Reactions of the Zn Proteome with Cd²⁺ and Other Xenobiotics: Trafficking and Toxicity

Understanding the molecular basis of inorganic chemical toxicity has lagged behind the proliferation of detailed mechanisms that explain the biochemical toxicology of many organic xenobiotics. In this perspective, general barriers to explicating the bioinorganic chemistry of toxic metals are considered, followed by a detailed examination of these issues in relation to the toxicology of Cd 2+ . The hypothesis is evaluated that Cd 2+ damages cells by replacing Zn 2+ in key Zn proteins. An emerging methodology to assess the speciation of metals among cell proteins is described. Then, a more general hypothesis is suggested, namely, that the Zn proteome is also the toxicological target of other metals such as Pb 2+ as well as NO and reactive oxygen species. The latter may damage cells by altering the structure and function of Zn 2+ binding sites that include thiol ligands. In the process, labilized Zn 2+ may also perturb cell biochemistry. Lastly, reactions of metal chelating ligands with the Zn proteome, including formation of ligand–Zn protein adducts, provide other potential avenues of biochemical toxicity.