Abstract
Gerbils administered iron dextran are the only animal species which have been shown to develop hemochromatosis of the liver and heart in the same manner as transfusion dependent homozygous thalassemics. The iron chelating hydroxypyridinone, CP94, has been administered prophylactically to iron overloaded gerbils in a dosing regime which favors the formation of bidentate chelated iron, to examine the possibility of additional toxicity being caused to the liver and heart by the bidentate chelated iron complex. Hepatic iron accumulation was inhibited by CP94 administration for up to 6 weeks, but not after 20 weeks. Iron accumulation in the heart was increased significantly after 6 and 20 weeks of chelator treatment. Pathological changes in both organs were markedly more severe after 20 weeks in chelator treated animals. There was a higher incidence of cardiofibrosis and more extensive liver fibrosis in iron overloaded, chelator treated animals after 20 weeks.
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References
Bancroft JD, Stevens A. 1977 Theory and Practice of Histological Techniques. London: Churchill Livingstone.
Basset ML, Halliday JW, Powell LW. 1986 Value of hepatic iron measurements in early haemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 6, 24–29.
Bothwell TH, Charlton RW, Motulsky AG. 1989 Hemochromatosis. In: Scrivener CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill; 1433–1462.
Buja LM, Roberts WC. 1971 Iron in the heart. Etiology and significance. Am J Pathol 51, 209–221.
Burkitt MJ, Mason RP. 1991 Direct evidence for in vivo hydroxyl-radical generation in experimental iron overload: an ESR spin-trapping investigation. Proc Natl Acad Sci USA 88 8440–8444.
Carthew P, Edwards RE, Smith AG, Dorman BM, Francis JE. 1991 Rapid induction of hepatic fibrosis in the gerbil after the parenteral administration of iron dextran complex. Hepatology 13, 534–540.
Carthew P, Edwards RE, Smith AG, Cox TM. 1992 Excessive ferritin accumulation in fibroblast cells is associated with hepatic fibrosis due to iron overload in man. In Gressner AM, Ramadori G, eds. Molecular and Cell Biology of Liver Fibrogenesis. Dordrecht: Kluwer; 15–1–15–4.
Carthew P, Dorman BM, Edwards RE,Francis JE, Smith AG. 1993 A unique model for both the cardiotoxic and hepatotoxic effects of prolonged iron overload. Lab Invest 69, 217–222.
Florence A, Ward RA, Peters TJ, Crichton RR. 1992 Studies of the in-vivo iron mobilisation by chelators in the ferrocene-loaded rat. Biochem Pharmacol 44, 1023–1027.
Graham G, Bates, GW, Rachmilewitz EA, Hershko C. 1979 Nonspecific serum iron in thalassemia. Am J Hematol 6, 207–217.
Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ. 1989 Non transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterisation by high performance liquid chromatography and nuclear magnetic resonance spectroscopy. J Biol Chem 264, 4417–4422.
Gyparaki M, Porter JB, Burke LC, Huehns ER, Hider RC. 1987 In vivo evaluation of hydroxypyridinone iron chelators in a mouse model. Acta Hematol (Basel) 78, 217–221.
Iancu TC, Ward RJ, Peters TJ. 1987 Ultrastructural observations on the carbonyl iron-fed rat: an animal model of hemochromatosis. Virchows Arch B 53, 208–217.
Kan YW. 1983 The Thalassemias. In Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill; 1711–1725.
Kontoghiorges GJ, Sheppard L, Hoffbrend AV, Charlambous J, Tiperkae J, Pippard MJ. 1987 Iron chelation studies using desferrioxamine and the potential oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one, in normal and iron overloaded rats. J Clin Pathol 40, 404–408.
Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicology in patients receiving subcutaneous deferoxamine infusions. N Eng J Med 314, 869–873.
Park CH, Bacon BR, Brittenham EM, Tavill AS. 1987 Pathology of dietary carbonyl iron overload in rats. Lab Invest 57, 555–563.
Parkes JG, Roshan A, Olivieri NF, Templeton DM. 1993 Effects of iron loading on uptake, speciation, and chelation of iron in cultured myocardial cells. J Lab Clin Med 122, 36–47.
Pootrakul P, Huebers HA, Finch CA, Pippard MJ, Cazzola M. 1988 Iron metabolism in Thalassemia. In: Thalassemia Pathophysiology and Management. March of Dimes Birth Defects Foundation 23, 3–8.
Porter JB, Huehns ER, Hider RC. 1989 The development of iron chelating drugs. Bailliere's Clin Haematol 2, 257–292.
Porter JB, Morgan J, Hoyes KP, Burke LC, Huehns ER, Hider RC. 1990 Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice. Blood 11, 2389–2396.
Siegenberg D, Baynes RD, Bothwell TH, Macfarlane BJ, Lamparelli RD. 1990 Factors involved in the regulation of iron transport through reticuloendothelial cells. Proc Soc Exp Biol Med 193, 65–72.
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Carthew, P., Smith, A.G., Hider, R.C. et al. Potentiation of iron accumulation in cardiac myocytes during the treatment of iron overload in gerbils with the hydroxypyridinone iron chelator CP94. Biometals 7, 267–271 (1994). https://doi.org/10.1007/BF00144120
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DOI: https://doi.org/10.1007/BF00144120