The Preclinical Study Exploring the Effects of Creatine Supplementation on Renal Antioxidant Enzymes Following Doxorubicin Treatment
Main Article Content
Abstract
Introduction: Doxorubicin is an effective chemotherapy drug, but its use is limited by its cytotoxicity. One of doxorubicin’s anticancer mechanisms is generation of reactive oxygen species which may lead to oxidative stress. The kidney, however, is very vulnerable to oxidative stress, and one way to manage oxidative stress is to scavenge reactive oxygen species via antioxidant enzymes. Although doxorubicin-induced oxidative stress has been extensively studied, a viable treatment to attenuate doxorubcin side effects has yet to be found. This study investigated the effect of creatine feeding on catalase, glutathione peroxide, and superoxide dismutase-1 expression in the kidney following doxorubicin treatment.
Methods: Twenty-eight male Sprague-Dawley rats were randomly assigned to four groups, control saline (C+SAL, n=7), control doxorubicin (C+DOX, n=7), creatine saline (Cr+SAL, n=6) and creatine doxorubicin (Cr+DOX, n=8). Control groups were fed normal chow, and creatine groups were fed chow supplemented with 3% creatine. After two weeks of feeding, doxorubicin groups received15 mg/kg doxorubicin whereas saline groups received saline as a placebo. Western blotting was used to access antioxidant enzyme expression in renal tissue.
Results: A significant between group difference was observed with catalase expression, but post hoc testing did not reveal where differences existed. A trend existed toward doxorubicin treatment increasing catalase expression and creatine attenuated this trend. Glutathione peroxidase and superoxide dismutase-1 presented a similar profile as catalase; however, no significant between group differences were observed. There was a trend, however, toward increased expression of glutathione peroxidase and superoxide dismutase-1 in doxorubicin-treated animals that seemed to be attenuated with creatine supplementation.
Conclusion: To our knowledge there are no studies exploring the antioxidant properties of creatine supplementation in the kidney with doxorubicin, and it is possible that creatine may enhance antioxidant properties that can attenuate the negative effects doxorubicin in the kidney. A trend towards antioxidant enzyme normalization promoted by creatine with doxorubicin suggests that creatine might have similar effect to that observed in previous studies using antioxidant drugs.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. 2. Sternberg SS. Cross-striated fibrils and other ultrastructural alterations in glomeruli of rats with daunomycin nephrosis. Lab Invest. Jul 1970;23(1):39-51.
3. Bucciarelli E, Binazzi R, Santori P, Vespasiani G. [Nephrotic syndrome in rats due to adriamycin chlorhydrate]. Lav Ist Anat Istol Patol Univ Studi Perugia. 1976;36(2):53-69.
4. Ayla S, Seckin I, Tanriverdi G, et al. Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. Int J Cell Biol. 2011;2011: 390238. doi:10.1155/2011/390238
5. Ozbek E. Induction of oxidative stress in kidney. Int J Nephrol. 2012;2012:465897. doi:10.1155/2012/465897
6. Bertani T, Poggi A, Pozzoni R, et al. Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest. Jan 1982;46(1):16-23.
7. De Boer E, Navis G, Tiebosch AT, De Jong PE, De Zeeuw D. Systemic factors are involved in the pathogenesis of proteinuria-induced glomerulosclerosis in adriamycin nephrotic rats. J Am Soc Nephrol. Nov 1999;10(11):2359-66. doi:10.1681/ASN.V10112359
8. Yasuda K, Park HC, Ratliff B, et al. Adriamycin nephropathy: a failure of endothelial progenitor cell-induced repair. Am J Pathol. Apr 2010;176(4):1685-95. doi:10.2353/ajpath.2010.091071
9. 9. Lee VW, Harris DC. Adriamycin nephropathy: a model of focal segmental glomerulosclerosis. Nephrology (Carlton). Jan 2011;16(1):30-8. doi:10.1111/j.1440-1797.2010.01383.x
10. Sindhu RK, Ehdaie A, Farmand F, et al. Expression of catalase and glutathione peroxidase in renal insufficiency. Biochim Biophys Acta. Mar 22 2005;1743(1-2):86-92. doi:10.1016/j.bbamcr.2004.08.013
11. Szalay CI, Erdélyi K, Kökény G, et al. Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain. PLoS One. 2015;10(6):e0127090. doi:10.1371/journal.pone.0127090
12. Walker JB. Creatine: biosynthesis, regulation, and function. Advances in enzymology and related areas of molecular biology. 1979;50:177-242.
13. Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. Jun 2001;53(2):161-76.
14. Matthews RT, Yang L, Jenkins BG, et al. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J Neurosci. Jan 1 1998;18(1):156-63.
15. Lawler JM, Powers SK. Oxidative stress, antioxidant status, and the contracting diaphragm. Can J Appl Physiol. Feb 1998;23(1):23-55. doi:10.1139/h98-002
16. Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. Jan 11 2002;290(1):47-52. doi:10.1006/bbrc.2001.6164
17. Sestili P, Martinelli C, Colombo E, et al. Creatine as an antioxidant. Amino Acids. May 2011;40(5):1385-96. doi:10.1007/s00726-011-0875-5
18. Deminice R, Jordao AA. Creatine supplementation reduces oxidative stress biomarkers after acute exercise in rats. Amino Acids. Aug 2012;43(2):709-15. doi:10.1007/s00726-011-1121-x
19. Araújo MB, Moura LP, Junior RC, et al. Creatine supplementation and oxidative stress in rat liver. J Int Soc Sports Nutr. Dec 10 2013;10(1):54. doi:10.1186/1550-2783-10-54
20. 20. Stefani GP, Nunes RB, Dornelles AZ, et al. Effects of creatine supplementation associated with resistance training on oxidative stress in different tissues of rats. J Int Soc Sports Nutr. Mar 24 2014;11(1):11. doi:10.1186/1550-2783-11-11
21. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. Jul 2000;80(3):1107-213. doi:10.1152/physrev.2000.80.3.1107
22. Ferreira LG, De Toledo Bergamaschi C, Lazaretti-Castro M, Heilberg IP. Effects of creatine supplementation on body composition and renal function in rats. Med Sci Sports Exerc. Sep 2005;37(9):1525-9. doi:10.1249/01.mss.0000177555.94271.44
23. Taes YE, Delanghe JR, De Vriese AS, Rombaut R, Van Camp J, Lameire NH. Creatine supplementation decreases homocysteine in an animal model of uremia. Kidney Int. Oct 2003;64(4):1331-7. doi:10.1046/j.1523-1755.2003.00206.x
24. Gualano B, Ugrinowitsch C, Novaes RB, et al. Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. Eur J Appl Physiol. May 2008;103(1):33-40. doi:10.1007/s00421-007-0669-3
25. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. May 07 1976;72:248-54. doi:10.1006/abio.1976.9999
26. Peres LA, da Cunha AD. Acute nephrotoxicity of cisplatin: molecular mechanisms. J Bras Nefrol. 2013;35(4):332-40. doi:10.5935/0101-2800.20130052
27. Guimarães-Ferreira L, Pinheiro CH, Gerlinger-Romero F, et al. Short-term creatine supplementation decreases reactive oxygen species content with no changes in expression and activity of antioxidant enzymes in skeletal muscle. Eur J Appl Physiol. Nov 2012;112(11):3905-11. doi:10.1007/s00421-012-2378-9
28. Agarwal A, Robo R, Jain N, Gutch M, Consil S, Kumar S. Oxidative stress determined through the levels of antioxidant enzymes and the effect of N-acetylcysteine in aluminum phosphide poisoning. Indian J Crit Care Med. Oct 2014;18(10):666-71. doi:10.4103/0972-5229.142176
29. Trimarchi H, Mongitore MR, Baglioni P, et al. N-acetylcysteine reduces malondialdehyde levels in chronic hemodialysis patients--a pilot study. Clin Nephrol. Jun 2003;59(6):441-6. doi:10.5414/cnp59441
30. Kasperczyk S, Dobrakowski M, Kasperczyk A, Machnik G, Birkner E. Effect of N-acetylcysteine administration on the expression and activities of antioxidant enzymes and the malondialdehyde level in the blood of lead-exposed workers. Environ Toxicol Pharmacol. Mar 2014;37(2):638-47. doi:10.1016/j.etap.2014.01.024
31. Wang L, Wang Z, Liu J. Protective effect of N-acetylcysteine on experimental chronic lead nephrotoxicity in immature female rats. Hum Exp Toxicol. Jul 2010;29(7):581-91. doi:10.1177/0960327109357270
32. Lei S, Liu Y, Liu H, Yu H, Wang H, Xia Z. Effects of N-acetylcysteine on nicotinamide dinucleotide phosphate oxidase activation and antioxidant status in heart, lung, liver and kidney in streptozotocin-induced diabetic rats. Yonsei Med J. Mar 2012;53(2):294-303. doi:10.3349/ymj.2012.53.2.294
33. Pastor A, Collado PS, Almar M, González-Gallego J. Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine. J Hepatol. Aug 1997;27(2):363-70. doi:10.1016/s0168-8278(97)80183-3
34. Kugler BA, Capps MJ, Hydock DS. Protection Against Late-Onset Doxorubicin Myotoxicity Using Creatine and Resistance Exercise. Medical Research Archives; Vol 10 No 6 (2022): Vol10 Issue 6 June 2022.
Doi: 1018103/mrav10i62852. 07/01 2022;
35. Bredahl EC, Busekrus RB, Hydock DS. The combined effect of creatine and resistance training on doxorubicin-induced muscle dysfunction. Nutr Cancer. 2020;72(6):939-947. doi:10.1080/01635581.2019.1670852
36. Torok ZA, Busekrus RB, Hydock DS. Effects of Creatine Supplementation on Muscle Fatigue in Rats Receiving Doxorubicin Treatment. Nutr Cancer. Jun 2019:1-8. doi:10.1080/01635581.2019.1623900
37. Aljobaily N, Viereckl MJ, Hydock DS, et al. Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence. Nutrients. Dec 24 2020;13(1) doi:10.3390/nu13010041