Abstract
Iron overload is a major health problem for patients who have to have continuous blood transfusions. It brings some metabolic problems together. Various iron chelating agents are being used for treatment of hemochromatosis which arises from excess iron accumulation. This study was conducted with the aim of determining whether deferasirox used as an iron chelator in patients with hemochromatosis has genotoxic effects. Commercial form of deferasirox, Exjade was used as test material. Test material showed a general mutagen character in mutant strains of Salmonella typhimurium. Deferasirox has also led to an increase in mutagenity-related polymorphic band count in random amplification of polymorphic DNA test done with bone marrow cells of rats. Similarly, test material has increased micronucleus formation in cultured in vitro human peripheral lymphocytes particularly in 48 h period. Consistently with the abovementioned findings, deferasirox reduced nuclear division index (NDI) compared to controls and some part of these reductions are statistically significant. NDI reductions were found at positive control levels at high concentrations.
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Anderson D, Yardley-Jones A, Vives-Bauza C, Chua-Anusorn W, Cole C, Webb J (2000) Effect of iron salts, haemosiderins, and chelating agents on the lymphocytes of a thalassaemia patient without chelation therapy as measured in the comet assay. Teratog Carcinog Muagen 20:251–264
Beall HD, Liu Y, Siegel D, Bolton EM, Gibson NW, Ross D (1996) Role of NAD(P)H:quinone oxidoreductase (DT-diaphorase) in cytotoxicity and induction of DNA damage by streptonigrin. Biochem Pharmacol 51:645–652
Brown KE, Mathahs MM, Broadhurst KA, Weydert J (2006) Chronic iron overload stimulates hepatocyte proliferation and cyclin D1 expression in rodent liver. Transl Res 148:55–62
Chakrabarti SK, Bai C, Subramanian KS (2001) DNA-protein crosslinks induced by nickel compounds in isolated rat lymphocytes: role of reactive oxygen species and specific amino acids. Toxicol Appl Pharmacol 170:153–165
Chantrel-Groussard K, Gaboriau F, Pasdeloup N, Havouis R, Nick H, Pierre JL, Brissot P, Lescoat G (2006) The new orally active iron chelator ICL670A exhibits a higher antiproliferative effect in human hepatocyte cultures than O-trensox. Eur J Pharmacol 541:129–137
Coogan TP, Rosenblum IY, Barsotti DA (1986) Bleomycin-induced DNA-strand damage in isolated male germ cells. Mutat Res 162:215–218
Dyavaiah M, Rooney JP, Chittur SV, Lin Q, Begley TJ (2011) Autophagy-dependent regulation of the DNA damage response protein ribonucleotide reductase 1. Mol Cancer Res 9:462–475
Eknoyan G (2008) Adolphe Quetelet (1796–1874)—the average man and indices of obesity. Nephrol Dial Transplant 23:47–51
Elledge SJ, Davis RW (1989) DNA damage induction of ribonucleotide reductase. Mol Cell Biol 9:4932–4940
Elledge SJ, Zhou Z, Allen JB, Navas TA (1993) DNA damage and cell cycle regulation of ribonucleotide reductase. BioEssays 15:333–339
Fenech M (2000) The in vitro micronucleus technique. Mutat Res 455:81–95
Ford SJ, Obeidy P, Lovejoy DB, Bedford M, Nichols L, Chadwick C, Tucker O, Lui GY, Kalinowski DS, Jansson PJ, Iqbal TH, Alderson D, Richardson DR, Tselepis C (2013) Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo. Br J Pharmacol 168:1316–1328. doi:10.1111/bph.12045
Hakura A, Suzuki S, Sawada S, Sugihara T, Hori Y, Uchida K, Kerns WD, Sagami F, Motooka S, Satoh T (2003) Use of human liver S9 in the Ames test: assay of three procarcinogens using human S9 derived from multiple donors. Regul Toxicol Pharmacol 37:20–27
Juckett MB, Shadley JD, Zheng Y, Klein JP (1998) Desferrioxamine enhances the effects of gamma radiation on clonogenic survival and the formation of chromosomal aberrations in endothelial cells. Radiat Res 149:330–337
Karakaş Z (2009) Talasemi tedavisinde güncel yaklaşımlar ve yeni şelatörler. Turkiye Klinikleri J Pediatr Sci 5:15–27
Lui GY, Obeidy P, Ford SJ, Tselepis C, Sharp DM, Jansson PJ, Kalinowski DS, Kovacevic Z, Lovejoy DB, Richardson DR (2013) The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol Pharmacol 83:179–190. doi:10.1124/mol.112.081893
Maron DM, Ames BN (1983) Revised method for the Salmonella mutagenicity test. Mutat Res 113:173–215
Marshall R, Tricta F, Galanello R, Leoni G, Kirkland D, Minto S, Spino M (2003) Chromosomal aberration frequencies in patients with thalassaemia major undergoing therapy with deferiprone and deferoxamine in a comparative crossover study. Mutagenesis 18:457–463
McKnight RE, Gleason AB, Keyes JA, Sahabi S (2006) Binding mode and affinity studies of DNA-binding agents using topoisomerase I DNA unwinding assay. Bioorg Med Chem Lett 17:1013–1017. doi:10.1016/j.bmcl.2006.11.038
Noel S, Rath SK (2006) Randomly amplified polymorphic DNA as a tool for genotoxicity: an assessment. Toxicol Ind Health 22:267–275
O’Donnell JP, Gehman M, Keeney JB (2010) Regulators of ribonucleotide reductase inhibit Ty1 mobility in Saccharomyces cerevisiae. Mob DNA 1:23. doi:10.1186/1759-8753-1-23
Pires VS, Gaboriau F, Guillon J, Nascimento S, Dassonville A, Lescoat G, Desplat V, Rochette J, Jarry C, Sonnet P (2006) Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes. J Enzyme Inhib Med Chem 21:261–270
Rotfuss A, Schütz P, Bochum S, Volm T, Eberhardt E, Kreirenberg R, Vogel W, Speit G (1986) Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families. Cancer Res 60:390–394
Schweitzer C, Scaiano JC (2003) Selective binding and local photophysics of the fluorescent cyanine dye PicoGreen in double-stranded and single-stranded DNA. Phys Chem Chem Phys 5:4911–4917
Song S, Christova T, Perusini S, Alizadeh S, Bao RY, Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M, Joseph B, Subramaniam R, Aman A, Chau A, Hogge DE, Weir SJ, Kasper J, Schimmer AD, Al-awar R, Wrana JL, Attisano L (2011) Wnt inhibitor screen reveals iron dependence of β-catenin signaling in cancers. Cancer Res 71:7628–7639
Steegmann-Olmedillas JL (2011) The role of iron in tumour cell proliferation. Clin Transl Oncol 13:71–76
Stinson TJ, Jaw S, Jeffery EH, Plewa MJ (1992) The relationship between nickel chloride-induced peroxidation and DNA strand breakage in rat liver. Toxicol Appl Pharmacol 117:98–103
Whittaker P, Seifried HE, San HRH, Clarke JJ, Dunkel VC (2001) Genotoxicity of iron chelators in L5178Ymouse lymphoma cells. Environ Mol Mutagen 38:347–356
Witte I, Zhu BZ, Lueken A, Magnani D, Stossberg H, Chevion M (2000) Protection by desferrioxamine and other hydroxamic acids against tetrachlorohydroquinone-induced cyto-and genotoxicity in human fibroblasts. Free Radic Biol Med 28:693–700
Zhang AS, Enns CA (2009) Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J Biol Chem 284:711–715
Zhang L, Bandy B, Davison AJ (1996) Effects of metals, ligands and antioxidants on the reaction of oxygen with 1,2,4-benzenetriol. Free Radic Biol Med 20:495–505
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This work was supported by the Basic Science Research and Support Group at the TUBITAK (Project no: 111T017).
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Ila, H.B., Topaktas, M., Arslan, M. et al. Signs of deferasirox genotoxicity. Cytotechnology 66, 647–654 (2014). https://doi.org/10.1007/s10616-013-9617-8
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DOI: https://doi.org/10.1007/s10616-013-9617-8