Application of Metallomics Techniques to Probe the Biotransformation of Toxic Metals in the Bloodstream-Organ System
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2024-09-17
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Abstract
Anthropogenic activities contribute significantly to the emission of toxic metal(loid) species (TMS) into the environment, thus exposing human populations, including children, to these pollutants via diet, drinking water and consumer products. Therefore, the influx of TMS into the bloodstream and their biochemistry are directly implicated in their chronic toxicity, presenting a new bioinorganic chemistry frontier. This thesis presents results obtained by applying metallomics methods to analyze biological fluids for TMS and metalloentities to unravel new aspects of their bioinorganic chemistry which are implicated in the etiology of environmental diseases. To this end size exclusion chromatography coupled with an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES) was used for the qualitative identification of major metalloproteins in (red blood cell) RBC cytosol, including hemoglobin, carbonic anhydrase I, and Cu, Zn superoxide dismutase, making this method useful for studying the role of these proteins in essential element dyshomeostasis following chronic exposure to TMS. In addition, intracellular biochemical processes between mercuric mercury (Hg2+) and methylmercury (MeHg+) with small molecular weight thiols were investigated at near physiological conditions. Using reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with ICP-AES and electrospray ionization mass spectrometry (ESI-MS), competitive interactions between Hg2+ and MeHg+, N-acetyl-L-cysteine (NAC), and glutathione (GSH) were examined. In the presence of equimolar concentrations of GAH and NAC, Hg2+ formed Hg(GS)(NAC) and Hg(NAC)2, while MeHg+ formed MeHg(GS) and MeHg(NAC) on the column, which suggests that NAC can modulate the metabolism of these mercurials within mammalian cells, offering insights into their potential mobilization from tissues. Metallomics tools were also employed to examine interactions between carbonic anhydrase I (CA I) released from ruptured RBCs with human blood plasma. Observing all endogenous Cu, Fe, and Zn-metalloproteins before and after adding CA I to plasma demonstrated that CA I does not bind to plasma proteins in vitro, suggesting that it could actively participate in adverse processes at the bloodstream-endothelial interface. Last but not least, I discuss in a perspective article that a deeper understanding of the bioinorganic chemistry of the bloodstream is essential for comprehending both the adverse effects of TMS on human health and the toxic side effects of metal-based anticancer drugs. The article highlights the critical role of metallomics tools in elucidating the underlying mechanisms.
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Doroudian, M. (2024). Application of metallomics techniques to probe the biotransformation of toxic metals in the bloodstream-organ system (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.