Paraoxonases in Inflammation, Infection, and Toxicology (eBook)

Acknowledgments 6
Contents 7
Contributors 9
ApoE Mimetic Peptide Reduces Plasma Lipid Hydroperoxide Content with a Concomitant Increase in HDL Paraoxonase Activity 16
References 19
Interrelationships Between Paraoxonase-1 and Monocyte Chemoattractant Protein-1 in the Regulation of HepaticInflammation 20
1 Oxidative Stress in Chronic Liver Impairment and Its Relationship to Inflammation and Fibrosis 21
2 Monocyte Chemoattractant Protein-1 (MCP-1) and the Regulation of Hepatic Inflammation 24
3 The Antioxidant and Hepatoprotective Function of Paraoxonase-1 (PON1) in Chronic Liver Impairment 25
4 Hepatic PON1 Synthesis and Its Relationships with MCP-1 and Inflammation in Chronic Liver Disease 27
5 Conclusion 29
References 30
Biomarkers of Sensitivity and Exposure in Washington State Pesticide Handlers 34
1 Introduction 34
2 ChE Monitoring in Washington State 35
3 Health Effects of OP/CB Exposure 35
4 Sensitivity to OP/CB Toxicity 36
5 Characterizing PON1 Status 36
6 Previous Epidemiologic Studies 37
7 PON1 Status and BuChE Inhibition Among Pesticide Handlers 37
8 Conclusions 39
References 39
Paraoxonase 1 Status as a Risk Factor for Diseaseor Exposure 43
1 Introduction 43
2 Two-Substrate Analyses of PON1 Status 45
3 Development of a PON1 Status Protocol with Non-OP Substrates 46
References 48
Engineering Human PON1 in an E. coli Expression System 50
1 Introduction 50
2 Expression and Purification of rHuPON1 from E. coli 52
3 Kinetic Properties of rHuPON1 192 Variants 54
4 Testing rHuPON1K192 as a Therapeutic 54
5 Conclusions 56
References 57
The Toxicity of Mixtures of Specific Organophosphate Compounds is Modulated by Paraoxonase 1 Status 59
1 PON1 and Detoxication of OP Compounds 60
2 PON1 Status 60
3 Toxicity of OP Mixtures 61
4 Effect of PON1 on the Interactive Toxicity of OP Mixtures 61
5 Inhibition of CaE by OP Compounds In Vitro 62
6 Inhibition of CaE by OP Compounds In Vivo 62
7 Effect of PON1 Status on the Toxicity of OP Compound Mixtures 63
8 Conclusions 67
References 68
Identification and Characterization of Biomarkersof Organophosphorus Exposures in Humans 73
1 Introduction 74
2 Modification of Blood and Plasma Biomarkers 75
3 Identification and Characterization of Biomarkers of OP Exposure from Human Blood 76
4 Conclusions 81
References 82
Temporal and Tissue-Specific Patterns of Pon3 Expressionin Mouse: In situ Hybridization Analysis 84
1 Introduction 85
2 Methods 86
2.1 Tissue Fixation, Embedding, and Pretreatment 86
2.2 cRNA Probe Preparation 86
2.3 Hybridization and Washing Procedures 86
2.4 Imaging 87
3 Results 87
3.1 Pon3 mRNA Expression in Newborn Mice 87
3.2 Pon3 mRNA Expression in Adult Mice 88
3.3 Pon3 mRNA Expression in Wild-Type and apoE --/-- Adult Mouse Hearts 89
4 Discussion 90
References 97
PON1 and Oxidative Stress in Human Sepsis and an Animal Model of Sepsis 99
1 Introduction 100
2 PON1 and Lipid Peroxidation in Sepsis Patients and Healthy Controls 100
3 PON1 and LPO in ICU Patients with and Without Sepsis 101
4 PON1 and LPO in Murine Cecal Ligation and Puncture Model of Sepsis 103
5 Conclusions 105
References 107
Paraoxonase 1 Attenuates Human Plaque Atherogenicity: Relevance to the Enzyme Lactonase Activity 108
1 Atherosclerotic Plaque and Oxidative Stress 109
1.1 Atherosclerotic Plaque Composition 109
1.2 Human Carotid Plaque Atherogenicity 111
2 Paraoxonase 1 Protection Against Atherosclerosis 111
2.1 Paraoxonase 1 in Human Atherosclerotic Plaque 112
3 Paraoxonase 1 Lactonase Anti-Atherogenic Activity 114
3.1 Characterization of Paraoxonase 1 Active Site, in Relation to Its Lactonase Activity 114
4 Perspectives and Future Directions 116
References 117
The Role of Paraoxonase 1 in the Detoxification of Homocysteine Thiolactone 121
1 Homocysteine Metabolism 121
2 Pathophysiology of Hyperhomocysteinemia 123
3 The Hcy-Thiolactone Hypothesis 124
4 Toxicity of Hcy-Thiolactone 124
5 Consequences of Protein N-Homocysteinylation by Hcy-Thiolactone 125
6 Prothrombotic Properties of N-Hcy-Fibrinogen 126
7 Autoimmunogenicity of N-Hcy-Protein 126
8 The Role of PON1 in Elimination of Hcy-Thiolactone 127
9 Conclusion 131
References 131
Alteration of PON1 Activity in Adult and Childhood Obesity and Its Relation to Adipokine Levels 136
1 Introduction 137
1.1 Obesity and Atherosclerosis: The Role of Adipokines in Atherogenesis and Lipid Peroxidation 137
1.2 Relationship of Leptin to PON1 139
1.2.1 Animal Studies 139
1.2.2 Human Studies 139
2 Relationship of Adipokines to PON1 in Adult Obesity 141
2.1 Relationship of Adiponectin to PON1 141
2.2 Relationship of Resistin to PON1 142
3 Relationship of Adipokines to PON1 in Childhood Obesity 144
3.1 Association of Adipokines and PON1 Activity in Childhood Obesity 144
3.2 Correlations Between Adipokine Levels and PON1 Phenotypes 145
4 Conclusions 147
References 148
Anti-Inflammatory Properties of Paraoxonase-1 in Atherosclerosis 150
1 Inflammation and Atherosclerosis 150
2 High-Density Lipoprotein (HDL) and Inflammation 151
2.1 Proinflammatory HDL 151
2.2 Anti-Inflammatory HDL 151
3 PON1 and Inflammation 153
3.1 PON1 and Cell Membrane Oxidation 154
4 Is PON1 Cytotoxic? 155
5 Conclusion 156
References 156
Paraoxonase 1 Interactions with HDL, Antioxidantsand Macrophages Regulate Atherogenesis -- A Protective Role for HDL Phospholipids 159
1 Atherosclerosis 159
1.1 Atherosclerosis Development 159
1.2 Atherosclerosis and Macrophages 160
1.3 PON1 and Its Protective Role Against Atherosclerosis 161
2 HDL 162
2.1 HDL Structure and Its Anti-atherogenic Properties 162
2.2 HDL Components Regulate PON1 Activity and Stability 162
3 PON1, HDL, Dietary Antioxidants, and Their Interactions with Macrophages 163
3.1 Effects of HDL Phospholipids Composition on HDL and PON1 Interactions with Macrophages 163
3.2 Binding and Internalization of HDL and PON1 into Macrophages 164
3.3 A Possible Role for Phospholipids in HDL PON1--Macrophage Interactions 166
4 Future Perspectives 168
References 168
The Effect of HDL Mimetic Peptide 4F on PON1 173
1 Can Apolipoprotein A-I Serve as a Therapeutic Agent? 173
2 ApoA-I Mimetic Peptide, the Search for an Ideal Agent 174
3 The Effects of Apolipoprotein Mimetic Peptides in Animal Models of Atherosclerosis 174
4 What is the Mechanism of Action of Apolipoprotein Mimetic Peptides? 175
5 Paraoxonase, Oxidized Lipids and Apolipoprotein Mimetic Peptides 175
6 Summary 176
References 177
The Contribution of High Density Lipoprotein Apolipoproteins and Derivatives to Serum Paraoxonase-1 Activity and Function 179
1 Introduction 179
2 Apolipoprotein AI 180
3 Apolipoprotein AII 181
4 Apolipoprotein J 184
5 Mimetic Peptides 185
6 Conclusions 185
References 186
Paraoxonase 1, Quorum Sensing, and P. aeruginosa Infection:A Novel Model 188
1 Introduction 189
2 Paraoxonases are Widely Conserved, but Have Not Been Found in Arthropods 191
3 Generating a PON1 Transgenic Drosophila melanogaster Infection Model 194
4 PON1 Transgenic Flies are Protected from Organophosphate Poisoning 194
5 PON1 Expression Protects Against Pseudomonas aeruginosa Lethality 195
6 Concluding Remarks 195
References 197
Index 199