Effect of the iron chelator desferrioxamine on manganese-induced toxicity of rat pheochromocytoma (PC12) cells.

Alterations in iron levels are likely to influence the biological actions of Mn in PC12 cells, because both metals are transported via the divalent metal transporter 1 (DMT1; also Nramp2 or DCT1). Studies were performed to determine the effect of the iron chelator desferrioxamine (DfO) on Mn-induced PC12 cell death and neuronal differentiation. Cell death almost doubled when PC12 cells were exposed for 24 hr to both DfO (10 microM) and Mn (0.3 mM) as opposed to Mn alone. DfO also stimulated Mn-induced neuronal differentiation by enhancing the phosphorylation of both ERK1 and 2 and also attenuated the increase in caspase 3-like activity induced by 0.3 mM Mn by approximately 50%, indicating that caspase activation, as reported previously, does not contribute to Mn-induced PC12 cell death. DfO also affected Mn-induced suppression of mitochondrial function as indicated by an additional 16% loss of ATP formation in PC12 cells cotreated with 0.3 mM Mn. Because sequestration of iron by DfO would be expected to lead to increased transport of Mn, studies were performed to determine whether iron inhibited Mn transport in PC12 cells. Iron inhibited 54Mn transport with an IC50 of approximately 20 microM. In addition, coincubation of DfO with Mn in PC12 cells resulted in increased expression of both the iron response element-positive and the iron response element-negative forms of DMT1. Taken together, these results demonstrate that iron status is likely to have a direct effect on the uptake and biological actions of Mn and probably other divalent metals that are transported by DMT1.