Biological Considerations for Iron Removal

The molecular pattern of iron deposition in tissues determines its accessibility to chelation, and depends upon the source of iron. Excessive intestinal absorption increases circulating levels of diferric transferrin, which deposits iron in hepatocytes and the parenchymal cells of other organs. Deposition in the reticuloendothelial system (RES) occurs only in advanced disease. On the other hand, transfused red cells are turned over in the RES and iron accumulates initially in the bone marrow, spleen, and Kupffer cells of the liver. In patients with aplastic anemia, loading is purely transfusional. However, in thalassemics with ineffective erythropoiesis there is a compensatory increase in intestinal iron absorption, and iron overload can occur even in the absence of transfusion (Ellis et al. 1954 Olivieri et al. 1992b). Therefore, even initial iron deposition in transfused thalassemics affects both RES and parenchymal cells, for example both the Kupffer cells and hepatocytes of the liver. 

Ferritin synthesis is stimulated by available iron. In the absence of Fe , the apo- form of an iron-binding protein binds to ferritin mRNA and blocks its translation (Caughman et al. 1988 Dix et al. 1992 Leibold and Guo 1992). However, with excessive iron the maximal rate of translation 

Recent Mossbauer studies by Shiloh et al. (1992) have provided new insight into the time course of iron deposition at the supramolecular, sub-cellular level. When cultured myocardial cells were loaded with iron it 

The principle of optimal hydrophobicity is illustrated by comparing the octanol water partition coefficients of a series of N-substituted 2-methyl-3-hydroxypyrid-4-ones with their ability to remove iron from hepatocyte cultures (Porter et al. 1988 Porter et al. 1986). Maximal removal of iron from the cells was achieved with derivatives having ATpan values between 0.5 and 1.5 for both the free form and the Fe(III) chelate. Less lipophilic compounds do not enter the cell as readily. Too great a degree of lipo-philicity may caues the chelator to partition into the membrane and not access cytosolic iron pools. Molecular size is also an important feature determining the efficacy of iron chelators. Levin has studied the effects of size and lipophilicity on permeability of the blood-brain barrier, assuming a model of diffusion from bulk aqueous phase to a lipid phase (Levin 1980). Permeability was proportional to P to about 400 daltons. At 

While chemical principles can be used to design chelators that form stable and specific Fe chelates, uncertainty about the nature and location of the chelatable iron pool and constraints on delivery of suitable chelators to the site of action have determined that iron chelator design is still dominated by empirical testing of structure-function relationships. This in itself adds a new challenge in that there is no perfect animal model for the human iron overload syndromes. Pitt (1981) has pointed out that rodents Fe-loaded with heat-damaged erythrocytes have been used most frequently to assess the ability of chelators to remove iron by the fecal (biliary) and urinary routes and lower parenchymal (liver) and RES (splenic) stores. He reviews LD50 and iron-removal data on many natural and synthetic hydroxa-mates, phenols, catechols, tropolones, salicylates, benzoates, azines, and carboxylates. No clear picture emerges and the search for the ideal iron chelator continues. 

---