Heterogeneity of the plasma iron pool: explanation of the Fletcher-Huehns phenomenon.

Observations on iron uptake by reticulocytes led Fletcher and Huehns to suggest differences in the behavior of the two iron-binding sites of the transferrin molecule. To clarify the continued controversy relating to this hypothesis, the original studies employing control plasma labeled with radioiron and the same plasma preincubated with reticulocytes were reexamined. Regardless of whether human or rabbit plasma was employed, there was a considerably higher uptake from the control plasma. Isoelectric focusing procedures and electrophoresis in urea gels revealed that the conspicuous difference in the amount of iron uptake is the result of differences in the proportion of di- to monoferric transferrin in the two plasmas and the competitive advantage of the diferric moiety. These studies provide an explanation for the Fletcher-Huehns phenomenon without invoking functional differences between the two sites for iron on the transferrin molecule.