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.
Li
L
L
Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132, USA.
Kaplan
J
J
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D015913:Chelation Therapy; D004591:Electrophoresis, Polyacrylamide Gel; D006207:Half-Life; D006801:Humans; D007457:Iodine Radioisotopes; D007501:Iron / Q000378:metabolism*; D007504:Iron Radioisotopes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000378:metabolism; D013820:Thermolysin / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution; D014168:Transferrin / Q000187:drug effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D007457:Iodine Radioisotopes; D007504:Iron Radioisotopes; D014168:Transferrin; D007501:Iron; D013820:Thermolysin