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Analysis of Metabolites and Therapeutics for Toxic Inhaled Agent Exposure

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Analysis of Metabolites and Therapeutics for Toxic Inhaled Agent Exposure South Dakota State University Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange Electronic Theses and Dissertations 2021 Analysis of Metabolites and Therapeutics for Toxic Inhaled Agent Exposure Abigail Bemah Donkor South Dakota State University Follow this and additional works at: https://openprairie.sdstate.edu/etd Part of the Chemistry Commons, and the Pharmacology, Toxicology and Environmental Health Commons Recommended Citation Donkor, Abigail Bemah, "Analysis of Metabolites and Therapeutics for Toxic Inhaled Agent Exposure" (2021). Electronic Theses and Dissertations. 5645. https://openprairie.sdstate.edu/etd/5645 This Dissertation - Open Access is brought to you for free and open access by Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange. For more information, please contact [email protected]. ANALYSIS OF METABOLITES AND THERAPEUTICS FOR TOXIC INHALED AGENT EXPOSURE BY ABIGAIL BEMAH DONKOR A dissertation submitted in partial fulfillment of the requirements for the Doctor of Philosophy Major in Chemistry South Dakota State University 2021 ii DISSERTATION ACCEPTANCE PAGE Abigail Bemah Donkor This dissertation is approved as a creditable and independent investigation by a candidate for the Doctor of Philosophy degree and is acceptable for meeting the dissertation requirements for this degree. Acceptance of this does not imply that the conclusions reached by the candidate are necessarily the conclusions of the major department. Brian Logue Advisor Date Douglas Raynie Department Head Date Nicole Lounsbery, PhD Director, Graduate School Date iii This dissertation is dedicated to my father; John Yaw Donkor, my mother; Christiana Donkor, siblings (Celestina, Jeremiah, and John Junior) and my loving husband; Albert Aidoo. I am grateful for your encouragement and tremendous support during my PhD journey. This achievement would never have been possible without your unconditional support and prayers. iv ACKNOWLEDGEMENTS I am eternally thankful to God almighty for his loving kindness, provision, divine health, faithfulness, and mercies throughout this academic journey. He has been my strong anchor and my source of encouragement. When things were gloomy and I felt I could not continue, He was by my side. I would not have come this far if not for the Lord. I am forever grateful. I also express my sincere gratitude to my advisor, Dr. Brian Alexander Logue for his mentorship, training, and guidance throughout my journey at SDSU. You have been a great teacher and coach and I will not forget the many nuggets of life you taught me. I thank my advisory committee members, Dr. Raynie Douglas, Dr. Fathi Halaweish and Dr. Christopher Schmidt for their practical feedback, reviews, and overall guidance throughout my doctoral studies. I am also grateful to Dr. Nesta Bortey-Sam, Dr. Obed Gyamfi, Dr. Frederick Ochieng and LARGE group for making my stay at SDSU a memorable one and Dr. Amanda Appel for teaching me most of the instrumentation I know today. My sincere appreciation goes to the funding institutions and the Department of Chemistry and Biochemistry for supporting me during my stay here. I am very thankful to my church family; Holy Life Tabernacle, Brookings for their immense support and for being a home away from home during my stay in Brookings, South Dakota. GLORY BE TO GOD v TABLE OF CONTENTS ABBREVIATIONS ...................................................................................................................... viii LIST OF FIGURES ....................................................................................................................... xii LIST OF TABLES ......................................................................................................................... xiv ABSTRACT ................................................................................................................................... xv Chapter 1. Introduction .................................................................................................................... 1 1.1. Overall Significance .............................................................................................................. 1 1.2. Project Objectives ................................................................................................................. 1 1.3. Toxic Inhaled Agents ............................................................................................................ 2 1.4. Sulfur Mustard ...................................................................................................................... 3 1.4.1. Exposure to sulfur mustard ............................................................................................ 3 1.4.2. Toxicity of sulfur mustard.............................................................................................. 4 1.4.3. Mechanism of action of sulfur mustard ......................................................................... 5 1.4.4. Metabolism of sulfur mustard ........................................................................................ 6 1.4.5. Treatments and countermeasures for sulfur mustard poisoning..................................... 7 1.5. Methyl isocyanate ................................................................................................................. 9 1.5.1. Exposure to Methyl isocyanate ...................................................................................... 9 1.5.2. Metabolism of Methyl isocyanate ................................................................................ 10 1.5.3. Toxicity and Mechanism of Action of Methyl Isocyanate ........................................... 11 1.6. 2-Mercaptoethane Sulfonate Sodium as a therapeutic for MIC and Sulfur Mustard exposure. ................................................................................................................................................... 13 1.6.1. Uses of MESNA .......................................................................................................... 13 1.6.2. Mechanism of action of MESNA ................................................................................. 13 1.6.3. Metabolism and pharmacokinetics of MESNA ........................................................... 14 1.6.4. Toxicity of MESNA ..................................................................................................... 15 Chapter 2. Identification and Analysis of a Methyl Isocyanate-Adduct for Exposure Verification ....................................................................................................................................................... 16 2.1. Introduction ......................................................................................................................... 16 2.2. Materials and Methods ........................................................................................................ 20 2.2.1. Materials ...................................................................................................................... 20 2.2. Synthesis of PMC and PMC-D5 ...................................................................................... 21 2.2.2 Biological samples ........................................................................................................ 22 2.2.3 Sample preparation ....................................................................................................... 23 2.2.4 HPLC-MS/MS analysis of PMC .................................................................................... 24 vi 2.2.5 Calibration, quantification, and limit of detection........................................................ 27 2.2.6 Recovery and matrix effect ............................................................................................ 28 2.2.7 Stability ......................................................................................................................... 28 2.3 Results and Discussion ........................................................................................................ 29 2.3.1 Mechanism of MIC-tyrosine adduct formation ............................................................. 29 2.3.2 Phenyl methyl carbamate as a biomarker for MIC exposure. ...................................... 32 2.3.3 Detection of serine as a by-product of base hydrolysis of MIC-tyrosine adducts ........ 37 2.3.4 HPLC-MS/MS analysis of PMC .................................................................................... 38 2.3.5 Accuracy and precision ................................................................................................. 39 2.3.6 Matrix effect and recovery ............................................................................................ 41 2.3.7 Stability of PMC and MIC-tyrosine adduct .................................................................. 41 3.8 Analysis of PMC from MIC-exposed animals and its correlation with MIC dose ........... 42 2.4 Conclusion ............................................................................................................................... 43 2.5 Acknowledgements ..................................................................................................................
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