Employing a Metallomics Tool to Probe Bioinorganic Processes in the Bloodstream
Date
2020-04-27
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Abstract
In this thesis, I have applied a metallomics method that is based on size exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES) to analyze biological fluids to gain insight into the bioinorganic chemistry of metals and their possible link to disease processes. The first study involved the qualitative identification of an iron-containing protein in blood plasma. One of the two major iron-containing proteins in human plasma was identified as a haptoglobin-hemoglobin (Hp-Hb) complex that is formed in plasma after red blood cells rupture. Previously identified plasma metalloproteins - transferrin, ceruloplasmin and α2-macroglobulin were also unequivocally confirmed. Since the employed metallomics method can measure the concentration of these metalloproteins in plasma, the results are important as the quantification of the Hp-Hb complex in plasma gave better insight into the lysis of red blood cells, which is of immediate health relevance. In the second study, the metallomics method was applied to investigate the potential of using plasma metalloproteins as disease biomarkers. Blood serum samples from multiple sclerosis patients (21), stroke patients (17) and healthy controls (21) were analyzed for copper, iron and zinc metalloproteins. The results revealed that the concentration of the Hp-Hb complex in serum was statistically significantly higher in stroke patients compared to the other groups, which can be rationalized by the rupturing of red blood cells during a stroke event. Since 330,000 people in Canada live with long term disability effects of stroke, my results demonstrate the usefulness of the developed analytical method to diagnose diseases. The third study involved the application of the metallomics method to gain insight into the plasma transport of an arsenic-selenium compound, [(GS)2AsSe]-, that is formed in red blood cells and is excreted in bile. The analysis of [(GS)2AsSe]- added to human plasma demonstrated that [(GS)2AsSe]- mobilized Zn from plasma proteins in a dose-dependent manner. The formation of [(GS)2AsSe]- in red blood cells and its release into plasma may perturb the metabolism of zinc therein and result in systemic toxic effects. These results are relevant because the mobilization of zinc is potentially implicated in the chronic exposure of human to AsIII, which currently affects >100 million people. Lastly, the metallomics method was employed to gain insight into the stability of a bimetallic complex that has anti-cancer activity in human blood plasma. The fact that ~70 % of Titanocref remains intact in plasma after 60 min implies that this anti-cancer drug is likely to reach cancer cells in vivo. These results exemplify that conceptually-straightforward in vitro studies can provide important insight into the degradation of a bimetallic anti-cancer drug in plasma. Metallomics studies are therefore destined to play an important role in the context of advancing more metal-based drugs to preclinical studies.
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Keywords
Alpha-2-macroglobulin, Anti-cancer drug, arsenic-selenium complex, Arsenic, Blood plasma, Bioinorganic chemistry of metals, Biological fluid, Biomarker, Blood serum, Ceruloplasmin, Copper, Disease, Ferritin, Gold, Haptoglobin-Hemoglobin, Inductively coupled plasma atomic emission spectrometer, Iron, Multiple Sclerosis, Mass spectrometer, Metallomics, Metalloproteins, NMR, Stroke, Size exclusion chromatography, Selenium, Titanium, Titanocref, Transferrin, X-ray absorption, Zinc
Citation
Sarpong-Kumankomah, S. (2020). Employing a Metallomics Tool to Probe Bioinorganic Processes in the Bloodstream (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.