Transport, Storage, and Toxicity of Iron

Under physiological conditions, i.e., in neutral aqueous solution with a. significant p02, ferric ion (Fe ) is the predominant species and ferrous ion (Fe ) can only exist if protected from oxidation by specific coordination (Schneider 1988). Transient, enzymatic reduction of Fe serves as a control point for the exchange of iron, for example in the mobilization of iron from ferritin stores and transport across lipid membranes. This is important in that most chelators presently in use or under investigation display sped- 

The iron-cataiyzed generation of hydroxyl radicals accounts for much of the cytotoxicity of the element. The resultant lipid peroxidation causes damage to the plasma membrane and to intracellular membranes of the mitochondria and lysosomes (Hershko and Weatherall 1988). Free radicals have been implicated in iron-induced injury to many tissues, including lung (Adamson et al. 1993), kidney (Alfrey et al. 1989), endothelium (Brieland et al. 1992), and heart (Hershko et al. 1987 Link et al. 1993 Scott et al. 1985). Iron-catalyzed lipid peroxidation in cell culture systems and its sup- 

This chapter discusses circumstances under which the normal pathways for the safe handling of iron become saturated or otherwise circumvented, and describes strategies for iron chelation that then become necessary to prevent radical-mediated tissue damage. 

Chronic Iron Overload and Clinical Need for Iron Chelators 

The mechanism and regulation of intestinal iron absorption remains elusive. A recent intriguing proposal is that integrins on the luminal surface of gut epithelia mediate the safe delivery to a cytosolic acceptor, mobilferrin, with some sequence similarity to the calcium-binding protein calreticulin (Conrad and Umbreit 1993 Conrad et al. 1993). Hereditary hemochromatosis is an inherited disorder in which hyperabsorption leads to iron 

---