alexa Toxicity Study of a Novel Oral Iron Chelator: 1-(N-Acetyl-6-Aminohexyl)-3 Hydroxy-2-Methylpyridin-4-One (CM1) in Transgenic b-Thalassemia Mice
ISSN: 2376-1318

Vitamins & Minerals
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Research Article

Toxicity Study of a Novel Oral Iron Chelator: 1-(N-Acetyl-6-Aminohexyl)-3 Hydroxy-2-Methylpyridin-4-One (CM1) in Transgenic b-Thalassemia Mice

Nittaya Chansiw1, Kanjana Pangjit1,2, Chada Phisalaphong3, Suthat Fucharoen4, Patricia Evans5, John B Porter5 and Somdet Srichairatanakool1*
1Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Thailand
2College of Medicine and Public Health, Ubon Ratchathani University, Thailand
3Institute of Research and Development, Government Pharmaceutical Organization, Ministry of Public Health, Bangkok 10400, Thailand
4Thalassemia Research Center, Institute of Molecular Bioscience, Mahidol University Salaya Campus, Thailand
5Department of Haematology, UCL Cancer Institute, Paul O' Gorman Building, Huntley Street, United Kingdom
Corresponding Author : Somdet Srichairattanakool
Department of Biochemistry, Faculty of Medicine
Chiang Mai University, Thailand
E-mail: [email protected]
Received July 08, 2013; Accepted August 01, 2013; Published August 06, 2013
Citation: Chansiw N, Pangjit K, Phisalaphong C, Fucharoen S, Evans P, et al. (2013) Toxicity Study of a Novel Oral Iron Chelator: 1-(N-Acetyl-6-Aminohexyl)-3 Hydroxy-2-Methylpyridin-4-One (CM1) in Transgenic ß-Thalassemia Mice. Vitam Miner 2:116. doi:10.4172/vms.1000116
Copyright: © 2013 Chansiw N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

Abstract

Deferiprone (DFP) (MW=139 Da, Kpart=0.11) is an effective iron chelator used for the treatment of iron overload in thalassemia patients, but the drug is not free from side effects. We have synthesized a novel oral bidentate iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) (MW=256 Da, Kpart=0.53), which is an analogue of DFP. This compound is more lipophilic than DFP and can bind iron efficiently. Our current results have demonstrated that CM1 reduced iron-induced redox damage and decreased levels of the intracellular iron pool (LIP) in cultured hepatocytes, effectively. However, the toxicity of CM1 remains largely unknown. The aim of this study was to therefore examine the toxicity of CM1 treatment in an animal model under normal and iron overload conditions. To induce iron overload, transgenic ß-thalassemia (BKO) mice were fed with a 0.2% (w/w) ferrocene-supplemented diet (Fe diet) for 240 days. The mice received three doses of CM1 orally (50,100 and 200 mg/kg), every day for 180 days. Blood was collected from the tail vein every 45 days during treatment for the measurement of hemoglobin (Hb) levels, white blood cells (WBC) and platelet numbers. We also determined the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), which are markers of liver damage. Treatment with CM1 at the assigned doses did not markedly alter the numbers of WBC and the platelets, and the Hb level in BKO mice fed with either N diet or Fe diet. Importantly, all the treatments slightly increased the activities of plasma AST, ALT and ALP in BKO mice after 150 days. Nonetheless, hematoxylin and eosin staining results did not show abnormal morphological changes of the spleen, liver and heart tissues. The results imply that CM1 may not be toxic to bone marrow cells and liver cell function in BKO mice under normal and iron overload conditions. *Corresponding author: Somdet Srichairattanakool, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Thailand, E-mail: [email protected] Received July 08, 2013; Accepted August 01, 2013; Published August 06, 2013 Citation: Chansiw N, Pangjit K, Phisalaphong C, Fucharoen S, Evans P, et al. (2013) Toxicity Study of a Novel Oral Iron Chelator: 1-(N-Acetyl-6-Aminohexyl)-3 Hydroxy-2-Methylpyridin-4-One (CM1) in Transgenic ß-Thalassemia Mice. Vitam Miner 2: 116. doi:10.4172/vms.1000116 Copyright: © 2013 Chansiw N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: 3-Hydroxypyridinone; Iron chelator; Iron overload; Toxicity; ß-thalassemia Introduction Iron is absolutely essential to living cells and plays many important roles in energy production, oxygen transport and DNA synthesis. Although iron is crucial for cells, an excess of iron is toxic [1]. In thalassemia patients, multiple blood transfusions and abnormal iron absorption cause iron overload and accumulation in tissues and organs [2]. Consequently, reactive oxygen species (ROS) are produced from the iron-catalyzed Fenton reaction, causing oxidative tissue damage and organ dysfunctions [3,4]. Iron chelation therapy is required, not just to restore iron balance, but also to reduce toxic iron species. Iron chelators, such as desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX), are available for clinical use, but these compounds still have many side effects and drawbacks. DFO is not orally active [5], DFX is associated with renal toxicity in some patients [6], and DFP can have side effects, including nausea, vomiting, gastrointestinal tract disturbances, leucopenia, thrombocytopenia and zinc deficiency [7]. We have successfully synthesized a novel oral bidentate iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1). It is DFP analogue and is more lipophilic than DFP. In a previous study, we found that CM1 was able to bind both ferric and ferrous ions, and was also able to chelate plasma non-transferrin bound iron (NTBI), efficiently [8]. Moreover, we found that the CM1 was not toxic to peripheral blood mononuclear cells and liver cells in an in vitro study [9]. However, the toxicity of CM1 in the in vivo study remains largely unknown. In this study, we examined the toxicity of CM1 on the liver and peripheral blood cells in transgenic ß-thalassemia mice under normal and iron overload conditions. Materials and Methods In the experimental design of this study, the heterozygous ß-thalassemia knockout

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