Antioxidant role of metallothioneins: a comparative overview

Metallothioneins (MTs) are sulfhydryl-rich proteins binding essential and non-essential heavy metals. MTs display in vitro oxyradical scavenging capacity, suggesting that they may specifically neutralize hydroxyl radicals. Yet, this is probably an oversimplified view, as MTs represent a superfamily of widely differentiated metalloproteins. MT antioxidant properties mainly derive from sulfhydryl nucleophilicity, but also from metal complexation. Binding of transition metals displaying Fenton reactivity (Fe,Cu) can reduce oxidative stress, whereas their release exacerbates it. In vertebrates, MT gene promoters contain metal (MRE) and glucocorticoid response elements (GRE), Sp and AP sequences, but also antioxidant response elements (ARE). MT neosynthesis is induced by heavy metals, cytokines, hormones, but also by different oxidants and prooxidants. Accordingly, MT overexpression increases the resistance of tissues and cells to oxidative stress. As for invertebrates, data from the mussel show that MT can actually protect against oxidative stress, but is poorly inducible by oxidants. In yeast, there is a Cu(I)-MT that in contrast to mammalCu-MT exhibits antioxidant activity, possibly due to differences in metal binding domains. Finally, as the relevance of redox processes in cell signaling is becoming more and more evident, a search for MT effects on redox signaling could represent a turning point in the understanding of the functional role of these protein.