Transferrin: physiology and function in iron transport

Since its identification about 30 years ago transferrin has attracted the interest of many investigators concerned with its structure, metal-binding properties, genetic polymorphism, and especially its role in the transport of iron within the body. Transferrin's two iron-binding sites appear to be structurally identical with equivalent iron binding after addition of iron in vitro. However, since the experiments of Fletcher and Huehns, the functional homogeneity of transferrin-bound iron has been questioned. Understanding of the precise mechanism of iron release from transferrin to receptor sites on reticulocytes and other tissues active in iron exchange is incomplete. Considerable evidence has been assembled from rats to support the Fletcher-Huehns hypothesis of selective release of A-site iron to erythrocyte precursors and placenta while B-site iron is delivered to hepatocytes. Results of experiments in rabbit and human systems remain controversial. Reasons for this controversy include: variations in the technique of iron addition to transferrin with the possibility of non-specific binding; variations in reticulocytes used in preparing selectively labelled transferrin and in its biological assay; and artifacts introduced in mixed-species experiments. Until methods are more refined and the transferrin-iron receptor interaction is better understood, the controversy about transferrins's iron transport function will persist.