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Chelation of transferrin iron by desferrioxamine in K562 cells. The partition of iron between ferrioxamine and ferritin.

ABSTRACT: In this study we have determined whether desferrioxamine can chelate iron delivered to human leukaemic cells by the transferrin endocytic cycle. The cellular uptake of desferrioxamine was investigated by an indirect method in which the conversion of repeated pulses of [59Fe]transferrin to [59Fe]ferrioxamine was determined at two concentrations of the drug. Maximum generation of [59Fe]ferrioxamine occurred in cells exposed to either 100 microM- or 500 microM-desferrioxamine after 40-60 min. Thereafter (up to 180 min) [59Fe]ferrioxamine levels remained steady with 20% of a 59Fe pulse partitioning to chelator at 100 microM and 50% at 500 microM. Of the cellular [59Fe]ferrioxamine loss 50% occurred within 90-120 min. In cells preloaded with desferrioxamine for 1 or 4 h the partitioning of iron during a 3 h incubation with [59Fe]transferrin was dependent upon the extracellular concentration of the chelator. Above 1 mM more than 80% of entering iron was converted to ferrioxamine and less than 5% partitioned to ferritin. Below this concentration (50-500 microM) a proportion of the iron became ferritin associated (7-41%). There was a linear increase in the total amount of intracellular [59Fe]ferrioxamine in accordance with cellular iron uptake showing that transferrin continued to cycle in the presence of high concentrations of desferrioxamine. The uptake of iron and generation of ferrioxamine were markedly reduced by 5 mM-methylamine, which prevented endosome acidification and uncoupling of iron from endocytosed transferrin.

SUBMITTER: Roberts S

PROVIDER: S-EPMC1135163 | biostudies-other | 1988 Sep

REPOSITORIES: biostudies-other

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Project description:Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone.Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year.Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months.The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number NCT00350662.

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Chelation of transferrin iron by desferrioxamine in K562 cells. The partition of iron between ferrioxamine and ferritin.

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