Interference of aluminium with iron uptake: Investigation of mechanisms involved

PÉREZ, G; PREGI, NICOLÁS; VITTORI, D; GARBOSSA, G; NESSE, A

Congreso; Fifth Keele Meeting on Aluminium: "Aluminium in life: From acid rain to Alzheimer?s disease?; 2003

In preliminary studies using K562 cells, we have observed that the presence of aluminium compounds (Al) induces inhibition of the haemoglobin (Hb) synthesis. At the same time, we found similar values of the affinity constants (Kd) of surface transferrin receptors (TfR) for their ligand transferrin (Tf) carrying either Al or iron (Fe). This similar affinity could account for a competitive binding to TfR when both Al-Tf and Fe-Tf are simultaneously present in the culture medium, thus causing a decreased cellular Fe uptake. Taking into account that the cell might respond to low levels of intracellular Fe, the aim of the present work was to investigate whether Al could interfere with different mechanisms related to Fe homeostasis. The presence of Al prevented normal incorporation of 59Fe to cells, whereas the removal of the metal led to increase cellular 59Fe uptake, exceeding the amounts incorporated by the respective controls. These results let us suggest a mechanism of up-regulation of TfR expression to compensate the deficit of Fe. However, such increment in TfR1 sites could not be demonstrated by flow cytometry employing anti-CD71 antibody. Moreover, no significant variations in mRNA levels of both receptors, TfR1 and TfR2, could either be detected by RT-PCR. The explanation came when the incorporation of 59Fe developed in Tf-free medium, after the same conditions of Al treatment, was found increased. Undoubtedly, Al might interfere with alternate Fe transport pathways rather than with the classical Tf-dependent one. The precise mechanisms by which Al interfere with this pathway remains to be clarified, since the Tf-independent mechanisms of Fe uptake are not fully understood yet. The results of this work support the following suggestions: the decreased Fe uptake due to Al interference at membrane level might up-regulate the expression of proteins involved in Tf-independent Fe uptake mechanisms. Nevertheless, an effect of Al on the TfR affinity, without affecting its number, cannot be discarded.