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Figure 4: Unraveling the metabolism of metal species is a prerequisite to gain deeper insight into the molecular basis of their adverse health effects in mammalian organisms. Toxicologically relevant interactions between metal species and endogenous ligands unfold in blood plasma, erythrocytes and hepatocytes and can be investigated by applying “bottom-up” or “top-down” techniques. Interactions between toxic metals (Hg2+, AsIII, SeIV, CH3Hg+) and small molecular weight ligands (GSH, Cys, NAC) that unfold within erythrocytes and/or hepatocyte cytosol and have been studied with “bottom up” LC approaches (Figure 3). Interactions between metal species (Cd2+, cisPt) and cytosolic and plasma proteins have been studied using “top-down” LC-based approaches. (a) Detection of Cd-metallothionein complexes in liver cytosol [110]. (b) Displacement of Zn2+ from a plasma metalloprotein by Cd2+ [26]. (c) Binding of Cd2+ to plasma proteins [26, 36, 111]. (d) Abstraction of Cd2+ from plasma proteins by chelating agents (CA) [36]. (e) Comparative binding of cis-platin/carboplatin to plasma proteins [53]. (f) Modulation of the interaction between cis-platin and plasma proteins by sodium thiosulfate (STS) [37]. Note that the combined application of “bottom-up” and “top-down” approaches will be required to better understand the interplay between metal species, small molecular weight ligands and proteins to ultimately unravel their adverse health effects and to develop better mitigation strategies by modulating their metabolism by the administration of chelating agents/ameliorating agents.