Effect of a novel oral active iron chelator: 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in iron-overloaded and non-overloaded mice

Nittaya Chansiw; Kanjana Pangjit; Chada Phisalaphong; John B Porter; Patricia Evans; Suthat Fucharoen; Somdet Srichairatanakool

doi:10.1016/S1995-7645(14)60223-6

Effect of a novel oral active iron chelator: 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in iron-overloaded and non-overloaded mice

Asian Pac J Trop Med. 2014 Sep:7S1:S155-61. doi: 10.1016/S1995-7645(14)60223-6.

Authors

Nittaya Chansiw¹, Kanjana Pangjit², Chada Phisalaphong³, John B Porter⁴, Patricia Evans⁴, Suthat Fucharoen⁵, Somdet Srichairatanakool⁶

Affiliations

¹ Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
² College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand.
³ Institute of Research and Development, Government Pharmaceutical Organization, Ministry of Public Health, Bangkok 10400, Thailand.
⁴ Department of Haematology, UCL Cancer Institute, Paul O'Gorman Building, 86, Huntley Street, London, WC1E 6BT, United Kingdom.
⁵ Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University Salaya Campus, Nakornpathom 73170, Thailand.
⁶ Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: ssrichai@med.cmu.ac.th.

PMID: 25312112
DOI: 10.1016/S1995-7645(14)60223-6

Abstract

Objective: To evaluate efficacy and toxicity of a novel orally active bidentate iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in mice under normal and iron overload conditions.

Methods: Wild type C57BL/6 mice were fed with normal and 0.2% (w/w) ferrocene-supplemented (Fe) diets, respectively for 240 d and orally given the CM1 (50, 100 and 200 mg/kg) for 180 d. Blood iron profiles, hematological indices, liver enzymes and histopathology were determined.

Results: CM1 treatment lowered plasma levels of labile plasma iron and non-transferrin bound iron, but not ferritin in the Fe-fed mice. However, the treatment did not impact blood hemoglobin level, white blood cell and platelet numbers in both normal diet and Fe diet-fed mice. Interestingly, CM1 treatment did not markedly elevate plasma aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities in the normal diet-fed mice but it tended to increase the levels of the liver enzymes slightly in the Fe-fed mice. Hematoxylin and eosin staining result showed no abnormal pathological changes in heart, liver and spleen tissues.

Conclusions: It is clear that CM1 would not be toxic to bone marrow and liver cells under normal and iron-overload conditions.

Keywords: Iron chelation; Iron overload; Liver enzyme; Thalassemia; Toxicity.