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An Investigation of Nicotine Metabolism in Mice

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An Investigation of Nicotine Metabolism in Mice AN INVESTIGATION OF NICOTINE METABOLISM IN MICE: THE IMPACT OF PHARMACOLOGICAL INHIBITION AND GENETIC INFLUENCES ON NICOTINE PHARMACOLOGY By Eric Chun Kit Siu A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Pharmacology University of Toronto ©Copyright by Eric Chun Kit Siu 2010 i AN INVESTIGATION OF NICOTINE METABOLISM IN MICE: THE IMPACT OF PHARMACOLOGICAL INHIBITION AND GENETIC INFLUENCES ON NICOTINE PHARMACOLOGY Eric Chun Kit Siu Doctor of Philosophy, 2010 Graduate Department of Pharmacology University of Toronto ABSTRACT INTRODUCTION: Smoking is one of the single greatest causes of numerous preventable diseases. We were interested in developing an animal model of nicotine metabolism that can be used to examine the effects of potential CYP2A6 inhibitors on nicotine metabolism and nicotine-mediated behaviours. Pharmacogenetic studies have demonstrated that in humans, smoking behaviour is associated with rates of nicotine metabolism by the CYP2A6 enzyme. Mouse CYP2A5 shares structural and functional similarities to human CYP2A6 and has been implicated in nicotine self-administration behaviours in mice, therefore the mouse represents a potential animal model for studying nicotine metabolism. METHODS: We characterized nicotine and cotinine metabolism in two commonly used mouse strains (DBA/2 and C57Bl/6). We also examined the association between nicotine self-administration behaviours and nicotine metabolism, and the impact of direct manipulation (i.e. inhibition) of nicotine metabolism on nicotine pharmacodynamics (hot-plate and tail-flick tests) in mice. Finally, we studied the effect of selegiline (a known cytochrome P450 mechanism-based inhibitor) on nicotine metabolism in mice and in human CYP2A6. RESULTS: Nicotine metabolism in mice in vitro was mediated by CYP2A5, and this enzyme was responsible for over 70% and 90% of the metabolism of nicotine to cotinine and cotinine to 3-hydroxycotinine as shown by immuno-inhibition studies, respectively. A polymorphism in CYP2A5 between mouse strains, known to alter the probe substrate coumarin’s metabolism, did not affect ii nicotine metabolism but dramatically altered cotinine metabolism. Nicotine self- administration behaviour in mice was associated with level of hepatic CYP2A5 proteins and rates of nicotine metabolism in male mice. In inhibition studies, the CYP2A5/6 inhibitor methoxsalen inhibited both in vitro and in vivo nicotine metabolism in mice and substantially increased the anti-nociceptive effect of nicotine. Finally, selegiline was found to be an inhibitor of CYP2A5 decreasing nicotine metabolism in vitro and in vivo in mice. Moreover, we showed that selegiline is a mechanism-based inhibitor of CYP2A6 inhibiting nicotine metabolism irreversibly. CONCLUSION: The above data suggested that the mouse model may be suitable for examining the impact of inhibition (and genetic variation) on nicotine metabolism and nicotine-mediated behaviours and may potentially be used to screen for novel inhibitors of nicotine metabolism. iii ACKNOWLEDGEMENTS As author of this thesis, I would like to thank those individuals who contributed their time and effort to the creation of this work. First, I would like to thank my supervisor, Professor Rachel Tyndale, for her guidance and support throughout my graduate training. I would also like to thank the past and present colleagues in the laboratory who shared their technical experience, particularly those who contributed to my various projects. These include Ewa Hoffmann, Sharon Miksys, Helma Nolte, Raj Sharma, Zhao Bin, and Linda Liu. I would also like to thank Howard Kaplan for his statistical assistance. I would like to acknowledge the support of my fellow graduate students in the laboratory, particularly Jill Mwenifumbo and Nael Al Koudsi. I am grateful to Dr. Denis Grant, Dr. Paul Fletcher, and Dr. Jack Uetrecht for sharing their knowledge and insight for the successful completion of my projects. I would also like to thank Dr. Dieter Wildenauer and Dr. Imad Damaj for their collaborations on my various projects. I am mostly graciously indebted to OGS, CIHR TUSP, CIHR STPTR, and CTCRI for the financial support that has insured my continuing success in this program. I am also very grateful to the support of Mr. and Mrs. Binh Chow through the years of my stay in Toronto. Finally, I am forever indebted to my loving parents Simon and Maggie Siu and my fiancé Teresa Tsui, which without their inspiration and support the completion of this thesis would not have been possible. iv TITLE PAGE Page i ABSTRACT Page ii-iii ACKNOWLEDGEMENTS Page iv TABLE OF CONTENTS Page v-ix LIST OF PUBLICATIONS Page x-xi SUMMARY OF ABBREVIATIONS Page xii LIST OF TABLES Page xiii LIST OF FIGURES Page xiv-xv STATEMENT OF RESEARCH PROBLEM Page 1 CHAPTER 1 INTRODUCTION Page 3 Section 1 Nicotine Metabolism Page 3 Section 1.1 Nicotine Metabolism in Mice Page 3 Section 1.2 Nicotine Pharmacokinetics in Mice Page 3 Section 1.3 Mouse Nicotine Metabolizing Enzymes Page 4 Section 1.3.1 Mouse Cytochrome P450 2A5 (CYP2A5; P450Coh; Page 4 Coumarin Hydroxylase) Section 1.3.2 Mouse Flavin-containing Monoxidase 1 (FMO1) Page 6 Section 1.3.3 Mouse Aldehyde Oxidase 1 (AOX1) Page 7 Section 1.4 Nicotine Metabolism in Humans Page 8 Section 1.5 Nicotine Pharmacokinetics in Humans Page 8 Section 1.6 Human Nicotine Metabolizing Enzymes Page 11 Section 1.6.1 Human Cytochrome P450 2A6 (CYP2A6; Page 11 Coumarin 7-hydroxylase) Section 1.6.2 Human Cytochrome P450 2A13 (CYP2A13) Page 14 Section 1.6.3 Human Cytochrome P450 2B6 (CYP2B6) Page 15 Section 1.6.4 Human Aldehyde Oxidase 1 (AOX1) Page 17 Section 1.6.5 Human Flavin-containing Monooxygenase 3 (FMO3) Page 18 Section 1.6.6 Human Uridine Diphosphate (UDP)-Glucuronosyl- Page 19 Transferase (UGT) Section 2 Pharmacological Treatments for Smoking Cessation Page 21 Section 2.1 Primary Treatments Page 21 v Section 2.1.1 Nicotine Replacement Therapies (NRTs) Page 21 Section 2.1.2 Bupropion Page 22 Section 2.1.3 Varenicline Page 23 Section 2.2 Secondary and Investigative (Non-approved) Page 25 Smoking Cessation Therapies Section 2.2.1 Nortriptyline Page 25 Section 2.2.2 Clonidine Page 25 Section 2.2.3 Serotonergic Agents Page 26 Section 2.2.3.1 Buspirone Page 26 Section 2.2.3.2 Selective Serotonin Reuptake Inhibitors (SSRIs) Page 27 Section 2.2.4 Naltrexone Page 27 Section 2.2.5 Rimonabant (SR141716) Page 28 Section 2.2.6 Nicotine Vaccines Page 30 Section 2.2.7 Monoamine Oxidase Inhibitors (MAOIs) Page 30 Section 2.2.7.1 Selegiline (l-deprenyl; Eldepryl ®) Page 32 Section 2.2.7.1.1 Selegiline Pharmacodynamics Page 32 Section 2.2.7.1.2 Selegiline Metabolism Page 33 Section 2.3 The Inhibition of Nicotine Metabolism and its Page 34 Application to Smoking Cessation Section 2.3.1 Inhibitors of Human CYP2A6 Page 34 Section 2.3.2 Inhibitors of Mouse CYP2A5 Page 35 Section 2.3.3 Mechanism-Based Inhibition Page 36 Section 2.3.3.1 Methoxsalen (8-methoxypsoralen; 8-MOP): Page 37 A CYP2A5 and CYP2A6 MBI Section 2.3.3.2 Selegiline as a MBI Page 37 Section 2.3.4 Improving Smoking Cessation through CYP2A6 Page 38 Inhibition Section 2.3.5 Reduction of Tobacco-Specific Nitrosamine Page 40 Activation through Human CYP2A6 Inhibition Section 3 Nicotine Pharmacological Behavioural Models Page 42 Section 3.1 Nicotine Self-Administration Page 42 Section 3.2 Analgesic Effect of Nicotine and Application in Page 43 Nicotine Studies Section 4 Outline of Chapters Page 45 vi Section 4.1 Chapter 2: Characterization and Comparison of Page 45 Nicotine and Cotinine Metabolism In Vitro and In Vivo in DBA/2 and C57BL/6 Mice Section 4.2 Chapter 3: Nicotine Self-Administration in Mice is Page 46 Associated with Rates of Nicotine Inactivation by CYP2A5 Section 4.3 Chapter 4: Inhibition of Nicotine Metabolism by Page 47 Methoxysalen: Pharmacokinetic and Pharmacological Studies in Mice Section 4.4 Chapter 5: Selegiline (L-Deprenyl) is a Mechanism- Page 48 based Inactivator of CYP2A6 Inhibiting Nicotine Metabolism in Humans and Mice CHAPTER 2 CHARACTERIZATION AND COMPARISON OF Page 50 NICOTINE AND COTININE METABOLISM IN VITRO AND IN VIVO IN DBA/2 AND C57BL/6 MICE Abstract Page 51 Introduction Page 52 Materials and Methods Page 54 Results Page 59 Discussion Page 73 Significance of Chapter Page 79 CHAPTER 3 NICOTINE SELF-ADMINISTRATION IN MICE IS Page 80 ASSOCIATED WITH RATES OF NICOTINE INACTIVATION BY CYP2A5 Abstract Page 81 Introduction Page 82 Materials and Methods Page 84 Results Page 88 Discussion Page 99 Significance of Chapter Page 104 CHAPTER 4 INHIBITION OF NICOTINE METABOLISM BY Page 105 BY METHOXSALEN: PHARMACOKINETIC AND PHARMACOLOGICAL STUDIES IN MICE vii Abstract Page 106 Introduction Page 107 Materials and Methods Page 109 Results Page 113 Discussion Page 128 Significance of Chapter Page 134 CHAPTER 5 SELEGILINE (L-DEPRENYL) IS A MECHANISM- Page 135 BASED INACTIVATOR OF CYP2A6 INHIBITING NICOTINE METABOLISM IN HUMANS AND MICE Abstract Page 136 Introduction Page 137 Materials and Methods Page 141 Results Page 147 Discussion Page 157 Significance of Chapter Page 163 CHAPTER 6 GENERAL DISCUSSION Page 164 Section 5 Metabolism Topics Page 164 Section 5.1 In Vitro Metabolism Page 164 Section 5.1.1 In Vitro Nicotine Metabolism Page 164 Section 5.1.2 In Vitro Cotinine Metabolism Page 167 Section 5.1.3 Effect of a CYP2A5 Polymorphism on Substrate Page 167 Metabolism Section 5.2 In Vivo Metabolism Page 168 Section 5.2.1 Biomarker of Nicotine Metabolism Page 170 Section 5.3 Mice (CYP2A5) as a Model to Study CYP2A6
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