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Covalent Protein Adduction by Drugs of Abuse Kevin Schneider Florida International University, [email protected]

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Covalent Protein Adduction by Drugs of Abuse Kevin Schneider Florida International University, Kevinjschneider@Gmail.Com Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 2-27-2013 Covalent Protein Adduction by Drugs of Abuse Kevin Schneider Florida International University, [email protected] DOI: 10.25148/etd.FI13040402 Follow this and additional works at: https://digitalcommons.fiu.edu/etd Recommended Citation Schneider, Kevin, "Covalent Protein Adduction by Drugs of Abuse" (2013). FIU Electronic Theses and Dissertations. 816. https://digitalcommons.fiu.edu/etd/816 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida COVALENT PROTEIN ADDUCTION BY DRUGS OF ABUSE A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in CHEMISTRY by Kevin J. Schneider 2013 To: Dean Kenneth G. Furton College of Arts and Sciences This dissertation, written by Kevin J. Schneider, and entitled Covalent Protein Adduction by Drugs of Abuse, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this dissertation and recommend that it be approved. ______________________________________________ Kenneth Furton ______________________________________________ Bruce McCord ______________________________________________ Alexander Mebel ______________________________________________ Berrin Serdar ______________________________________________ Anthony DeCaprio, Major Professor Date of Defense: February 27, 2013 The dissertation of Kevin J. Schneider is approved. ______________________________________________ Dean Kenneth G. Furton College of Arts and Sciences ______________________________________________ Dean Lakshmi N. Reddi University Graduate School Florida International University, 2013 ii © Copyright 2013 by Kevin J. Schneider All rights reserved. iii ABSTRACT OF THE DISSERTATION COVALENT PROTEIN ADDUCTION BY DRUGS OF ABUSE by Kevin J. Schneider Florida International University, 2013 Miami, Florida Professor Anthony DeCaprio, Major Professor Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs. This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating iv in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine. v TABLE OF CONTENTS CHAPTER .............................................................................................................................................. PAGE 1. INTRODUCTION ..................................................................................................................................... 1 2. LITERATURE REVIEW .......................................................................................................................... 2 2.1. Xenobiotic Biotransformation ............................................................................................................ 2 2.2. Cytochrome P450 Isozymes ............................................................................................................... 8 2.3. Drug of Abuse Metabolism: Cocaine, Methamphetamine, and Morphine ....................................... 10 2.4. In Vitro Metabolic Assays ................................................................................................................ 13 2.5. Biomarkers of Exposure, Protein Adduction, and Adduction Mechanisms ...................................... 16 2.6. Protein Adduction by Drugs of Abuse .............................................................................................. 23 2.7. Research Objectives .......................................................................................................................... 27 3. METHODOLOGY .................................................................................................................................. 29 3.1. Instrumentation ................................................................................................................................. 29 3.2. Synthesis of Monohydroxylated Cocaine Metabolite Isomers ......................................................... 29 3.3. Comprehensive Drug Metabolite Analysis ....................................................................................... 30 3.4. Metabolic Assays .............................................................................................................................. 31 3.5. Cytochrome P450 Isoform Metabolic Assays for Reaction Phenotyping ......................................... 33 3.6. Reactive Metabolite Trapping and Protein Adduction Model Systems ............................................ 36 3.7. Protein Adduct rhCYP Isoform Assays ............................................................................................ 39 3.8. Quantum Mechanical Calculations for Reactivity and Adduction Potential ..................................... 39 4. RESULTS AND DISCUSSION .............................................................................................................. 41 4.1. Cocaine Metabolite Synthesis and Analytical Characterization ....................................................... 41 4.2. Metabolic Assays .............................................................................................................................. 48 4.2.1. Cocaine .................................................................................................................................... 50 4.2.2. Methamphetamine ................................................................................................................... 57 4.2.3. Morphine .................................................................................................................................. 62 4.2.4. Discussion of Drug of Abuse In Vitro Metabolism Results ..................................................... 64 4.2.4.1. Cocaine Metabolism Discussion ....................................................................................... 65 4.2.4.2. Methamphetamine Metabolism Discussion ...................................................................... 68 4.2.4.3. Morphine Metabolism Discussion .................................................................................... 70 4.3. rhCYP Assays ................................................................................................................................... 71 4.3.1. Positive Control Probes............................................................................................................ 71 4.3.2. Cocaine .................................................................................................................................... 73 4.3.3. Methamphetamine ................................................................................................................... 75 4.3.4. Morphine .................................................................................................................................. 77 4.3.5. Discussion of Results from Drug of Abuse rhCYP Reaction Phenotyping ............................. 78 4.4. Reactive Metabolite Trapping and Protein Adduction Model Systems ............................................ 81 4.4.1. Cocaine Adduction Products .................................................................................................... 83 4.4.1.1. Cocaine‒ N-Acetylcysteine Adduction ............................................................................
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