The Hepatoprotective Role of Thiol Reductants against Mitoxantrone-Induced Liver Injury

Document Type : Research(Original) Article

Authors

Department of Pharmacology-Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

Abstract

Mitoxantrone is anthracycline antibiotic highly effective against various human cancers. Hepatotoxicity is associated with mitoxantrone administration. On the other hand, there is no effective therapeutic option against chemotherapy-induced liver injury. The current investigation was designed to evaluate the effect of thiol reductants on mitoxantrone-induced liver injury in two experimental models. As an ex vivo model, isolated rat liver was exposed to increasing concentrations of mitoxantrone (100, 250, 750, and 1000 µM) alone or in combination with thiol-reductants (Dithiothreitol; DTT, and N-acetyl cysteine; NAC). In addition, rats (in vivo) received mitoxantrone (2.5 mg/kg, i.p, at days 1, 10, and 20), NAC (100 and 300 mg/kg/day, i.p, for 20 consecutive days) and DTT (15 and 30 mg/kg/day, i.p, for 20 consecutive days), then liver and serum pathological changes were monitored. Mitoxantrone-induced liver injury was evident in both ex vivo and in vivo experiments as assessed by pathological changes in biomarkers of liver injury, along with tissue histopathological changes. Furthermore, an increase in liver tissue markers of oxidative stress was detected in the mitoxantrone-treated group. It was found that thiol reductants significantly mitigated mitoxantrone hepatotoxicity. The data indicate that thiol reductants might serve as hepatoprotective agents against chemotherapy-induced liver injury.

Keywords

References

  1. Corsini A, Bortolini M. Drug-Induced Liver Injury: The Role of Drug Metabolism and Transport. J Clin Pharmacol. 2013;53;463-474.
  2. Thatishetty AV, Agresti N, O'Brien CB. Chemotherapy-Induced Hepatotoxicity. Clinic Liver Dis. 2013;17;671-686.
  3. Chun YS, Laurent A, Maru D, Vauthey J-N. Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol. 2009;10;278-286.
  4. King PD, Perry MC. Hepatotoxicity of Chemotherapy. The Oncologist. 2001;6;162-176.
  5. Morgan C, Tillett T, Braybrooke J, Ajithkumar T. Management of uncommon chemotherapy-induced emergencies. Lancet Oncol. 2011;12;806-814.
  6. Robinson K, Lambiase L, Li J, Monteiro C, Schiff M. Case report: Fatal Cholestatic Liver Failure Associated with Gemcitabine Therapy. Dig Dis Sci.48;1804-1808.
  7. Floyd J, Mirza I, Sachs B, Perry MC. Hepatotoxicity of Chemotherapy. Seminar Oncol. 2006;33;50-67.
  8. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives. Drug Safety. 2013;36;491-503.
  9. Llesuy SF, Arnaiz SL. Hepatotoxicity of mitoxantrone and doxorubicin. Toxicology. 1990;63;187-198.
  10. Kingwell E, Koch M, Leung B, Isserow S, Geddes J, Rieckmann P, Tremlett H. Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. Neurology. 2010;74;1822-1826.
  11. Alderton PM, Gross J, Green MD. Comparative Study of Doxorubicin, Mitoxantrone, and Epirubicin in Combination with ICRF-187 (ADR-529) in a Chronic Cardiotoxicity Animal Model. Cancer Res. 1992;52;194-201.
  12. Tokarska-Schlattner M, Zaugg M, Zuppinger C, Wallimann T, Schlattner U. New insights into doxorubicin-induced cardiotoxicity: The critical role of cellular energetics. J Mol Cell Cardiol. 2006;41;389-405.
  13. Bulucu F, Ocal R, Karadurmus N, Sahin M, Kenar L, Aydin A, Oktenli C, Koc B, Inal V, Yamanel L, Yaman H. Effects of N-Acetylcysteine, Deferoxamine and Selenium on Doxorubicin-Induced Hepatotoxicity. Biol Trace Element Res. 2009;132;184.
  14. Injac R, Strukelj B. Recent Advances in Protection against Doxorubicin-induced Toxicity. Technol Cancer Res Treat. 2008;7;497-516.
  15. Zhang S, Liu X, Bawa-Khalfe T, Lu L-S, Lyu YL, Liu LF, Yeh ETH. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Med. 2012;18;1639-1642.
  16. Suk KT, Kim DJ. Drug-induced liver injury: present and future. Clin Mol Hepatol. 2012;18;249-257.
  17. Stephens C, Andrade RJ, Lucena MI. Mechanisms of drug-induced liver injury. Current Opin Allergy Clin Immunol. 2014;14;286-292.
  18. Jones DP, Lemasters JJ, Han D, Boelsterli UA, Kaplowitz N. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Intervention. 2010;10;98.
  19. Rossato LG, Costa VM, Dallegrave E, Arbo M, Dinis-Oliveira RJ, Santos-Silva A, Duarte JA, de Lourdes Bastos M, Palmeira C, Remião F. Cumulative mitoxantrone-induced haematological and hepatic adverse effects in a subchronic in vivo study. Basic Clin Pharmacol Toxicol. 2014;114;254-262.
  20. Bessems M, Tolba R, Doorschodt BM, Leuvenink HGD, Ploeg RJ, Minor T, van Gulik TM, others. The isolated perfused rat liver: standardization of a time-honoured model. Lab Animal. 2006;40;236-246.
  21. Ferrigno A, Richelmi P, Vairetti M. Troubleshooting and improving the mouse and rat isolated perfused liver preparation. J pharmacol Toxicol Method. 2012;67;107-114.
  22. Heidari R, Rasti M, Shirazi Yeganeh B, Niknahad H, Saeedi A, Najibi A. Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine. BioImpacts. 2016;6;3-8.
  23. Heidari R, Taheri V, Rahimi HR, Shirazi Yeganeh B, Niknahad H, Najibi A. Sulfasalazine-induced renal injury in rats and the protective role of thiol-reductants. Renal Failure. 2016;38;137-141.
  24. Heidari R, Jamshidzadeh A, Niknahad H, Safari F, Azizi H, Abdoli N, Ommati MM, Khodaei F, Saeedi A, Najibi A. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver. Trend Pharm Sci. 2016;2;59-76.
  25. Heidari R, Sadeghi N, Azarpira N, Niknahad H. Sulfasalazine-Induced Hepatic Injury in an Ex Vivo Model of Isolated Perfused Rat Liver and the Protective Role of Taurine. Pharm Sci. 2015;21.
  26. Rossato LG, Costa VM, Dallegrave E, Arbo M, Silva R, Ferreira R, Amado F, Dinis-Oliveira RJ, Duarte JA, Bastos MdL, Palmeira C, Remião F. Mitochondrial Cumulative Damage Induced by Mitoxantrone: Late Onset Cardiac Energetic Impairment. Cardiovas Toxicol. 2014;14;30-40.
  27. Heidari R, Jamshidzadeh A, Keshavarz N, Azarpira N. Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice. Sci Pharm. 2014;83;143-158.
  28. Heidari R, Jamshidzadeh A, Niknahad H, Mardani E, Ommati MM, Azarpira N, Khodaei F, Zarei A, Ayarzadeh M, Mousavi S, Abdoli N, Yeganeh BS, Saeedi A, Najibi A. Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia. Toxicolog Report. 2016;3;870-879.
  29. Heidari R, Jafari F, Khodaei F, Shirazi Yeganeh B, Niknahad H. The Mechanism of Valproic Acid-Induced Fanconi Syndrome Involves Mitochondrial Dysfunction and Oxidative Stress in Rat Kidney. Nephrology. 2017;In-Press.
  30. Heidari R, Babaei H, Eghbal MA. Cytoprotective Effects of Organosulfur Compounds against Methimazole-Induced Toxicity in Isolated Rat Hepatocytes. Adv Pharm Bull. 2013;3;135-142.
  31. Sedlak J, Lindsay R. Estimation of Total, Protein-Bound, and Nonprotein Sulfhydryl Groups in Tissue with Ellman’s Reagent Analyt Biochem. 1968;25;192-205.
  32. Heidari R, Babaei H, Roshangar L, Eghbal MA. Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine. Adv Pharm Bull. 2014;4;21-28.
  33. Niknahad H, Heidari R, Firuzi R, Abazari F, Ramezani M, Azarpira N, Hosseinzadeh M, Najibi A, Saeedi A. Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats. Adv Pharm Bull. 2016;6;617–625.
  34. Heidari R, Niknahad H, Jamshidzadeh A, Azarpira N, Bazyari M, Najibi A. Carbonyl Traps as Potential Protective Agents against Methimazole-Induced Liver Injury. J Biochem Mol Toxicol. 2015;29;173-181.
  35. Moezi L, Heidari R, Amirghofran Z, Nekooeian AA, Monabati A, Dehpour AR. Enhanced anti-ulcer effect of pioglitazone on gastric ulcers in cirrhotic rats: The role of nitric oxide and IL-1b. Pharmacol Rep. 2013;65;134-143.
  36. Rodriguez-Frias EA, Lee WM. Cancer Chemotherapy I: Hepatocellular Injury. Clinic Liver Dis. 2007;11;641-662.
  37. Arnaiz SL, Llesuy S. Oxidative stress in mouse heart by antitumoral drugs: a comparative study of doxurobicin and mitoxantrone. Toxicology. 1993;77;31-38.
  38. Duthie SJ, Grant MH. The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells. Brit J Cancer. 1989;60;566-571.
  39. Mewes K, Blanz J, Ehninger G, Gebhardt R, Zeller K-P. Cytochrome P-450-induced cytotoxicity of mitoxantrone by formation of electrophilic intermediates. Cancer Res. 1993;53;5135-5142.
  40. Liebler DC. Protein Damage by Reactive Electrophiles: Targets and Consequences. Chem Res Toxicol. 2008;21;117-128.
  41. Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother. 2003;57;145-155.
  42. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundament Clin Pharmacol. 2008;22;335-353.
  43. Heidari R, Niknahad H, Jamshidzadeh A, Eghbal MA, Abdoli N. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury. Adv Pharm Bull. 2015;5;1-11.
Trends in Pharmaceutical Sciences
Volume 3, Issue 2 - Serial Number 2
12
June 2017
Pages 113-122

Files

Share

How to cite

Statistics