Alteration in the organ distribution of iron by truncated transferrin: implications for iron chelation therapy

The ability of the partial molecule of transferrin, truncated transferrin (t-Tf), to act as an excretable biologic iron chelator was examined. We confirmed the observations of Zak and Aisen (Zak O, Aisen P. Biochem Biophys Acta 1985;1952:24-8) that thermolysin treatment of human transferrin produces half molecules that retain iron-binding capacity. These molecules are poorly recognized by surface receptors on either human or murine cells. Although the plasma half-life of human transferrin in mice is moderately long (40 hours), injection of t-Tf into mice results in its rapid clearance (half-life = 10 minutes). Injection of iron 59-labeled transferrin results in the deposition of iron in the major hematopoetic organs of mice such as the spleen, bone marrow, and liver. Injection of 59Fe-labeled t-Tf results in the quantitative recovery of iron in the kidneys: 59Fe is retained in the kidney for substantial periods of time with little evidence of its excretion into urine. Injection of iodine 125-labeled t-Tf also results in the deposition of radioactivity in the kidneys, but 125I is rapidly excreted into the urine, where it is detected as free iodine. These results indicate that although t-Tf is directed to the kidney and filtered by the glomerulus, the molecule is reabsorbed and degraded, and iron is retained. These results have implications in the design of iron chelators.