Cover
Vol. 4 No. 1 (2026)

Published: June 1, 2026

Pages: 124-131

Research Article

Hepatoprotective Role of Zinc Gluconate against Hepatotoxicity Induced by Mitoxantrone In Rats

taif mohammed maryoosh 1 Kasim S. Hmood 1 Raghad A. Khaleel 2 Dhilal dhiaa Nasser 3 Noor M. Fadhil 4
1 Al-Kut University College
2 University of Al-Iraqia College of Medicine Department of Pharmacology, Baghdad, Iraq
3 Department of Aesthetic and Laser Techniques, College of Health and Medical Techniques, University of Kut, Wasit, 52001
4 Department of Pharmacology and Toxicology, College of Pharmacy, University of Kut, Wasit, Iraq, 52001
History
  • Received: January 24, 2026
  • Accepted: February 6, 2026
  • Available Online: June 1, 2026

Abstract

Mitoxantrone is a chemotherapeutic very effective against a variety of human malignancies Administration of Mitoxantrone is associated with hepatotoxicity Zinc has protective effect in liver illness. This study aimed to determine the role of zinc gluconate as a hepatoprotective agent in Mitoxantrone induced hepatotoxicity in rats. Methods there were twenty-four male and female rats used. Rats were divided up Into three groups, each consisting of eight animals. Distilled water is in Group I (negative control).Group II Mitoxantrone was delivered intraperitoneally with a dosage of 2.50 mg/ kg in order to achieve a cumulative complete dosage of 7.50 mg /kg by day 20. Group III Zinc gluconate was orally provided at a dosage of 20 mg/ kg/day, and Mitoxantrone was injected intraperitoneally at a rate of 2.50 mg/kg. The goal was to attain a cumulative total dosage of 7.50mg/ kg by day 20.After 48 hours following the completion of the treatment period, diethyl ether was used to euthanize each animal (i.e., on day 22). Serum was used to determine the activity of the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes.Each animal's liver was removed in order to perform a terminal deoxynucleotidyl-transferase-mediated-deoxyuridine-triphosphate, necked labeling (TUNEL) test to detect DNA fragmentation. Results Zinc gluconate significantly (P<0.05) decreased blood ALT and AST, and group III showed a higher percentage of normal hepatocyte cells and a lower percentage of apoptotic cells than group II. Conclusions Zinc gluconate may have a protective effect against the hepatotoxicity induced by Mitoxantrone in rats.

Keywords

References

  1. Seiter K. Toxicity of the topoisomerase II inhibitors. Expert opinion on drug safety. 2005;4(2):219-34. https://doi.org/10.1517/14740338.4.2.219.
  2. Neuhaus O, Kieseier BC, Hartung H-P. Therapeutic role of mitoxantrone in multiple sclerosis. Pharmacology & therapeutics. 2006;109(1-2):198-209.https://doi.org/10.1016/j.pharmthera.2005.07.002.
  3. Kathiravan MK, Khilare MM, Nikoomanesh K, Chothe AS, Jain KS. Topoisomerase as target for antibacterial and anticancer drug discovery. Journal of enzyme inhibition and medicinal chemistry. 2013;28(3):419-35. https://doi.org/10.3109/14756366.2012.658785.
  4. Maryoosh TM, N. Al-Shawi N, S. Salih E. Effects of Two Different Doses of Zinc Sulfate on Serum Troponin I 3 Enzyme Level and Cardiac Malondialdehyde Contents in Mitoxantrone-Induced Cardiotoxicity in Rats. Iraqi Journal of Pharmaceutical Sciences.. 25 2025 Feb.;29(1):115-22 https://doi.org/10.31351/vol29iss1pp115-122
  5. Rossato LG, Costa VM, de Pinho PG, Arbo MD, de Freitas V, Vilain L, et al. The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity. Archives of toxicology. 2013;87(10):1809-20. https://doi.org/10.1038/s00204-013-1040-6.
  6. Taif M. Maryoosh, Nada N. Al-Shawi, Eman S. Saleh, Suhair H. Alkutbi. Journal of Global Pharma Technology 2019 ;11 (9) :340-347.
  7. Rossato LG, Costa VM, Vilas-Boas V, de Lourdes Bastos M, Rolo A, Palmeira C, et al. Therapeutic concentrations of mitoxantrone elicit energetic imbalance in H9c2 cells as an earlier event. Cardiovascular toxicology. 2013;13(4):413-25. https://doi.org/10.1007/s12012-013-9224-0
  8. Saner F, Heuer M, Meyer M, Canbay A, Sotiropoulos G, Radtke A, et al. When the heart kills the liver: acute liver failure in congestive heart failure. European journal of medical research. 2009;14(12):541-6. https://doi.org/10.1186/2047-783x-14-12-541
  9. King PD, Perry MC. Hepatotoxicity of chemotherapy. The oncologist. 2001;6(2):162-76. https://doi.org/10.1634/theoncologist.6-2-162
  10. Gunes AK, Serin I, Demir I, Sarifakiogullari S, Durusoy SS, Akkurt DM, et al. Comparison of mitoxantrone–melphalan and BEAM conditioning regimens in patients with lymphoma. Hematology/Oncology and Stem Cell Therapy. 2021. https://doi.org/10.1016/j.hemonc.2021.03.005
  11. Juntti‐Patinen L, Kuitunen T, Pere P, Neuvonen PJ. Drug‐related visits to a district hospital emergency room. Basic & clinical pharmacology & toxicology. 2006;98(2):212-7. https://doi.org/10.1111/j.1742-7843.2006.pto_264.x
  12. Deshpande JD, Joshi MM, Giri PA. Zinc: The trace element of major importance in human nutrition and health. Int J Med Sci Public Health. 2013;2(1):1-6. DOI:10.5455/ijmsph.2013.2.1-6
  13. Rossato LG, Costa VM, Dallegrave E, Arbo M, Silva R, Ferreira R, et al. Mitochondrial cumulative damage induced by mitoxantrone: late onset cardiac energetic impairment. Cardiovasc Toxicol . 2014; 14(1): 30-40. https://doi.org/10.1007/s12012-013-9230-2
  14. Al-bayti, Ayoub & Ahmed, Fidan & Abdullah, Sami & Ghareeb, Ozdan. (2022). The protective effect of zinc and its relationship with some hematological, biochemical, and histological parameters in adult male rats. Archivos Venezolanos de Farmacologia y Terapeutica. 41. 400-405.
  15. Thatishetty AV, Agresti N, O'Brien CB. Chemotherapy-induced hepatotoxicity. Clinics in liver disease. 2013;17(4):671-86. . https://doi.org/10.1016/j.cld.2013.07.010
  16. King PD, Perry MC. Hepatotoxicity of Chemotherapy. The Oncologist. 2001;6;162-76.
  17. Llesuy SF, Arnaiz SL. Hepatotoxicity of mitoxantrone and doxorubicin. Toxicology. 1990;63;187-98.
  18. 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;1822-6
  19. Volkova M, Russell R. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Current cardiology reviews. 2011;7(4):214-20https://doi.org/10.2174/157340311799960645
  20. Suk KT, Kim DJ. Drug-induced liver injury: present and future. Clinical and molecular hepatology. 2012;18(3):249https://doi.org/10.3350/cmh.2012.18.3.249.
  21. 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;566-71.
  22. Stephens C, Andrade RJ, Lucena MI. Mechanisms of drug-induced liver injury. Current opinion in allergy and clinical immunology. 2014;14(4):286-92https://doi.org/10.1097/ACI.0000000000000070
  23. Liebler DC. Protein damage by reactive electrophiles: targets and consequences. Chemical research in toxicology. 2008;21(1):117-28. https://doi.org/10.1021/tx700235t
  24. Niknahad H, Hosseini H, Gozashtegan F, Ebrahimi F, Azarpira N, Abdoli N, et al. The hepatoprotective role of thiol reductants against mitoxantrone-induced liver injury. Trends in Pharmaceutical Sciences. 2017;3(2):113-22. DOI:10.1111/tips.v3i2.123
  25. Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D'Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016 Apr;8(4):603-19. doi: 10.18632/aging.100934. PMID: 27019364; PMCID: PMC4925817.
  26. Park SH, Lee J, Kang MA, Jang KY, Kim JR. Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO pathway. Oncol Lett. 2018; 15(6): 9687–9696.
  27. Xie B, He X, Guo G, Zhang X, Li J, Liu J, Lin Y. High-throughput screening identified mitoxantrone to induce death of hepatocellular carcinoma cells with autophagy involvement. Biochem Biophys Res Commun. 2020 Jan 1;521(1):232-237. doi: 10.1016/j.bbrc.2019.10.114. Epub 2019 Oct 22. PMID: 3165334
  28. Bandhu H, Dani V, Garg M, Dhawan D. Hepatoprotective role of zinc in lead-treated, protein-deficient rats. Drug and chemical toxicology. 2006;29(1):11-24 .https://doi.org/10.1080/01480540500408507.
  29. Al-Jawad FH, Sharquie KE, Raghif AA, Nashtar SB. Hepatoprotective effects of zinc sulphate and silymarin against thallium-induced poisoning in rats. AL-yarmouk Journal. 2015(1): 42-57.https://www.iasj.net/iasj/download/04667c65079ff11d
  30. Yoshioka H, Onosaka S. Zinc sulfate pretreatment prevents carbon tetrachloride-induced lethal toxicity through metallothionein-mediated suppression of lipid peroxidation in mice. Fundamental Toxicological Sciences. 2016;3(4):151-6. https://doi.org/10.2131/fts.3.151
  31. Chengelis C, Dodd DC, Means JR, Kotsonis FN. Protection by zinc against acetaminophen induced hepatotoxicity in mice. Toxicological Sciences. 1986;6(2):278-84. https://doi.org/10.1016/0272-0590(86)90241-1
  32. Choucair F , Saliba E, Jaoude IA, Hazzouri M. Antioxidants modulation of sperm genome and epigenome damage: Fact or fad? Converging evidence from animal and human studies. Middle East Fertility Society Journal 2018; 23(2): 85-90
  33. Barman S and Srinivasan K. Attenuation of oxidative stress and cardioprotective effects of zinc supplementation in experimental diabetic rats.British Journal of Nutrition 2017; 117: 335–350.
  34. Rogalska J, Pilat-Marcinkiewicz B, Brzóska MM. Protective effect of zinc against cadmium hepatotoxicity depends on this bioelement intake and level of cadmium exposure: a study in a rat model. Chem Biol Interact. 2011 Sep 30;193(3):191-203. doi: 10.1016/j.cbi.2011.05.008. Epub 2011 May 24. PMID: 21627960.