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FORMATION and METABOLISM of 15-DEOXY-∆12,14-PROSTAGLANDIN J2 in VIVO by Klarissa D. Hardy Dissertation Submitted to the Facult

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FORMATION and METABOLISM of 15-DEOXY-∆12,14-PROSTAGLANDIN J2 in VIVO by Klarissa D. Hardy Dissertation Submitted to the Facult 12,14 FORMATION AND METABOLISM OF 15‐DEOXY‐ ‐PROSTAGLANDIN J2 IN VIVO By Klarissa D. Hardy Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmacology May, 2011 Nashville, Tennessee Approved: Professor John A. Oates Professor L. Jackson Roberts, II Professor Lawrence J. Marnett Professor H. Alex Brown Professor Michael A. Freeman ACKNOWLEDGEMENTS First, I thank God for blessing me with the opportunity to complete this dissertation research with an outstanding group of scientists, mentors, and friends. This work would not have been possible without the help and support of many, for whom I am truly grateful. Dr. Ginger Milne has been a constant source of guidance and encouragement throughout my graduate studies at Vanderbilt University. From the time that I joined Dr. Morrow’s research group, Ginger has been there to share her knowledge and skills, answer my questions, and offer valuable advice to guide my research and ensure its successful completion. I admire the selfless way in which Ginger is attentive to the needs of others, and her example has taught me so much about how to be a better scientist and leader. Through the triumphs as well as the difficult, trying times, Ginger had been there to share a kind word and help me stay focused and grounded. She is a great mentor and friend and has truly been like my guardian angel. I thank the entire Morrow and Roberts Labs and other members of the Clinical Pharmacology faculty and staff for providing an enjoyable and exciting place to work. Specifically, I wish to thank Dr. Huiyong Yin for his thoughtful contributions to my research, especially regarding metabolite identification. I thank our lab manager, Stephanie Sanchez, for her patience and technical expertise. I also thank Dr. Claus Schneider for his suggestions regarding experimental methods, which made much of the analytical and biochemical studies possible, and I thank Dr. Sean Davies for thought provoking questions and advice. I am honored to have such an exceptional group of scientists as my thesis committee. Drs. John Oates, Larry Marnett, Alex Brown, and Michael Freeman have offered their expertise and thoughtful suggestions that have helped guide this research as well as foster my ii development as a scientist. They have also opened their doors to me, sharing valuable advice that has influenced my career in a very meaningful way. My family has been a tremendous source of support throughout my graduate studies. I thank my parents, Dr. William and Mrs. Kathryn Hardy, for instilling within me the principle of working with diligence and faith to accomplish my goals. Their love and encouragement have motivated me to persevere in completing this dissertation. I thank my sisters, Karen, Karla, Kimberly, and my brother William for being my role models and constant cheerleaders in all of my academic endeavors. I also thank David for his friendship and invaluable support during my graduate school career. Finally, I would like to thank my mentors Drs. Jason Morrow and Jack Roberts, without whom this thesis research would not have been possible. Though my time under Jason’s mentorship was shorter than I would have hoped, he taught me a great deal about believing in myself, approaching my research with confidence, and always striving for excellence. Jason had a special way making me feel like a valuable member of his lab. His constant positive and enthusiastic demeanor was a source of encouragement and inspiration to me, and I will always remember the legacy he left behind. I wish to especially thank Dr. Jack Roberts for taking me on as his student after Jason’s passing. I thank Jack for believing in me and my work enough to stick with me and see me through to the completion of my thesis research. I also appreciate the special interest he has demonstrated in my future success. Through my time under Jack’s mentorship, I have come to admire his keen ability to recognize an interesting and relevant scientific problem and make discoveries that promise to have a profound impact on improving human health. I hope that my work, present and future, will follow in the great legacy of my mentors. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ................................................................................................................. .. ii LIST OF FIGURES ............................................................................................................................ .vii LIST OF ABBREVIATIONS .................................................................................................................. x Chapter I. INTRODUCTION ...................................................................................................................... 1 Generation of eicosanoids from arachidonic acid ........................................................... 1 Cyclooxygenase‐derived prostaglandins ...................................................................... 2 Lipoxygenases and leukotrienes .................................................................................. 7 Cytochrome P450s and epoxyeicosatrienoic acids .................................................... 10 Prostaglandin metabolism ........................................................................................... 10 Enzymatic catabolism of prostaglandins .................................................................... 11 Cyclopentenone prostaglandins ................................................................................. 13 Discovery of 15‐d‐PGJ2 ............................................................................................... 16 Biological activity of 15‐d‐PGJ2 ..................................................................................... 18 Chemical reactivity ..................................................................................................... 19 PPAR‐dependent effects ........................................................................................... 21 PPAR‐independent effects ........................................................................................ 24 Evidence for the formation of 15‐d‐PGJ2 in Vivo ........................................................ 33 Metabolism of cyclopentenone prostaglandins ......................................................... 36 Oxidative stress ............................................................................................................ 39 Reactive oxygen species ............................................................................................. 39 Endogenous and exogenous sources of ROS ............................................................. 40 Biological functions of ROS ......................................................................................... 42 Cellular antioxidant defenses ..................................................................................... 43 Biological consequences of oxidative stress .............................................................. 45 Oxidative DNA damage .............................................................................................. 45 Protein oxidation ........................................................................................................ 46 Lipid peroxidation ....................................................................................................... 48 Discovery of Isoprostanes ............................................................................................. 50 Mechanism of isoprostane formation ........................................................................ 51 Distinction between IsoPs and COX‐derived PGs ....................................................... 53 Other products of the IsoP pathway .......................................................................... 54 IsoPs: Biomarkers of oxidative stress ......................................................................... 55 IsoPs: Mediators of oxidative stress ........................................................................... 57 Metabolism of cyclopentenone IsoPs ........................................................................ 58 Cross‐talk between the COX and IsoP pathways ........................................................... 60 Specific aims of this research ........................................................................................ 62 iv II. NONENZYMATIC FREE RADICAL‐CATALYZED GENERATION OF 12,14 15‐DEOXY‐ ‐PROSTAGLANDIN J2‐LIKE COMPOUNDS (DEOXY‐J2‐ISOPROSTANES) IN VIVO ................................................................................................................................. 63 Introduction ........................................................................................................ 63 Materials and Methods ....................................................................................... 68 Materials ........................................................................................................... 68 Oxidation of arachidonic acid in vitro ............................................................... 68 Isolation of 15‐d‐PGJ2‐like compounds (deoxy‐J2‐IsoPs) from rat liver ............ 68 Analysis of 15‐d‐PGJ2‐like compounds (deoxy‐J2‐IsoPs) LC/MS/MS ................. 69 Adduction of deoxy‐J2‐IsoPs with glutathione in vitro ..................................... 70 Results ...............................................................................................................
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