The Animal Biology

Bìol. Tvarin, 2018, volume 20, issue 1, pp. 28–39

STATUS OF PROOXIDATIVE-ANTIOXIDATIVE BALANCE AND ACTIVITY OF KREBS CYCLE ENZYMES IN LIVER, HEART AND KIDNEY TISSUES FOR ACTION OF VARIOUS CUMULATIVE DOSES OF DOXORUBICIN

V. O. Dziuba1, O. B. Kuchmenko1,2, O. V. Yakoviichuk1
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1Melitopol State Pedagogical University named after Bogdan Khmelnytsky,
20 Hetmanska str., Melitopol 72312, Ukraine

2National University “Kyiv-Mohyla Academy”,
2 Hryhoriya Skovorody str., Kyiv 04070, Ukraine

Doxorubicin is a powerful anthracycline antibiotic used to treat many human neoplasms. Doxorubicin may also cause cardiotoxicity, hepatotoxicity and nephrotoxicity when used for a prolonged period of time, thereby limiting its clinical use. The cytotoxic effect of doxorubicin is very dangerous, since it can lead to the development of irreversible chronic side effects.
30 male rats with an average body weight of 240 g were used in this study. Animals were randomly assigned to one of three groups (control, 3 weeks of therapy, or 5 weeks of therapy). Heart, liver and kidney tissues were used to study the biochemical markers of antioxidant and energy systems. The use of doxorubicin led to a growing number of TBA-active products in all experimental tissues, indicating the pro-oxidant properties of drug. Moreover, doxorubicin can directly affect the activity of antioxidant enzymes. In our study, it was found that doxorubicin caused an increase the activity of antioxidant enzymes in the tissues of heart and liver, and decreased it in kidneys. The activity of citric acid cycle enzymes increased in the liver and decreased in the kidneys after doxorubicin therapy. Activity of the enzymes of Krebs cycle in heart increased only for 3 first weeks of therapy and after that began to decrease. After treatment with doxorubicin, the activity of aspartate aminotransferase in rat tissues varied similar to the enzymatic activity of Krebs cycle dehydrogenases.
Increased activity of succinate dehydrogenase and alpha ketoglutarate dehydrogenase may represent a compensatory or survival response to the onset of functional defects. Assessment of the complex effect of doxorubicin on intracellular processes will help to develop new protecting systems from doxorubicin-induced cytotoxicity, but work in this direction requires more detailed research.

Keywords: ASPARTATE AMINOTRANSFERASE, CITRIC ACID CYCLE, TBA-ACTIVE PRODUCTS, CATALASE, SUPEROXIDE DISMUTASE, CYTOTOXICITY, ANTHRACYCLINE

  1. Abdel-Raheem I. T., Abdel-Ghany A. A. Hesperidin alleviates doxorubicin-induced cardiotoxicity in rats. J. Egypt Natl. Canc. Inst., 2009, 21 (2), pp. 175–184.
  2. Ahmed F., Urooj A. Cardioprotective activity of standardized extract of Ficus racemosa stem bark against doxorubicin-induced toxicity. Pharmaceutical biology, 2012, vol. 50, no. 4, pp. 468–473. https://doi.org/10.3109/13880209.2011.613848
  3. Arozal W., Suyatna F. D., Juniantito V., Rosdiana D. S., Amurugam S., Aulia R., Monayo E. R., Siswandi R. The Effects of Mangiferin (Mangifera indica L.) in Doxorubicin-induced Cardiotoxicity in Rats. Drug Res. (Stuttq), 2015, vol. 65, no. 11, pp. 574–580. https://doi.org/10.1055/s-0034-1394457
  4. Bazikov I. A., Beyer E. V., Lukinova V. V., Maltsev A. N. Comparative evaluation of acute toxicity doxorubicin and it’s in niosomes. Medical news of north caucasus, 2015, vol. 10, no. 3, pp. 403–406. https://doi.org/10.14300/mnnc.2015.10098
  5. Bradford, M. M. A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Anal. Biochem., 1976, vol. 72, pp. 248–254. https://doi.org/10.1016/0003-2697(76)90527-3
  6. Bugger H., Guzman C., Zecher C., Palmeri M., Russell R. R. 3rd. Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increase reactive oxygen species generation. Cancer Chemother Pharmacol, 2011, 67 (6), pp. 1381–1388. https://doi.org/10.1007/s00280-010-1441-7
  7. Carvalho R. A., Sousa R. P. B., Cadete V. J. J., Lopaschuk G. D., Palmeira C. M. M., Bjork J. A., Wallace K. B. Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy. Toxicology, 2010, 270 (2–3), pp. 92–98. https://doi.org/10.1016/j.tox.2010.01.019
  8. Chen C. T., Wang Z. H., Hsu C. C., Lin H. H., Chen J. H. In vivo protective effects of diosgenin against doxorubicin-induced cardiotoxicity. Nutrients, 2015, 7 (6), pp. 4938–4954. https://doi.org/10.3390/nu7064938
  9. Childs A. C., Phaneuf S. L., Dirks A. J., Phillips T., Leeuwenburgh C. Doxorubicin treatment in vivo causes cytochrome c release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Research, 2002, 62 (16), pp. 4592–4598.
  10. Dyomshina O. O., Ushakova G. O., Stepchenko L. M. The effect of biologically active feed additives of humilid substances on the antioxidant system in liver mitochondria of gerbils. Regulatory Mechanisms in Biosystems, 2017, 8 (2), pp. 185–190. https://doi.org/10.15421/021729
  11. El-Sheikh A. A., Morsy M. A., Mahmoud M. M., Rifaai R. A. Protective mechanisms of coenzyme-Q10 may involve up-regulation of testicular P-glycoprotein in doxorubicin-induced toxicity. Environ. Toxicol. Pharmacol., 2014, 37 (2), pp. 772–781. https://doi.org/10.1016/j.etap.2014.02.010
  12. Eshhenko N. D., Volskij G. G. Determination of the amount of succinic acid and SDH activity. Methods of biochemistry research. Leningrad, p.h.LSU, 1982, 327 p. (in Russian)
  13. Gholami S., Hosseini M. J., Jafari L., Omidvar F., Kamalinejad M., Mashayekhi V., Hosseini S. H., Kardan A., Pourahmad J., Eskandari M. R. Mitochondria as a Target for the Cardioprotective Effects of Cydonia oblonga Mill. and Ficus carica L. in Doxorubicin-Induced Cardiotoxicity. Drug Res. (Stuttq), 2017, 67 (6), pp. 358–365. https://doi.org/10.1055/s-0043-101824
  14. Gupta S. C., Dekker E. E. Evidence for the Identity and Some Comparative Properties of a-Ketoglutarate and 2-Keto-4-hydroxyglutarate Dehydrogenase. The J. Biol. Chem, 1980, 255 (3), pp. 1107–1112.
  15. Ionov I. A., Shapovalov S. O., Rudenko E. V., Dolgaya M. N., Ahtyrskyi A. V., Zozulia Ju. A., Komisova T. E., Kostiuk I. A. Criteria and methods of controlling metabolism in animals and birds. Kharkiv, Institute of Animal Husbandry, 2011, 378 p. (in Ukrainian)
  16. Kalender Y., Yel M., Kalender S. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats the effects of vitamin E and catechin. Toxicology, 2005, 209, pp. 39–45. DOI: https://doi.org/10.1016/j.tox.2004.12.003
  17. Koroljuk M. A., Yvanova L. Y., Majorova Y. G., Tokareva V. E. Method for the determination of catalase activity. Lab. work, 1988, 1, pp. 16–19. (in Russian)
  18. Mikuliak N. I., Kinzirskaya Yu. A. Experimental study of parameters of lipid peroxidation under the influence of doxorubicin and mexidol. Vestnik VolgGMU, 2011, 1 (37), pp. 101–103. (in Russian)
  19. Mohammadrezaei F. M., Movaghar A. F., Ghraghabi M. The effect of caffeine and chk2 inhibitor on doxorubicin-induced cellular senescence in MCF-7 cells. Drug Res (Stuttq), 2016, 66, pp. 250–454. https://doi.org/10.1055/s-0042-109390
  20. Mustafa H. N., El Awdan S. A., Hegazy G. A., Jaleel G. A. A. Prophylactic role of coenzyme Q10 and Cynara scolymus L. on doxorubicin-induced toxicity in rats: biochemical and immunohistochemical study. Indian J. Pharmacol., 2015, 47 (6), pp. 649–656. https://doi.org/10.4103/0253-7613.169588
  21. Mustafa H. N., Hegazy G. A., Awdan S. A. E., AbdelBaset M. Protective role of CoQ10 or L-carnitine on the integrity of the myocardium in doxorubicin induced toxicity. Tissue Cell, 2017, 49 (3), pp. 410–426. https://doi.org/10.1016/j.tice.2017.03.007
  22. Nagai K., Fukuno S., Konishi H. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs, 2016, 27 (1), pp. 17–23. https://doi.org/10.1097/CAD.0000000000000299
  23. Pal S., Sil P. C. A 43 kD protein from the leaves of the herb Cajanus indicus L. modulates doxorubicin induced nephrotoxicity via MAPKs and both mitochondria dependent and independent pathways. Biochimie, 2012, 94, pp. 1356–1367. https://doi.org/10.1016/j.biochi.2012.03.003
  24. Panchuk R. R., Skorochyd N. R., Kozak Y. S., Lehka L. V., Chumak V. V., Omelyanchik S. N., Gurinovich V. A., Moiseenok A. G., Stoika R. S. Antioxidants selenomethionine and D-pantethine decrease the negative side effects of doxorubicin in NL/Ly lymphoma-bearing mice. Croat. Med. J., 2016, 57, pp. 180–192. https://doi.org/10.3325/cmj.2016.57.180
  25. Sirota T. V. A method for determining the antioxidant activity of superoxide dismutase and chemical compounds. Pat. 2144674 Russian Federation, G01N33/52, G01N33/68 no. 99103192/14 Publish. 24.02.1999; 20.01.2000. (in Russian)
  26. Quiles J. L., Huertas J. R., Battino M., Mataix J., Ramirez-tortosa M. C. Antioxidant nutrients and adriamycin toxicity. Toxicology, 2002, 180 (1), pp. 79-95. https://doi.org/10.1016/S0300-483X(02)00383-9
  27. Quinlan C. L., Goncalves R. L., Hey-Mogensen M., Bunik V. I., Brand M. D. The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. The Journal of Biological Chemistry, 2014, 289, pp. 8312–8325. https://doi.org/10.1074/jbc.M113.545301
  28. Reitman S., Frankel S. A coloric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Amer. J. Clin. Pathol., 1957, 28, pp. 56–63. https://doi.org/10.1093/ajcp/28.1.56
  29. Sankhadeep P., Parames C. S. A 43 kD protein from the leaves of the herb Cajanus indicus L. modulates doxorubicin induced nephrotoxicity via MAPKs and both mitochondria dependent and independent pathways. Biochimie, 2012, 94 (6), pp. 1356-1367. https://doi.org/10.1016/j.biochi.2012.03.003
  30. Sterba M., Popelova O., Vavrova A., Jirkovsky E., Kovarikova P., Gersl V., Simunek T. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid. Redox Signal, 2013, 18 (8), pp. 899–929. https://doi.org/10.1089/ars.2012.4795
  31. Tokarska-Schlattner M., Lucchinetti E., Zaugg M., Kay L., Gratia S., Guzun R., Saks V., Schlattner U. Early effects of doxorubicin in perfused heart: transcriptional profiling reveals inhibition of cellular response genes. Am. J. Physiol. Requl. Inteqr. Comp. Physiol., 2010, 298 (4), pp. 1075–1088. https://doi.org/10.1152/ajpregu.00360.2009
  32. Tokarska-Schlattner M., Zaugg M., Zuppinger C., Wallimann T., Schlattner U. New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics. Journal of molecular and cellular cardiology, 2006, 41 (3), pp. 389–405. https://doi.org/10.1016/j.yjmcc.2006.06.009
  33. Turunen M., Olsson J., Dallner G. Metabolism and function of coenzyme Q. Biochimia et Biophysica Acta (BBA) — Biomembranes, 2004, 1660 (1–2), pp. 171–199. https://doi.org/10.1016/j.bbamem.2003.11.012
  34. Wallace K. B. Doxorubicin-induced cardiac mitochondriopathy. Pharmacology and Toxicology, 2003, 93, pp. 105–115. https://doi.org/10.1034/j.1600-0773.2003.930301.x
  35. Wang Y., Mei X., Yan J., Lu W., Li B., Xu D. Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats. Toxicol. Appl. Pharmacol., 2015, 289 (1), pp. 1–11. https://doi.org/10.1016/j.taap.2015.08.017
  36. Wei S. N., Zhao W. J., Zeng X. J., Kang Y. M., Du J., Li H. H. Microarray and co-expression network analysis of genes associated with acute doxorubicin cardiomiopathy in mice. Cardiovasc. Toxicol., 2015, 15 (4), pp. 377–393. https://doi.org/10.1007/s12012-014-9306-7
  37. Xu L., Jin L., Pan H., Zhang A., Wei G., Li P., Lu W. Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin. Acta Pharmacologica Sinica, 2006, 27, pp. 1333–1339. https://doi.org/10.1111/j.1745-7254.2006.00409.x

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