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Salsolinol-Like Compounds As Biomarkers of Human Alcohol Consumption, Disease and Toxicity

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Salsolinol-Like Compounds As Biomarkers of Human Alcohol Consumption, Disease and Toxicity Salsolinol-like compounds as biomarkers of human alcohol consumption, disease and toxicity ______________________________________________________________________________ Thesis Presented by Sean Edward Kocur to The Bouvè Graduate School of Health Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Pharmaceutical Sciences with an Interdisciplinary Specialization NORTHEASTERN UNIVERSITY BOSTON, MASSACHUSETTS December, 2016 ii Signature page 1 (Signed by Dean and Library) Northeastern University Bouve Graduate School of Health Sciences Thesis title: Salsolinol-like compounds as biomarkers of human alcohol consumption, disease and toxicity Author: Sean Edward Kocur Program: Pharmaceutical Science with an Interdisciplinary Specialization Approval for thesis requirements of the Doctor of Philosophy in Pharmaceutical Science Thesis Committee (Chairman) _____________________________ Date:__________ _____________________________ Date:__________ _____________________________ Date:__________ _____________________________ Date:__________ _____________________________ Date:__________ _____________________________ Date:__________ Director of the Graduate School _____________________________ Date:__________ Dean _____________________________ Date:__________ Copy Deposited in Library Date: _____________________________ Date:__________ iii Signature page 2 (Not Signed by Dean and Library) Northeastern University Bouve Graduate School of Health Sciences Thesis title: Salsolinol-like compounds as biomarkers of human alcohol consumption, disease and toxicity Author: Sean Edward Kocur Program: Pharmaceutical Science with an Interdisciplinary Specialization Approval for thesis requirements of the Doctor of Philosophy in Pharmaceutical Science Chairman: _____________________________ Date:__________ Thesis Committee Member _____________________________ Date:__________ Thesis Committee Member _____________________________ Date:__________ Thesis Committee Member _____________________________ Date:__________ Thesis Committee Member _____________________________ Date:__________ Thesis Committee Member _____________________________ Date:__________ Director of the Graduate School _____________________________ Date:__________ iv Table of Contents Page # LIST OF TABLES …………………………………………...……………………….………. ..vii LIST OF FIGURES ……………………………………………..……………………….. ……viii LIST OF ABBREVIATIONS …………………………………………....………………….……x ABSTRACT ………………………………………………………………………………….…xii ACKNOWLEDGEMENTS …………………………………………….……………….............xv OBJECTIVE ……………………………………………………………….………………...…xvi SPECIFIC AIMS ……………………………………………...........................…………….…xvii CHAPTER 1. THE BIOLOGY OF ETHANOL CONSUMPTION AND ALCOHOLISM 1. Alcoholism and Alcohol Use Disorders……………………………………………………....1 1.1. History of ethanol use…………………………………………………………………….2 1.2. Epidemiology………………………………………………………………………..……4 1.3. Clinical Presentation……………………………………………………………….…..…7 1.4. Metabolism……………………………………………………………………...………10 1.5. Health Effects………………………………………………………………….…….….14 1.6. Treatments, Interactions, and Disulfiram……………………………………….………21 1.7. Significance of Study…………………………………………………………………....24 CHAPTER 2. METABOLIC DISORDERS AND DISEASES ASSOCIATED WITH ALCOHOL CONSUMPTION 2. Metabolic Disorders…………………………………………………………………………25 2.1. Introduction………………………………………………………………………….….26 2.2. Metabolic syndrome…………………………………………………………….………27 2.3. Glucose Metabolism………………………………………………………………...…..28 2.4. Lysosomal Storage Diseases…………………………………………………………….29 2.5. Alzheimer’s Disease…………………………………………………………………….30 v CHAPTER 3. EFFECTS OF TETRAHYDROISOQUINOLINES ASSOCIATED WITH ALCOHOL CONSUMPTION 3. Tetrahydroisoquinolines (TIQs)………………………………………………………….…..32 3.1. Introduction……………………………………………………………………………...33 3.2. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)……………………………..….33 3.3. Salsolinol…………………………………………………………………………..……35 3.4. Carboxysalsolinol……………………………………………………………………….38 3.4.1. 1-Carboxysalsolinol……………………………………………………………..39 3.4.2. 3-Carboxysalsolinol……………………………………………………………..41 3.5. N-Methyl-Salsolinol………………………………………………………………….....42 3.6. 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ)…..………………….42 CHAPTER 4. SIMULTANEOUS QUANTITATION OF CATECHOLAMINES AND SALSOLINOL-LIKE TETRAHYDROISOQUINOLINES BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY/MASS SPECTROMETRY 4. Quantitation Method 4.1. Introduction………………………………………………………………………...……46 4.2. Methods & Materials……………………………………………………………………46 4.3. Results…………………………………………………………………………………...58 4.4. Conclusions……………………………………………………………………………...60 CHAPTER 5. DETERMINATION OF ENDOGENOUS LEVELS OF SALSOLINOL-LIKE TETRAHYDROISOQUINOLINES IN MOUSE BRAINS 5. Endogenous Level 5.1. Introduction………………………………………………………………………...……62 5.2. Results………………………………………………………………………………..….65 5.3. Conclusions……………………………………………………………………………...67 CHAPTER 6. REGIONAL DISTRIBUTION OF 3-CARBOXYSALSOLINOL IN MOUSE BRAINS FOLLOWING IV INJECTION 6. Distribution with IV dosing 6.1. Introduction………………………………………………………………………..…….69 6.2. Results………………………………………………………………………………..….71 6.3. Conclusions…………………………………………………………………………..….72 vi CHAPTER 7. REGIONAL DISTRIBUTION OF 3-CARBOXYSALSOLINOL & 6-METHOXY-3- CARBOXYSALSOLINOL FOLLOWING IV DOSING OF 3-CARBOXYSALSOLINOL IN MOUSE BRAINS AT TIME POINTS 1,6, AND 10 MINUTES 7. Ethanol and L-DOPA 7.1. Introduction……………………………………………………………………………...73 7.2. Results………………………………………………………………………………..….76 7.3. Conclusions…………………………………………………………………………...…79 CHAPTER 8. EVALUATION OF THE EFFECTS OF COMT, MAO, AND AADC INHIBITORS ON THE FORMATION OF CATECHOLAMINES, METABOLITES AND SALSOLINOL-LIKE TETRAHYDROISOQUINOLINES 8. MAO & COMT Inhibitors 8.1. Introduction………………………………………………………………………….…..81 8.2. Results………………………………………………………………………………..….85 8.3. Conclusions……………………………………………………………………..……….88 CHAPTER 9. EVALUATION OF THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL ADMINISTRATION ON CATECHOLAMINE AND SALSOLINOL-LIKE TETRAHYDROISOQUINOLINES LEVELS IN THE MOUSE BRAIN 9. Acute & Chronic Alcohol 9.1. Introduction……………………………………………………………………….....….90 9.2. Results……………………………………………………………………………….….93 9.3. Conclusions……………………………………………………………………………..99 CHAPTER 10. CONCLUSIONS 10. Conclusions 10.1. Conclusions……………………………………………………………………..100 10.2. Future Considerations………………………………………………………..…102 REFERENCES . …………...……104 APPENDICES……………………………………………………………………………….…124 vii LIST OF TABLES 1. MRM parameters of catecholamines, tetrahydroisoquinolines, & metabolites…….57 2. Method validation data for CA’s and TIQs in mouse brain…………………………59 3. Enzymes, substrates, and inhibitors…………………………………………………...83 viii LIST OF FIGURES 1. Global incidence rates for alcohol……………………………………………………....5 2. Historical trends of ethanol consumption 1850-1997.……………………………..…..6 3. Ethanol as the most harmful drug in the world…………………………………..……7 4. Blood alcohol concentrations and associated effects…………………...........................8 5. Oxidative pathways for ethanol metabolism………………………………………….11 6. Genetic mutations that affect ethanol consumption……….…………………………13 7. Non-oxidative consequences of ethanol consumption………………………………...14 8. Ethanol allosteric binding site on the GABA receptor……………………………….16 9. Ethanol targets receptors, signaling systems, and neuromodulators………………..17 10. Possible long term effects of ethanol……………………………………………….….18 11. Lipid metabolism in diabetes mellitus………………………………………………...22 12. Common therapeutic classes with drug-alcohol interactions………………………..23 13. Bioenergetic homeostasis link between diabetes & neurodegeneration………….…26 14. MPTP like structures of tetrahydroisoquinolines…………………………………….35 15. Pathways for the formation of salsolinol and N-methylsalsolinol…………………...38 16. Formation of 1-carboxysalsolinol, 3-carboxysalsolinol and salsolinol……………....41 17. Salsolinol and 1-carboxysalsolinol in Alcoholics and Non-Alcoholics……………....41 18. Formation of ADTIQ from Dopamine and Methylglyoxal……………………..……44 19. Alternative Products of Glycolysis & Formation of ADTIQ…………………...……45 20. Interplay between glucose, catecholamine, and ethanol metabolism………………..49 21. Pictet-Spengler reaction for the formation of 3-carboxysalsolinol…………………..51 22. Methylation of 3-carboxysalsolinol to 6,7-methoxy-3-carboxysalsolinol……………52 23. Chromatogram of catecholamines and TIQs……….…………………………….…..55 24. Mass spectrum for 3-carboxysalsolinol………………………………………………..56 25. Enzymatic & non-enzymatic metabolism of CA’s and the formation of TIQs……..63 26. Endogenous levels of 3-carboxysalsolinol in mouse striatum…………………….….65 27. Endogenous levels of salsolinol in mouse brains………………………………...……66 28. Endogenous TIQs in Mouse Brain…………………………………………………….68 29. 3-carboxysalsolinol in mouse brain after IV injection………………………………..72 30. Methylation of 3-carboxysalsolinol by COMT………………………………………..74 ix 31. 3-CS and 6M-3-CS in mouse brain at 1 minute……………………………………....76 32. 3-CS and 6M-3-CS at 6 minutes in mouse brain……………………………………...77 33. 3-CS and 6M-3-CS at 10 minutes in mouse brain……………………………...……..78 34. Time course for 3-CS in mouse striatum………………………..…………………….80 35. Metabolism pathway for TIQs, catecholamines, and their metabolites………….....82 36. MAO, COMT, and the benserazide inhibitors…………………………………….….84 37. 3-carboxysalsolinol in mouse striatum……………………………………………...…85 38. In vivo formation of HVA in mouse striatum …………………...……………..…….86 39. In vivo formation of salsolinol in mouse striatum……………………………...…….87 40. Levels of TIQs & metabolites in mouse brain…………………………………..…….89 41. Catecholamine and TIQs
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