Ukr.Biochem.J. 2015; Volume 87, Issue 2, Mar-Apr, pp. 122-132

doi: https://doi.org/10.15407/ubj87.02.122

Biochemical indicators of hepatotoxicity in blood serum of rats under the effect of novel 4-thiazolidinone derivatives and doxorubicin and their complexes with polyethyleneglycol-containing nanoscale polymeric carrier

L. I. Kоbylinska1, D. Ya. Havrylyuk1, А. О. Ryabtseva2, N. E. Mitina2,
О. S. Zаichenko2, R. B. Lesyk1, B. S. Zіmenkovsky1, R. S. Stoika3

1Danylo Halytsky Lviv National Medical University, Ukraine;
e-mail: lesya8@gmail.com;
2Lviv Polytechnic National University, Ukraine;
3Іnstitute of Cell Biology, National Academy of Sciences of Ukraine, Lviv

The aim of this study was to compare the effect of new synthetic 4-tiazolidinone derivatives (compounds 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethyleneglycol-containing nanoscale polymeric carrier on the biochemical indicators of hepatotoxicity in blood serum of rats. The activity of enzymes considered as the markers of hepatotoxicity, as well as the concentration of total protein, urea and creatinine were measured in blood serum of rats. It was found that after injection of investigated compounds the activities of alanine aminotransferase, alkaline phosphatase and α-amylase increased in comparison to control. Doxorubicin injection was accompanied by 4-fold increase in the activity of γ-glutamyltransferase, and injection of compound 3833 led to 2.5-fold elevation of the activity of this enzyme. Complexation of these аntineoplastic derivatives with a synthetic nanocarrier lowered the activity of the investigated enzymes substantially if compared to the effect of these compounds in free form. The most evident decrease was measured for α-amylase, γ-glutamyltransferase and lactate dehydrogenase activities. The normalization of concentrations of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with a polymeric carrier comparing with their introduction in free form was also detected. Thus, the immobilization by novel polymeric carrier of anticancer drugs possessing high general toxicity in the treated organism mitigates their toxic effect, which is evident as normalization of specific biochemical indicators of the hepatodestructive effects of the anticancer drugs.

Keywords: , , , , , ,


References:

  1. Perry MC, Doll DC, Freter CE. The Chemotherapy Source Book. Philadelphia: Walters Kluwer, Lippincott Williams & Wilkins, 2012; 248 p.
  2. Patent UA u201114202, N 69857. 3-{2-[5-(3,5-diaryl)-4,5-dihydropyrazol-1-yl]-4-oxo-4H-thiazol-5-iliden}-1,3-dihydroindol-2-ones, that possess anticancer activity /Havrylyuk D. Ya., Zimenkovsky B. S., Lesyk R. B., Roman O. M. Publ. 10.05.2012, Bull. N 19. (In Ukrainian).
  3. Ramadori G, Cameron S. Effects of systemic chemotherapy on the liver. Ann Hepatol. 2010 Apr-Jun;9(2):133-43. Review. PubMed
  4. Mohort M. A., Seredinska M. N., Kyrychok L. M. Cardiotoxic effects of doxorubicin and expedience of their pharmacological correction by the antagonists of calcium of dihydropyridine type and activators of the АТP-sensitive potassium channels of guanidine type. Pharmacol. Med. Toxicol. 2010;(4(7)):35-44. (In Ukrainian).
  5. Panchyshyn YuM, Radchenko OM, Makarenko TM, Komarytsya OJ, Huk-Leshnevska ZO. Fundamentals of Diagnosis and Treatment of Hepatitis and Liver Cirrhosis. Lviv, 2010; 276 p. (In Ukrainian).
  6. Hyman J. Zimmerman Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. Lippincott Williams & Wilkins, 1999; 789 p.
  7. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006 Feb 16;354(7):731-9. Review. PubMed, CrossRef
  8. Arzamastsev EV, Gouscova TA, Berezov­skaya IV. Methodological Instructions on research of general toxicity of pharmaceuticals. Manual on experimental (preclinical) study of new pharmacological substances. Moscow. 2000:18-26. (In Russian).
  9. Havrylyuk D, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Synthesis of new 4-thiazolidinone-, pyrazoline-, and isatin-based conjugates with promising antitumor activity. J Med Chem. 2012 Oct 25;55(20):8630-41. PubMed, CrossRef
  10. Havrylyuk D, Zimenkovsky B, Vasylenko O, Lesyk R. Synthesis, anticancer and antiviral activity of new 2-pyrazoline substituted 4-thiazolidinones. J Heterocyclic Chem. 2013;50(S1):E55-E62. CrossRef
  11. Boiko NM, Klyuchivska OYu, Kobylinska LI, Havrylyuk DYa, Mitina NYe, Lesyk RB, Zaichenko OS, Stoika RS. Vitality and morphology of tumor cells treated with 4-thiazolidinone derivatives immobilized on nanoscale polymer carrier. Biotechnologia Acta. 2015;8(1):39-48. CrossRef
  12. Chumak VV, Panchuk RR, Manko NO, Havrylyuk D, Kobylinska L, Lesyk R, Zіmenkovsky BS, Stoika RS. Comparative study of the cytotoxic properties of isatin-containing derivatives of 4-thiazolidinone with different structure toward human tumor cells in vitro. Studia Biologica. 2014;8(2):29-42. (In Ukrainian).
  13. Kobylinska L, Havrylyuk D, Patereha I, Kotsyumbas I, Lesyk R, Stoika R. Study of acute toxicity and cumulative properties in rats of novel synthetic 4-tiazolidone derivatives with potential antineoplastic activity. Modern Probl Toxicol Food Chem Safety. 2013;4(63):38-43. (In Ukrainian).
  14. Kоbylinska LI, Havrylyuk DYa, Ryabtseva АО, Mitina NE, Zаichenko ОS, Zіmenkovsky BS, Stoika RS. Study of rat blood serum biochemical indicators of cardiotoxic action of novel 4-thiazolidone derivatives and doxorubicin in complexes with polyethylenglycol-containing polymeric carrier. Ukr Biochem J. 2014 Nov-Dec;86(6):84-95. (In Ukrainian). PubMed, CrossRef
  15. Bharali DJ, Khalil M, Gurbuz M, Simone TM, Mousa SA. Nanoparticles and cancer therapy: a concise review with emphasis on dendrimers. Int J Nanomedicine. 2009;2009(4):1-7. Review.  PubMed, PubMedCentral, CrossRef
  16. Caruthers SD, Wickline SA, Lanza GM. Nanotechnological applications in medicine. Curr Opin Biotechnol. 2007 Feb;18(1):26-30. Review.  PubMed, CrossRef
  17. Senkiv Yu, Ryabtseva A, Heffeter P, Boyko N, Shlyahtina Y., Mitina N, Berger V, Zaichenko OS, Stoika RS. Immobilization of doxorubicin on oligoelectrolyte polymeric VEP-GMA-PEG carrier enhances delivery of this anticancer agent in tumor cells and efficiency of its cytotoxic action. Studia Biologica. 2012;6(2):1-12. (In Ukrainian).
  18. Senkiv Y, Riabtseva A, Heffeter P, Boiko N, Kowol CR, Jungwith U, Shlyakhtina Y, Garasevych SG, Mitina N, Berger W, Zaichenko A, Stoika R. Enhanced anticancer activity and circumvention of resistance mechanisms by novel polymeric/ phospholipidic nanocarriers of doxorubicin. J Biomed Nanotechnol. 2014 Jul;10(7):1369-81. PubMed, CrossRef
  19. Kobylinska L, Patereha I, Ryabtseva АО, Mitina NE, Zаichenko ОS, Kotsyumbas I, Zіmenkovsky BS, Stoika R. Study of acute toxicity of nanosized drug delivery system based on PEG comb-like carriers in white laboratory rats and mice. Modern Probl Toxicol Food Chem Safety. 2014;3-4(66. 67):43-48. (In Ukrainian).
  20. European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes (Strasbourg, March 18, 1986). Available at http:. zakon2.rada.gov.ua. laws. show. 994_137 (InUkrainian).
  21. Establishing the order of conduct for preclinical studies of pharmaceutical substances and expert evaluation of materials from preclinical studies of pharmaceutical substances: Decree No 944 by Ministry of Health of Ukraine issued on 14.12.2009 – Available at http:. zakon.rada.gov.ua. cgi-bin. laws. main.cgi?nreg=z0053-10.
  22. Stefanov OV. Preclinical Studies of Medicines. Methodological Recommendations. Kyiv, 2001; 527 p. (In Ukrainian).
  23. Mukund Joshi, Kuldip Singh Sodhi, Rajesh Pandey, Jasbir Singh, Subhash Goyal, Suvarna Prasad, Harnam Kaur, Neeru Bhaskar, Shikhaa Mahajan. Cancer chemotherapy and hepatotoxicity: an update. Indo Am J Pharm Res. 2014;4(6):2976-2984.
  24. Riabtseva A., Mitina N., Boiko N., Garasevich S., Yanchuk I., Stoika R., Slobodyanyuk O., Zaichenko A. Structural and Colloidal-Chemical Characteristics of Nanosized Drug Delivery Systems Based on Pegylated Comb-like Carriers. Chem Chem Technol. 2012;6(3):291-295.
  25. Bioethical expertise of preclinical and other scientific studies conducted on animals. Kyiv, 2006; 28 p. (In Ukrainian).
  26. Kamyshnikov VS. Manual on Clinical Biochemical Investigations and Laboratory Diagnostics. Moscow: MEDpress-inform, 2004; 911 p. (In Russian).

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