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Drug Res (Stuttg) 2023; 73(02): 113-120
DOI: 10.1055/a-1967-2066
Original Article

Mitochondrial Transplantation Therapy against Ifosfamide Induced Toxicity on Rat Renal Proximal Tubular Cells

Abdollah Arjmand
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Melika Mashhadi
2   Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Armin Kaveh
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Farzaneh Kamranfar
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
,
Enayatollah Seydi
3   Department of Occupational Health and Safety Engineering, School of Health, Alborz University of Medical Sciences, Karaj, Iran
4   Research Center for Health, Safety and Environment, Alborz University of Medical Sciences, Karaj, Iran
,
Jalal Pourahmad
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract

Mitochondrial dysfunction is a basic mechanism leading to drug nephrotoxicity. Replacement of defective mitochondria with freshly isolated mitochondria is potentially a comprehensive tool to inhibit cytotoxicity induced by ifosfamide on renal proximal tubular cells (RPTCs). We hypothesize that the direct exposure of freshly isolated mitochondria into RPTCs affected by ifosfamide might restore mitochondrial function and reduce cytotoxicity. So, the aim of this study was to assess the protective effect of freshly isolated mitochondrial transplantation against ifosfamide-induced cytotoxicity in RPTCs. Therefore, the suspension of rat RPTCs (106 cells/ml) in Earle’s solution with the pH of 7.4 at 37°C was incubated for 2 h after ifosfamide (4 mM) addition. Fresh mitochondria were isolated from the rat kidney and diluted to the needed concentrations at 4°C. The media containing suspended RPTCs was replaced with mitochondrial-supplemented media, which was exposed to cells for 4 hours in flasks-rotating in a water bath at 37°C. Statistical analysis demonstrated that mitochondrial administration reduced cytotoxicity, lipid peroxidation (LPO), reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, lysosomal membrane damage, extracellular oxidized glutathione (GSSG) level, and caspase-3 activity induced by ifosfamide in rat RPTCs. Moreover, mitochondrial transplantation increased the intracellular reduced glutathione (GSH) level in RPTCs affected by ifosfamide. According to the current study, mitochondrial transplantation is a promising therapeutic method in xenobiotic-caused nephrotoxicity pending successful complementary in vivo and clinical studies.

Key words

Mitochondrial Transplantation - Ifosfamide - Oxidative Stress - Nephrotoxicity.


Publication History

Received: 12 September 2022

Accepted: 10 October 2022

Article published online:
17 November 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Nissim I, Horyn O, Daikhin Y. et al. Ifosfamide-induced nephrotoxicity: mechanism and prevention. Cancer Res 2006; 66: 7824-7831
    CrossrefPubMedGoogle Scholar
  • 2 Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy 1997; 17: 146s-154ss
    CrossrefPubMedGoogle Scholar
  • 3 Verma S, Younus J, Stys-Norman D. et al. Ifosfamide-based combination chemotherapy in advanced soft-tissue sarcoma: a practice guideline. Curr Oncol 2007; 14: 144-148
    CrossrefPubMedGoogle Scholar
  • 4 Voûte PA, van den Berg H, Behrendt H. et al. Ifosfamide in the treatment of pediatric malignancies. Semin Oncol 1996; 23: 8-11
    PubMedGoogle Scholar
  • 5 Wagner T. Ifosfamide clinical pharmacokinetics. Clinical pharmacokinetics 1994; 26: 439-456
    CrossrefPubMedGoogle Scholar
  • 6 Ensergueix G, Pallet N, Joly D. et al. Ifosfamide nephrotoxicity in adult patients. Clin Kidney J 2020; 13: 660-665
    CrossrefPubMedGoogle Scholar
  • 7 Han HY, Choi MS, Yoon S. et al. Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney. Int J Mol Sci 2021; 22: 12201
    CrossrefPubMedGoogle Scholar
  • 8 Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 2003; 41: 190-197
    CrossrefPubMedGoogle Scholar
  • 9 Nissim I, Weinberg JM. Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats. Kidney Int 1996; 49: 684-695
    CrossrefPubMedGoogle Scholar
  • 10 Lind MJ, McGown AT, Hadfield JA. et al. The effect of ifosfamide and its metabolites on intracellular glutathione levels in vitro and in vivo. Biochem Pharmacol 1989; 38: 1835-1840
    CrossrefPubMedGoogle Scholar
  • 11 Springate J, Taub M. Ifosfamide toxicity in cultured proximal renal tubule cells. Pediatr Nephrol 2007; 22: 358-365
    CrossrefPubMedGoogle Scholar
  • 12 Katrangi E, D’Souza G, Boddapati SV. et al. Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function. Rejuvenation Res 2007; 10: 561-570
    CrossrefPubMedGoogle Scholar
  • 13 Clark MA, Shay JW. Mitochondrial transformation of mammalian cells. Nature 1982; 295: 605-607
    CrossrefPubMedGoogle Scholar
  • 14 Islam MN, Das SR, Emin MT. et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18: 759-765
    CrossrefPubMedGoogle Scholar
  • 15 Kesner EE, Saada-Reich A, Lorberboum-Galski H. Characteristics of Mitochondrial Transformation into Human Cells. Sci Rep 2016; 6: 26057
    CrossrefPubMedGoogle Scholar
  • 16 Boom SP, Gribnau FW, Russel FG. Organic cation transport and cationic drug interactions in freshly isolated proximal tubular cells of the rat. J Pharmacol Exp Ther 1992; 263: 445-450
    PubMedGoogle Scholar
  • 17 Schafer JA, Watkins ML, Li L. et al. A simplified method for isolation of large numbers of defined nephron segments. Am J Physiol 1997; 273: F650-F657
    PubMedGoogle Scholar
  • 18 Everse J, Reich RM, Kaplan NO. et al. New instrument for rapid determination of activities of lactate dehydrogenase isoenzymes. Clin Chem 1975; 21: 1277-1281
    CrossrefPubMedGoogle Scholar
  • 19 Preble JM, Pacak CA, Kondo H. et al. Rapid isolation and purification of mitochondria for transplantation by tissue dissociation and differential filtration. J Vis Exp 2014; e51682
    PubMedGoogle Scholar
  • 20 Shaki F, Hosseini MJ, Ghazi-Khansari M. et al. Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochim Biophys Acta 2012; 1820: 1940-1950
    CrossrefPubMedGoogle Scholar
  • 21 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
    CrossrefPubMedGoogle Scholar
  • 22 Rezaei M, Salimi A, Taghidust M. et al. A comparison of toxicity mechanisms of dust storm particles collected in the southwest of Iran on lung and skin using isolated mitochondria. Toxicological & Environmental Chemistry 2014; 96: 814-830
    CrossrefPubMedGoogle Scholar
  • 23 Baracca A, Sgarbi G, Solaini G. et al. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta 2003; 1606: 137-146
    CrossrefPubMedGoogle Scholar
  • 24 Al Maruf A, O'Brien PJ, Naserzadeh P. et al. Methotrexate induced mitochondrial injury and cytochrome c release in rat liver hepatocytes. Drug Chem Toxicol 2018; 41: 51-61
    CrossrefPubMedGoogle Scholar
  • 25 Andersson BS, Aw TY, Jones DP. Mitochondrial transmembrane potential and pH gradient during anoxia. Am J Physiol 1987; 252: C349-C355
    CrossrefPubMedGoogle Scholar
  • 26 Pourahmad J, Rabiei M, Jokar F. et al. A comparison of hepatocyte cytotoxic mechanisms for chromate and arsenite. Toxicology 2005; 206: 449-460
    CrossrefPubMedGoogle Scholar
  • 27 Beach DC, Giroux E. Inhibition of lipid peroxidation promoted by iron(III) and ascorbate. Arch Biochem Biophys 1992; 297: 258-264
    CrossrefPubMedGoogle Scholar
  • 28 Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 1976; 74: 214-226
    CrossrefPubMedGoogle Scholar
  • 29 Sakahira H, Enari M, Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 1998; 391: 96-99
    CrossrefPubMedGoogle Scholar
  • 30 Bereiter-Hahn J, Vöth M, Mai S. et al. Structural implications of mitochondrial dynamics. Biotechnol J 2008; 3: 765-780
    CrossrefPubMedGoogle Scholar
  • 31 Meier O, Boucke K, Hammer SV. et al. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J Cell Biol 2002; 158: 1119-1131
    CrossrefPubMedGoogle Scholar
  • 32 Mahammad S, Parmryd I. Cholesterol depletion using methyl-β-cyclodextrin. Methods in membrane lipids. Springer; 2015. p 91-102
    Google Scholar
  • 33 Lundin A. Use of firefly luciferase in ATP-related assays of biomass, enzymes, and metabolites. Methods Enzymol 2000; 305: 346-370
    CrossrefPubMedGoogle Scholar
  • 34 Hosseini MJ, Shaki F, Ghazi-Khansari M. et al. Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ROS production. Cell Biochem Biophys 2014; 70: 367-381
    CrossrefPubMedGoogle Scholar
  • 35 Rieder H, Decker K. Phagocytosis of hepatocyte mitochondria by rat Kupffer cells in vitro. Hoppe Seylers Z Physiol Chem 1984; 365: 175-184
    CrossrefPubMedGoogle Scholar
  • 36 Fujii F, Nodasaka Y, Nishimura G. et al. Anoxia induces matrix shrinkage accompanied by an increase in light scattering in isolated brain mitochondria. Brain Res 2004; 999: 29-39
    CrossrefPubMedGoogle Scholar
  • 37 Ulger O, Kubat GB. Therapeutic applications of mitochondrial transplantation. Biochimie 2022; 195: 1-15
    CrossrefPubMedGoogle Scholar
  • 38 Ho PT, Zimmerman K, Wexler LH. et al. A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer 1995; 76: 2557-2564
    CrossrefPubMedGoogle Scholar
  • 39 Choucha-Snouber L, Aninat C, Grsicom L. et al. Investigation of ifosfamide nephrotoxicity induced in a liver-kidney co-culture biochip. Biotechnol Bioeng 2013; 110: 597-608
    CrossrefPubMedGoogle Scholar
  • 40 Hanly L, Chen N, Rieder M. et al. Ifosfamide nephrotoxicity in children: a mechanistic base for pharmacological prevention. Expert Opin Drug Saf 2009; 8: 155-168
    CrossrefPubMedGoogle Scholar
  • 41 Connors TA, Cox PJ, Farmer PB. et al. Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol 1974; 23: 115-129
    CrossrefPubMedGoogle Scholar
  • 42 Norpoth K. Studies on the metabolism of isopnosphamide (NSC-109724) in man. Cancer Treat Rep 1976; 60: 437-443
    PubMedGoogle Scholar