SUBCELLULAR-DISTRIBUTION OF DESFERRIOXAMINE AND HYDROXYPYRIDIN-4-ONE CHELATORS IN K562 CELLS AFFECTS CHELATION OF INTRACELLULAR IRON POOLS

The interactions of iron chelators with intracellular iron pools have been examined by measuring the subcellular distribution of radiolabell ed desferrioxamine (DFO) and the orally active hydroxypyridinone (HPO) chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94), as well as the ab ility of these chelators to modify the subcellular distribution of Fe- 59 delivered by the receptor mediated endocytosis of transferrin. K562 cells were pulsed with Fe-59 transferrin and challenged with DFO or C P94 (100 mum IBE) for 20 or 240 min and then subjected to subcellular fractionation. At 20 min there was a significant decrease (P < 0.05) i n both lysosomal/particulate Fe-59 (750% of control) and cytosolic Fe- 59 ferritin (50% of control) in cells incubated with CP94, unlike cell s treated with DFO where no decrease was observed. By 240 min. in addi tion to the above, Fe-59 accumulation was significantly decreased in t he nuclear, mitochondrial, and low molecular weight cytosolic fraction s with CP94 (P < 0.05). With DFO a significant decrease in Fe-59 in on ly the lysosomal/particulate and cytosolic ferritin compartments was o bserved at 240 min (P < 0.05). At this time, however, there was a sign ificant accumulation of both cytosolic low molecular weight Fe-59 and cytosolic DFO. The relatively rapid decrease of Fe-59 within intracell ular compartments seen with CP94 compared to DFO was paralleled by a s ignificantly higher accumulation of CP94 than DFO in nuclear, lysosoma l/particulate and low molecular weight cytosolic compartments at 20 mi n (P < 0.05). These results suggest that transferrin derived endosomal iron may be chelated by HPOs, unlike DFO. due to their faster uptake into these organelles. The more rapid access of HPOs than DFO to certa in intracellular iron pools may explain the greater possibility of HPO s to inhibit proliferation of cells in vivo.