Cellular pharmacology of deferrioxamine B and derivatives in cultured rat hepatocytes in relation to iron mobilization.
Two radiolabelled derivatives of deferrioxamine B (DF) have been synthesized: methyl-DF and acetyl-DF. Both derivatives are non cytotoxic and stable in cell culture but they are degraded in human plasma and more extensively in rat plasma. Methyl-DF, acetyl-DF and DF mobilize radioiron to the same extent from hepatocytes loaded with 59Fe citrate in the same range of extracellular concentrations. The uptake and release of the 3H-labelled derivatives and their corresponding iron complexes have been measured and appear to represent a passive phenomenon resulting from the gradient of concentration between the cellular compartment and the extracellular medium. The results indicate that only a limited pool of cellular iron is accessible for chelation and that neither the permeability of the cellular membrane, nor the intracellular concentration of the chelators are the limiting factors for iron mobilization. On the basis of the subcellular distribution of the 3H-DF analogues, methylamine inhibition of iron chelation by siderophores in cell cultures and the positive effect of acidic pH and hydrolysis by lysosomal enzymes on in vitro iron mobilization from radiolabelled ferritin, we suggest that iron mobilization by DF and its derivatives occurs in lysosomes where they complex iron released from ferritin under the conjugate actions of acidic pH and lysosomal enzymes.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004355:Drug Stability; D005293:Ferritins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism; D007504:Iron Radioisotopes; D007553:Isotope Labeling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008744:Methylamines / Q000494:pharmacology; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D014316:Tritium
D002614:Chelating Agents; D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D008744:Methylamines; C045136:N-acetyldeferrioxamine B; D014316:Tritium; D005293:Ferritins; C045135:N-methyldeferrioxamine B; C027451:methylamine; D007501:Iron; D003676:Deferoxamine