Iron-overload diseases

Siderophores like desferrioxamine may, therefore, find increasing applications not only in the treatment of iron poisoning and iron-overloaded disease states but also as chemotherapeutic agents, although the possible problems noted above cannot be ignored. 

Siderophores are iron-complexing compounds of low molecular weight that are synthesized by bacteria and fungi, and serve to deliver iron to the microbes. Because of their exclusive affinity and specificity for Fe3+, natural siderophores and synthetic derivatives have been exploited in the treatment of human iron-overload diseases. The most successfully used example is Desferal , which is the methane sulfonate derivative of iron-free ferrioxamine B, a linear trihydroxamate (Figure 3.2). Ferrioxamine was isolated in 1958 from the culture supernatant of Streptomyces... 

Adaptive Response of Iron Absorption in Iron-overload Diseases... 

Ponka et al. [372] showed that pyridoxal isonicotinoyl hydrazone (PIH, Figure 19.23) is an iron chelating agent. Numerous studies showed the possibility of using this chelator for the treatment of iron overload disease [373], In subsequent studies the antioxidant activity of PIN has been confirmed. For example, Hermes-Lima et al. [374,375] showed that PIN protected plasmid pUC-18 DNA and 2-deoxyribose against hydroxyl radical damage. 

Desferrioxamine (108) is the only clinically approved iron chelator. As well as being used for the treatment of iron overload diseases it is... 

Metabolic disorders such as Wilson s disease (copper storage disease) and haemochro-matosis (iron overload disease),... 

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

Desferrioxamine (DFO-B), the natural siderophore initially isolated from Streptomyces pilosus, is the only iron chelator currently used for clinical treatment of iron-overload disease such as thalassemia, sickle cell anemia and hemochromatosis ° . ... 

Due to their capacity to specifically chelate ferric iron, siderophores have been used for chelation therapy to treat iron overload diseases . ... 

Mann, S. Wade.V.J. Dickson, D.P.E. Reid, N.M.K. Ward, R.J. O Connell, M. Peters, T.J. (1988) Structural specificity of haemosi-derin iron cores in iron-overload diseases. FEES Lett. 234 69-72 Mann, S. Webb, J. Williams, R.J.P. (eds.) (1989 a) Biomineralization Chemical and biochemical perspectives. VCH Weinheim, 541 p. 

Hemochromatosis A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the hver. Also called iron overload disease. [NIH]... 

D. R. Richardson and P. Ponka, Development of Iron Chelators to Treat Iron Overload Disease, Am. J. Hematol. 1998,58, 299. 

St. Pierre, T. G. Chan, R Bauchspiess, K. R. Webb, J. Betteridge, S. Walton, S. Dickson, D. P. E. Synthesis, structure and magnetic properties of ferritin cores with varying composition and degrees of structural order models for iron oxide deposits in iron-overload diseases. Coord. Chem. Rev. 1996, 151, 125-143. 

The bleomycin assay has been applied to assess the levels of available, nontransferrin-bound iron in plasma samples in patients with iron overload disease (Peters et al., 1985), with acute leukaemia before and after drug chemotherapy (Halliwell et al., 1988), as well as patients with rheumatoid arthritis (Winyard et al., 1987). 

Powell, L.W. Hereditary hemochromatosis and iron overload diseases. J. Gastroenterol. Hepatol. 2002 17 (Suppl.) 191 -195... 

Iron-overload disease, or hemochromatosis, may occur as a consequence of an, as yet, undefined genetic defect, or as a secondary effect of another medical disorder, such as thalassemia. In the former condition, primary hemochromatosis, iron accumulates in various tissues because of a lack of control of iron absorption from the gut. In the latter, or secondary hemochromatosis, the accumulation of iron results from the breakdown of red blood cells and the consequent need for frequent blood transfusions, which lead to an increase in the levels of tissue iron. In both cases the predominant store for iron is hemosiderin (147). 

As described in Section 3, iron can promote peroxidation of biological macromolecules due to its reactions with ROS and, thus, is of high toxic potential for cells, if it is not kept in a toxicologi-cally inactivated form bound to specific proteins. Only when iron is tightly bound to a chelator is its capacity for promoting LPO minimal. Amongst synthetic chelators of iron, fois-(2-aminoethyl)-amine-A, N,A, N -penta-acetic acid, desferrioxamine, o-phenanthroline and bathophenanthroline are able to complex Fe + and, thus, slow down reduction of Fe to Fe + by reductants like ascorbic acid or (O2) in vitro, but EDTA is ineffective. Desferrioxamine was originally developed for the treatment of iron overload disease because it binds Fe +... 

The way in which the iron core in ferritin might build up and the structure of the mineral and its properties have been considered by many researchers over the years and yet there are still many questions that remain to be answered satisfactorily. From one viewpoint the subject belongs in the area of biomineralization, from a different standpoint the nanoscale properties have been of interest, and a third important area of research concerns the health aspects of iron storage and homeostasis. For this latter field the problems of too much or too little are to the fore, with iron overload disease a serious problem in much of Africa and the Middle East while in the Western world iron deficiency is more likely to be a problem. A key aspect to such health problems concerns the response of the organism to local iron levels and is regulated in healthy subjects by an iron response element (IRE) which also seems to involve metalloproteins within the so-called iron response protein. However, this has but little bearing on coordination chemistry aspects of ferritins that we are considering here whereas the chemical questions behind the mineralization processes and the measurement and interpretation of the physical properties of such nanoscale particles are of intense interest. It turns out to be helpful to consider these two aspects in tandem, as one tends to inform the other. 

There is a downside to this abundance of iron in the general food supply. Well over a million Americans suffer from an inherited genetic disorder called hemochromatosis, or iron overload disease. Such individuals accumulate excess iron in their bodies. The excess iron causes damage to major organs such as the liver, pancreas, and heart. The disease most often affects men between the ages of 30 and 50. Women with the disorder are often protected from developing all the complications of the disease because of their natural loss of iron through menstruation. However, they do develop some of the complications. 

Fellman V, Rapola J, Pihko H, Varilo T and Raivio KO (1998) Iron overload disease in infants involving fetal growth retardation, lactic acidosis, liver hemosiderosis and aminoaciduria. Lancet 351, 490-493. 

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