The influence of metallothionein on exposure to metals: An in vitro study on cellular models

In the present study, the interactions between zinc (Zn) and copper (Cu) or iron (Fe) have been examined. Rat hepatoma cell line H4-II-E-C3, fibroblast cell line mutant MT−/−, and wild-type MT+/+ cells treated with ZnSO4 or CuSO4 or FeSO4 or CuSO4 + ZnSO4 or ZnSO4 + FeSO4 for different times have been employed to study the effect of metallothionein (MT), glutathione (GSH) and metal (Cu, Fe and Zn) accumulation during cellular adaptation to supraphysiological metal concentrations. To investigate the different biological functions in the processes of metal homeostasis and detoxification, the levels of both MT-1 and MT-2 mRNAs have been evaluated. The three cell lines responded differently to metal treatments suggesting that the uptake and storage of these metals are affected by the specific cellular model and MT presence. In particular, Zn treatment significantly decreased Fe accumulation (p < 0.05), whereas MT induced by Zn increased intracellular Cu content (p < 0.05). Moreover, in H4-II-E-C3 cells administration of metals resulted in a rapid and transient induction of MT (p < 0.05) and in GSH accumulation (p < 0.05) suggesting synergistic interactions in which both appear essential for a protective regulatory function against the redox activity of metals. Taken together these results demonstrate that Zn affects the cellular levels of Cu and Fe by competition with the same ligand sites and/or by coordinate regulation of MT and GSH content.