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Ann Arbor, MI 48106 THE ROLE OF FATTY ACIDS AND RELATED ANALOGS IN MEDIATING PEROXISOME PROLIFERATION IN PRIMARY CULTURES OF RAT HEPATOCYTES A Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Urusa Intrasuksri, B.S. The Ohio State Unversity 1991 Dissertation Committee: Approved by Dennis R. Feller, Ph.D. Lane J. Wallace, Ph.D. Allan M. Burkman, Ph.D. Adviser Robert W. Brueggemeier, Ph.D. College of Pharmacy To My Parents ii ACKNOWLEDGEMENTS I wish to express my sincere thanks to: My adviser, Dr. Dennis R. Feller, for his guidance, patience, and support throughout my graduate studies. His steady concern, friendship and encouragement make me feel as if I were not far away from home. The members of my dissertation committee: Dr. Lane J. Wallace, Dr. Allan M. Burkman and Dr. Robert W. Brueggemeier, for their valuable suggestions and comments. Dr. P.E. Kolattukudy, Julie Li, and Leena Hiremath from Biotechnology Center for their willing help and instructions on the molecular works. John Mitchell and Erin Hooksin for their assistance on Electron microscopic studies. My senior friends, Tim Esbenshade and Tom Kocarek, for their instructions and guidance in the hepatocyte culture system. My American, Korean, Egyptian, Indian, Venezualian and Chinese friends, in the Division of Pharmacology, whom make the fifth floor of Parks Hall a very enjoyable and memorable place, and whom open my world to other cultures. My Thai friends, Suparp, Vimon, Suchada, Chawewan, Sirinart, Rutaiwan, Precha, Wirot, Kasem, Pitsanu, Panida,..., for their worthwhile amity. Their presence make O.S. U. as well as Neil Hall an unforgettable place of mine. My room-mate and my close neighbor, Kulaya and Tidawadee, for their inestimable help, support and understanding. Their assistance in and out the apartment made it possible for me to devote all my time in writing this dissertation. My parents and my sister. I thank you for your sincere confidence in me and for your eternal support and encouragement throughout my studies. The Thai Ministry of Public Health, Department of Medical Sciences for partial stipend support. Finally, I would like to thank the Ohio State University and the United States of America for giving me an opportunity to pursue the Ph.D. degree. The financial support and the education which I received from here will always be appreciated. VITA October 27, 1960 ..................................................... Bom - Bangkok, Thailand March, 1984 .............................................................B.S. Pharmacy, Mahidol University, Bangkok, Thailand April, 1984 - Aug., 1986 ........................................Medical Scientist, Ministry of Public Health, Thailand September, 1986 - Present .........................................Graduate Student, College of Pharmacy, The Ohio State University January, 1987 - Present .......................................... Graduate Teaching Associate and Graduate Research Associate, The Ohio State University PUBLICATIONS Intrasuksri, U. and Feller, D.R., Comparison of the Effects of Selected Monocarboxylic, Dicarboxylic and Perfluorinated Fatty Acids on Peroxisome Proliferation in Primary Cultured Rat Hepatocytes. Biochem. Pharmacol. 42: 184-188, 1991. Intrasuksri, U., and Feller, D.R., Characteristics of Peroxisome Proliferation by Perfluorinated Octanoic Acid (PFOA) in Cultured Rat Hepatocytes. FASEB Journal 5: A1571, 1991. Miller, D.D., Hamada, A., Clark, M.T., Adejare, A., Patil, P.N., Shams, G., Romstedt, R.J., Kim, S.U., Intrasuksri, U., McKenzie, J.L., and Feller, D.R., Synthesis and ct2- ' Adrenoceptor Effects of Substituted Catecholimidazoline and Catecholimidazole Analogues in Human Platelets. Medicinal Chemistry 33: 1138-1144,1990. Intrasuksri, U., and Feller, D.R., Comparison of Selected Mono and Dicarboxylic Acids on Induction of Peroxisome Proliferation in Cultured Rat Hepatocyte. FASEB Journal 4: A583, 1990. PUBLICATIONS (continued) Feller, D.R., Shams, G., Romstedt, K.J., Kim, S.U., Intrasuksri, U., Fashempour, J., Tantishaiyakul, V., Hamada, A., and Miller, D.D., Structure Function Relationships of Tolazoline Analogs on Human Platelet Aggregation: a-Adrenoceptor Activities. The Pharmacologist 32: A190, 1990. Intrasuksri, U., and Feller, D.R., Are Fatty Acids Mediators of Peroxisome Proliferation in Cultured Rat Hepatocytes ? FASEB Journal 3: A307, 1989. Intrasuksri, U., Shams, G., Romstedt, K.J., Adejare, A., Clark, M., Hamada, A., Miller, D.D., and Feller, D.R., Effects of 2-Benzylimidazoline and 2-Benzylimidazole Analogs on a-2 Adrenoceptors in Human Platelets. The Pharmacologist 30: A185, 1988. Feller, D.R., Adejare, A., Intrasuksri, U., Shin, Y., and Kirk, K.L., Alpha-adrenergic Agonist Properties of Ring 2- and 6-Fluorinated Analogs of Epinephrine. The Pharmacologist 30: A53, 1988. Intrasuksri, U. and Janviriyasopak, U., Study on the Hypoglycemic Effect of Largerstroemia Speciosa Pers. Bachelor Thesis (in TTiai), Mahidol University, Thailand, 1984. FIELD OF STUDY Major Field: Pharmacy Studies in Pharmacology v TABLE OF CONTENTS DEDICATION.......................................................................................................................iii ACKNOWLEDGEMENTS................................................................................................... iv VITA ................................................................................................................................... v TABLE OF ABBREVIATIONS ........................................................................................... xi LIST OF TABLES ...............................................................................................................xiii LIST OF FIGURES................................................................................................................ xv CHAPTER I. INTRODUCTION.......................................................................................... 1 A. Overview of Peroxisome Proliferation ........................................................................ 1 B. Peroxisomes .................................................................................................................. 2 1. Morphology ........................................................................................................... 2 2. Biochemical characteristics................................................................................... 3 3. Peroxisome biogenesis ........................................................................................ 4 4. Functions of peroxisomes ...................................................................................... 5 5. Peroxisomal disorders ....................................... 7 6. Peroxisomes and lipid metabolism ........................................................................ 8 C. Peroxisome Proliferators ..............................................................................................11 1. Fibric acids ..............................................................................................................12 2. Non-fibric acid hypolipidemic drugs ...................................................................... 12 3. Plasticizers and related compounds ......................................................................... 13 4. Phenoxy acid herbicides ........................................................................................... 13 5. Miscellaneous d ru g s .................................................................................................14 6. Physiological and dietary effects .............................................................................. 14 7. Fatty acids and related compounds ........................................................................