayama A, Takebe H, Matsui S, Yagi T (1998) Molecular analysis of mutations induced by acrolein in human fibroblast cells using supf shuttle vector plasmids. Mut Res Gen Toxicol Environ Mutagen 417:65–73

    Article  CAS  Google Scholar 

  12. Fouladi M, Stempak D, Gammon J (2001) Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin and etoposide chemotherapy in children with refractory carcinoma. Cancer 92:914–923

    Article  CAS  PubMed  Google Scholar 

  13. Schrauzer GN (2003) The nutritional significance, metabolism, and toxicology of selenomethionine. Adv Food Nutr Res 47:73–112

    Article  CAS  PubMed  Google Scholar 

  14. Flohe L, Gunzler WA, Loschen G (1979) The glutathione peroxidase reaction: a key to understand the selenium requirement of mammals. Trace metals in health and disease. Raven, New York, pp 263–286

    Google Scholar 

  15. Bauer G, Wendel A (1980) The activity of the peroxide-metabolizing system in human colon carcinoma. J Cancer Res Clin Oncol 97:267–273

    Article  Google Scholar 

  16. Cao S, Durrani FA, Rustum YM (2004) Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin Cancer Res 10:2561–2569

    Article  CAS  PubMed  Google Scholar 

  17. Ayhanci A, Uyar R, Aral E, Kabadere S, Appak S (2008) Protective effect of zinc on cyclophosphamide-induced hematoxicity and urotoxicity. Biol Trace Elem Res 126:186–193

    Article  CAS  PubMed  Google Scholar 

  18. Mohan IK, Khan M, Shobha JC, Naidu MU, Prayag A, Kuppusamy P (2006) Protection against cisplatin-induced nephrotoxicity by Spirulina in rats. Cancer Chemother Pharmacol 586:802–808

    Article  Google Scholar 

  19. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  20. Levine LA, Richie JP (1989) Urological complications of cyclophosphamide. J Urol 141:1063–1069

    CAS  PubMed  Google Scholar 

  21. Ayhanci A, Yaman S, Sahinturk V, Uyar R, Bayramoglu G, Senturk H, Altuner Y, Appak S, Gunes S (2009) Protective effect of seleno-L-methionine on cyclophosphamide-induced urinary bladder toxicity in rats. Biol Trace Elem Res. doi:10.1007/s 12011-009-8458-y

    Google Scholar 

  22. Philips FS, Sternberg SS, Cronin AP, Vidal PM (1961) Cyclophosphamide and urinary bladder toxicity. Cancer Res 21:1577–1589

    CAS  PubMed  Google Scholar 

  23. Levine S, Sowinski R (1974) Cyclophosphamide-induced cerebral and visceral lesions in rats. Arch Pathol 98:177–182

    CAS  PubMed  Google Scholar 

  24. Hsu HC, Tsai HM (1982) Cyclophosphamide-induced glomerular injury in newborn mice. Lab Invest 47:281–285

    CAS  PubMed  Google Scholar 

  25. Senthilkumar S, Devaki T, Manohar BM, Babu MS (2006) Effect of squalene on cyclophosphamide-induced toxicity. Clin Chim Acta 364:335–342

    Article  CAS  PubMed  Google Scholar 

  26. Cayir K, Karadeniz A, Yildirim A, Kalkan Y, Karakoc A, Keles M, Tekin SB (2009) Protective effect of L-carnitine against cisplatin-induced liver and kidney oxidant injury in rats. Cent Eur J Med 4(2):184–191

    Article  CAS  Google Scholar 

  27. Lu Y, Cederbaum A (2007) The mode of cisplatin-induced cell death in CYP2E1-overexpressing HepG2 cells: modulation by ERK, ROS, glutathione, and thioredoxin. Free Radic Biol Med 43:1061–1075

    Article  CAS  PubMed  Google Scholar 

  28. Nannelli A, Messina A, Marini S, Trasciatti S, Longo V, Gervasi PG (2007) Effects of the anticancer dehydrotarplatin on cytochrome P450 and antioxidant enzymes in male rat tissues. Arch Toxicol 81:479–487

    Article  CAS  PubMed  Google Scholar 

  29. Whanger PD (1981) Selenium and heavy metal toxicity. In: Spallholz JE, Martin JL, Ganther HE (eds) Selenium in biology and medicine. AVI, Westport, pp 230–255

    Google Scholar 

  30. Diplock AT, Watkins WJ, Heurson M (1986) Selenium and heavy metals. Ann Clin Res 18:55–60

    CAS  PubMed  Google Scholar 

  31. Ip C (1986) Selenium and experimental cancer. Ann Clin Res 18:22–29

    CAS  PubMed  Google Scholar 

  32. Jamba L, Nehru B, Bansal MP (1997) Selenium supplementation during cadmium exposure: changes in antioxidant enzymes and the ultrastructure of the kidney. The Journal of Trace Elements in Experimental Medicine 10:233–242

    Article  CAS  Google Scholar 

  33. Gray KJ, Engelmann UH, Fishman IJ (1986) Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (cytoxan) therapy. J Urol 133:497–500

    Google Scholar 

  34. Furst A (2002) Can nutrition affect chemical toxicity? Int J Toxicol 21:419–424

    Article  CAS  PubMed  Google Scholar 

  35. Tripathi DN, Jena GB (2008) Ebselen attenuates cyclophosphamide-induced oxidative stress and DNA damage in mice. Free Radic Res 42(11):966–977

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Arts and Science Department of Biology, Eskisehir Osmangazi University, Meselik Campus F5, 26480, Eskisehir, Turkey

    Adnan Ayhanci, Sibel Günes, Mustafa Cengiz, Yilmaz Altuner & Suzan Yaman

  2. Faculty of Medicine Department of Histology, Eskisehir Osmangazi University, Eskisehir, Turkey

    Varol Sahinturk

  3. Department of Molecular Biology & Genetics, Izmir Institute of Technology, Izmir, Turkey

    Sila Appak

  4. Faculty of Medicine Department of Physiology, Eskisehir Osmangazi University, Eskisehir, Turkey

    Ruhi Uyar

Authors
  1. Adnan Ayhanci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sibel Günes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Varol Sahinturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sila Appak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruhi Uyar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mustafa Cengiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yilmaz Altuner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Suzan Yaman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adnan Ayhanci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ayhanci, A., Günes, S., Sahinturk, V. et al. Seleno l-Methionine Acts on Cyclophosphamide-Induced Kidney Toxicity. Biol Trace Elem Res 136, 171–179 (2010). https://doi.org/10.1007/s12011-009-8535-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-009-8535-2

Keywords

Search

Navigation