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Metabolism of Levulinate and Conversion to the Drug Of METABOLISM OF LEVULINATE AND CONVERSION TO THE DRUG OF ABUSE 4-HYDROXYPENTANOATE by STEPHANIE R. HARRIS Submitted in partial fulfillment of the requirements For the Degree of Doctor of Philosophy Thesis Advisor: Henri Brunengraber, M.D., Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY August 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of STEPHANIE R. HARRIS candidate for the ________________________________ Doctor of Philosophy degree *. (signed) ________________________________________________ Edith Lerner, PhD (Chair of the committee) ________________________________________________ Henri Brunengraber, MD, PhD ________________________________________________ Colleen Croniger, PhD ________________________________________________ Paul Ernsberger, PhD ________________________________________________ Janos Kerner, PhD ________________________________________________ Michelle Puchowicz, PhD (date) _______________________June 16, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. ii DEDICATION I dedicate this work to my parents and to my husband, Paul. My parents have provided continuous love, encouragement, and guidance throughout my life. They have taught me to set my goals high. My husband has been a source of strength and inspiration, and his dedication and enthusiastic support have helped me achieve this work. iii TABLE OF CONTENTS Table of Contents………………………………………………………………………... iv List of Tables…………………………………………………………………………....viii List of Figures…………………………………………………………………………… ix Acknowledgements…………………………………………………………………....... xi List of Abbreviations…………………………………………………………………... xiii Abstract………………………………………………………………………………..... xv CHAPTER 1: FATTY ACID OXIDATION 1.1. Overview……………………………………………………………………………...1 1.2. Transport of Fatty Acids into Cells…………………………………………………..2 1.3. Activation of Fatty Acids…………………………………………………………….6 1.3.1. The Carnitine Palmitoyltransferase System…………………………………...7 1.4. Reactions of Mitochondrial β-oxidation……………………………………….……10 1.4.1. The Trifunctional Protein Complex…………………….…………………….13 1.4.2. Reversibility of 3-Ketoacyl-CoA Thiolase…………………………………...13 1.4.3. Peroxisomal β-oxidation……………………………………………………...15 1.4.4. Fates of Acetyl-CoA Derived from Fatty Acid Oxidation…………………...17 1.5. Fatty Acid Alpha- and Omega-Oxidations...………………………………………..22 1.6. Regulation of Mitochondrial β-oxidation…………………………………………...23 1.6.1. Regulation of CPT-I by Malonyl-CoA…………………….…………………23 1.6.2. Redox Regulation of Mitochondrial β-oxidation……………………………..28 1.6.3. Feedback Regulation of Mitochondrial β-oxidation………………………….28 1.6.4. The Role of Carnitine and Free CoA in Fatty Acid β-oxidation……………..29 iv CHAPTER 2: 4-HYDROXYACID METABOLISM 2.1. Overview of What is Known About 4-Hydroxyacids ………...…………………....32 2.2. 4-Hydroxyacids: Products of Lipid Peroxidation (C9, C6).………………………...33 2.2.1. 4-Hydroxyacids: Drugs of Abuse (C4, C5).………………………………….35 2.3. Recent Development in 4-Hydroxyacid Metabolism ...…………………………….41 2.3.1. Nomenclature of Mass Isotopomers……………………………………. ……41 2.3.2. Pathways of 4-Hydroxyacid Catabolism.……………………………………..41 2.3.3. Formation of 4-Phosphoacyl-CoAs from 4-Hydroxyacids…………………...46 2.3.4. Trapping of CoA into Intermediates of 4-Hydroxyacid Catabolism………....52 CHAPTER 3: LEVULINIC ACID 3.1. Overview……………………………………………………………………….……56 3.2. Production and Industrial Applications of Levulinic Acid………………………….56 3.3. Levulinic Acid as a Calcium Salt ……………………………………………..…...58 3.4. Past Observations of Levulinate Metabolism……………………………………….61 CHAPTER 4: HEXANE TOXICITY 4.1. Overview…………………………………………………………………………….64 4.2. Metabolism of n-Hexane……………………… ……………………………………64 4.3. Hexane Toxicity via the Formation of Pyrrole Adducts…………………………….65 CHAPTER 5: RESEARCH PLAN 5.1. Overview…………………………………………………………………………….69 5.2. Part A: Metabolism of Levulinate ± Ethanol in Perfused Rat Livers and in Live Rats…………...…………………………………….………………………….70 v 5.2.1. Mechanisms for the Conversion of Levulinate to 4-Hydroxypentanoate…….70 5.2.2. Pathways of Levulinate Catabolism………………………………………….73 5.2.3. Public Health Relevance……………………………………………………...77 5.2.4. Strategy……………………………………………………………………….77 5.2.4.1. In Vivo Experiments…………………………………………………...78 5.2.4.2. Liver Perfusion Experiments…………………………………………...79 5.2.4.3. Pilot Enzyme Assays…………………………………………………...79 5.2.4.4. Analytical Procedures…………………………………………………..80 5.3. Part B: Metabolism of Calcium Levulinate………………………………………...83 5.3.1. Metabolism of Calcium Levulinate Given Enterally ± Ethanol………………83 5.3.2. Strategy…………………………………………………………………. ……85 5.3.2.1. Analytical Procedures…………………………………………………..85 CHAPTER 6: PUBLICATIONS 6.1. Overview…………………………………………………………………………….87 6.1.1. Harris, S.R., Zhang, G.F., Sadhukhan, S., Murphy, A.M., Tomcik, K.A., Vazquez, E.J., Anderson, V.E., Tochtrop, G.P., Brunengraber, H. Metabolism of levulinate in perfused rat livers and in live rats: Conversion to the drug of abuse 4-hydroxypentanoate. J. Biol. Chem. 286: 5895-5904, 2011. …………………………………………………………………...88 6.1.2. Harris, S.R., Zhang, G.F., Sadhukhan, S., Puchowicz, M.A., Anderson, V.E., Tochtrop, G.P., Brunengraber, H. Cyclical CoA esters derived from Levulinate. (To be submitted to J. Biol. Chem. July 2011) ………………………………………………………………….126 vi CHAPTER 7: DISCUSSION, IMPLICATIONS, AND FUTURE DIRECTIONS 7.1. Reduction of Levulinate to 4-Hydroxypentanoate In Vivo and in Isolated Livers………………………………….…………………………………………..156 7.1.1. Discussion and Conclusions…...……………………………………………156 7.1.2. Future Directions………………………………………….…………………157 7.2. Mechanisms for the Conversion of Levulinate to 4-Hydroxypentanoate……... ….158 7.2.1. Discussion and Conclusions…………………………………………………158 7.2.2. Future Directions…………………………………………………………….160 7.3. Pathways of Levulinate Catabolism……………………………………………….162 7.3.1. Discussion and Conclusions…………………………………………………162 7.3.2. Future Directions…………………………………………………………….167 7.4. Metabolism of Oral Calcium Levulinate Ethanol………..…...………………..…171 7.4.1. Discussion and Conclusions…………………………………………………171 7.4.2. Future Directions………………………………………………………….…175 7.5. New Cyclical CoA Esters Derived from Levulinate…………………………….…177 7.5.1. Discussion and Conclusions…...……………………………………………177 7.5.2. Future Directions………………….…………………………………………180 7.6. Overall Summary and Implications……......……….……………………………..182 LITERATURE CITED……………………………………………………………….183 vii LIST OF TABLES CHAPTER 6 Table 6.1. Concentrations of Acyl-CoAs in Perfused Rat Livers…..…………………124 13 Table 6.2. Mass Isotopomer Distribution of Products of [ C5]levulinate Metabolism in Perfused Rat Livers.……………………………………………………..125 Table 6.3. Distribution of Labeled Mass Isotopomers of C7 CoA Esters and Acetyl-CoA in Rat Livers Perfused with Levulinate and Substrates Labeled with 13C, 15N or Both ………..…………………………………………………………155 viii LIST OF FIGURES CHAPTER 1 Fig 1.1. Mechanisms of Fatty Acid Transport into Cells…………………………...……5 Fig 1.2. The Carnitine Palmitoyltransferase System……………………………………..9 Fig 1.3. Mitochondrial β-oxidation Spiral and Sites of Regulation……………………..12 Fig 1.4. Lipogenesis from Ketone Bodies in the Liver………………………………….21 Fig 1.5. Regulation of CPT-I Activity…………………………………………………..27 CHAPTER 2 Fig 2.1. Structures of 4-Hydroxybutyrate and 4-Hydroxypentanoate…………………..40 Fig 2.2. Proposed Scheme for the Catabolism of 4-Hydroxyacids……………………..45 Fig 2.3. Fragmentation Patterns of 4-Phosphopentanoyl-CoA………………………....49 Fig 2.4. Accumulation of 4-Phosphoacyl-CoAs derived from 4-Hydroxyacids………..50 Fig 2.5. Concentrations of 4-Phosphobutyryl-CoA in the Brain and Liver of Mice Deficient in Succinic Semialdehyde Dehydrogenase….………………………51 Fig 2.6. Evidence of CoA Trapping in CoA Esters Derived from 4-Hydroxy-n-acids …………………………………………………………………………………55 CHAPTER 3 Fig 3.1. Biochemical Parameters in the Blood of Premature Babies Following Treatment with Calcium Levulinate……..………………………………………………..63 CHAPTER 4 Fig 4.1. Formation of a Dimethylpyrrole Adduct from 2,5-Diketohexane and an Amine…………………………………………………………………………..68 ix CHAPTER 5 Fig 5.1. Proposed Scheme for the Catabolism of Levulinate…………………………...82 CHAPTER 6 Fig 6.1. Proposed Scheme for the Metabolism of Levulinate and 4-Hydroxypentanoate ………………………………………………………………………………..120 Fig 6.2. Profiles of Plasma Concentrations of Levulinate and 4-Hydroxypentanoate in Rats Infused Intravenously with Sodium Levulinate ± Ethanol …………….121 Fig 6.3. Effect of Ethanol on Levulinate Uptake and Metabolism in Perfused Rat Livers ………………………………………………………………………..122 13 13 Fig 6.4. Release of [ C]formate by Rat Livers Perfused with [ Cn]levulinate………123 Fig 6.5. Proposed Scheme for the Formation of Cyclical CoA Esters from Levulinate…………………………………………………………………….150 Fig 6.6. Concentrations of Levulinate and 4-Hydroxypentanoate in Plasma of Rats Gavaged with Calcium Levulinate ± Ethanol……………………………......151 Fig 6.7. Liver Concentrations of the Main C5 Acyl-CoAs Derived from Levulinate in Rats Gavaged with Calcium Levulinate ± Ethanol…………………………..152 Fig 6.8. Liver Concentrations of the C7 Cyclical CoA Esters Derived from Levulinate in Rats Gavaged with Calcium Levulinate ± Ethanol………….………………..153 Fig 6.9. Brain Concentrations of the Main C5 Acyl-CoAs Derived from Levulinate in Rats Gavaged with Calcium Levulinate ± Ethanol…………………………..154 CHAPTER 7 Fig 7.1. Trapping of Heart CoA by the Metabolites of Levulinate……………………169 Fig 7.2. Tentative Strategy for Measuring the Distribution of Levulinate Catabolism…………………………………………………………………...170
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