Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches

During the past 6 decades, much attention has been devoted to understanding the uses, metabolism and hazards of iron in living systems. A great variety of heme and non-heme iron-containing enzymes have been characterized in nearly all forms of life. The existence of both ferrous and ferric ions in low- and high-spin configuration, as well as the ability of the metal to function over a wide range of redox potentials, contributes to its unique versatility. Not surprisingly, the singular attributes of iron that permit it to be so useful to life likewise render the metal dangerous to manipulate and to sequester. All vertebrate animals are prone to tissue damage from exposure to excess iron. In order to protect them from this threat, a complex system has evolved to contain and detoxify this metal. This is known as the iron withholding defense system, which mainly serves to scavenge toxic quantities of iron and also for depriving microbial and neoplastic invaders of iron essential for their growth. Since 1970, medical scientists have become increasingly aware of the problems involved in cellular iron homeostasis and of the disease states related to its malfunctioning. Scores of studies have reported that excessive iron in specific tissue sites is associated with development of infection, neoplasia, cardiomyopathy, arthropathy and a variety of endocrine and neurologic deficits. Accordingly, several research groups have attempted to develop chemical agents that might prevent and even eliminate deposits of excess iron. A few of these drugs now are in clinical use, e.g. deferiprone (L1). In the present review, we focus on recent developments in (i) selected aspects of the iron withholding defense system, and (ii) pharmacologic methods that can assist the iron-burdened patient.