Metabonomics in Toxicity Assessment

Preface......Page 8
Contents......Page 12
Contributors......Page 16
1. INTRODUCTION......Page 18
2. THE METABOLIC CONTINUUM......Page 22
3. BIOMARKERS......Page 29
4. BRIEF OVERVIEW OF METABONOMICS TECHNIQUES......Page 30
5. METABONOMICS APPLICATIONS......Page 35
6. SUMMARY......Page 38
1. INTRODUCTION......Page 44
2. BIOMARKERS OF EXPOSURE......Page 48
2.1. Biomarkers of Internal Dose......Page 50
2.2. Biomarkers of Effective Dose......Page 52
3. BIOMARKERS OF RESPONSE......Page 61
3.1. Enzyme Activity......Page 64
3.2. Breath Analysis......Page 68
3.3. Genomics......Page 69
3.4. Proteomics......Page 71
4. BIOMARKERS OF SUSCEPTIBILITY......Page 73
4.1. Enzymes of Biotransformation as Biomarkers of Susceptibility......Page 75
4.2. Other Biomarkers of Susceptibility......Page 79
1. INTRODUCTION......Page 92
2.1. Basic Theory......Page 94
2.2. Parameters from an NMR Spectrum......Page 97
3. OPERATIONAL METHODS......Page 102
4. REALIZATION OF NMR SPECTROSCOPY IN A METABONOMICS LABORATORY......Page 109
5. CONCLUSIONS......Page 119
1. INTRODUCTION......Page 122
3. TECHNIQUES FOR RESONANCE ASSIGNMENT IN NMR SPECTRA OF BIOFLUIDS......Page 126
4.1. Properties and Biochemical Composition of CSF......Page 129
4.3. NMR Spectroscopy of CSF in Disease Studies......Page 130
5.1. Properties of Blood and Blood Plasma......Page 132
5.2. Comparative Biochemistry of Blood Plasma using H NMR Spectroscopy......Page 133
5.4. Molecular Dynamics and Interactions from H NMR Spectra of Blood Plasma......Page 138
5.5. NMR Spectra of Blood Plasma in Pathological States......Page 140
5.6. H NMR Spectroscopy of Whole Blood and Red Cells......Page 143
6.1. Sample Details for NMR Spectroscopy......Page 146
6.2. Chemical Exchange and Solvent Effects on NMR Spectra of Urine......Page 149
6.3. Physiological Effects on Urine Composition by NMR Spectroscopy......Page 151
6.4. NMR Spectra of Urine in Disease......Page 152
6.5. Evaluation of Toxic Effects of Xenobiotics Using NMR Spectroscopy of Urine......Page 156
7.1. Composition of Seminal Fluids......Page 159
7.2. NMR Spectroscopy of Seminal Fluids......Page 160
8.2. NMR Spectroscopy of Bile and Dynamic Interactions of Metabolites......Page 163
9.2. Milk......Page 165
9.3. Synovial Fluid......Page 166
9.4. Miscellaneous Fluids......Page 168
10. NMR STUDIES OF DYNAMIC INTERACTIONS......Page 170
11. CONCLUDING REMARKS......Page 175
1. INTRODUCTION......Page 190
2.1. Theory......Page 192
2.2. Sample Preparation......Page 194
3.1. Toxicology in Animal Systems......Page 197
3.2. Toxicology Using Cell Culture Systems......Page 201
3.3. Correlation of Metabonomics Data With other "-omic" Technologies......Page 204
4. FUTURE DIRECTIONS AND CHALLENGES FOR 1H MAS NMR SPECTROSCOPY......Page 205
1.2. Why Use Metabonomics as a Screening Tool?......Page 212
2.1. Urinary NMR: Why? and How?......Page 214
2.2. Rodent Models......Page 224
3.1. Examples of Metabonomics for Rat-Induced Toxicities......Page 228
3.2 Example of Metabonomics for Mouse- Induced Toxicities......Page 230
4. SCREENING MODELS......Page 235
5. CONCLUSION......Page 237
Animal Use Disclaimer......Page 238
1. INTRODUCTION......Page 242
2.1. NMR-Based Techniques......Page 243
2.2. Liquid Chromatography-Mass Spectrometry-Based Methods......Page 247
3.1. Solid Phase Extraction=Chromatography (SPEC)-NMR......Page 250
3.2. Examples of SPEC for Unknown Endogenous Metabolites......Page 252
3.3. An Example of SPEC for Xenobiotic Metabolites......Page 254
3.5. Characterization and Identification of Compounds in SPEC Fractions......Page 255
4.1. HPLC-NMR......Page 256
4.2. HPLC-NMR-MS......Page 262
5. MINIATURIZATION......Page 269
6. CONCLUSIONS......Page 274
1. INTRODUCTION 1.1. General Considerations......Page 280
1.2. Pattern Recognition......Page 281
1.3. Projection Methods......Page 282
1.4. Transition from Multi- to Megavariate Data Analysis......Page 283
2.1. Pretreatment of Data......Page 284
2.2. Centering and Scaling......Page 285
2.3. Principal Component Analysis......Page 289
2.4. Partial Least Squares Projections to Latent Structures, PLS......Page 300
3.1. Background to Data-set......Page 314
3.2. An Overview PCA-Model......Page 315
3.3. PLS-Discriminant Analysis (PLS-DA)......Page 318
3.4. PLS-DA of Groups "s" and "sc"......Page 319
3.5. Disjoint PCA-ModelingofGroups "s" and "sc"......Page 321
3.6. Discussion of First Example......Page 324
4.1. Background to Data-set......Page 325
4.2. BSPC: A Method to Handle Three-way Data Tables......Page 327
4.3. Base Level PLS-Model......Page 328
4.4. Classifying Individual Urine Samples......Page 331
4.7. Discussion of Second Example......Page 334
5.1. The Usefulness of Multivariate Projection Methods in Metabonomics......Page 336
5.2. Additional Preprocessing Tools......Page 338
5.3. Some Extensions of PCA and PLS......Page 343
5.4. Related Methods......Page 346
6. CONCLUDING REMARKS......Page 347
ACKNOWLEDGEMENTS......Page 348
1. INTRODUCTION......Page 354
2.1. The Liver as a Target Organ......Page 355
2.2. Using Metabonomics to Study Acute Hepatic injury - Comparison to Clinical Chemistry and Morphologic Pathology......Page 357
2.3. Metabonomic Studies of Dose-Dependent Hepatotoxicity......Page 361
2.4. Phospholipidosis......Page 366
2.5. Magic Angle Spinning (MAS) of Liver Tissue......Page 367
2.6. Chemometric Analysis of Hepatotoxin-Induced Urinary Metabolite Changes......Page 371
2.7. Metabonomic Studies of Hepatic Injury in Man......Page 373
2.8. Current Limitations in the Use of Metabonomics to Study Liver Injury......Page 375
3.1. The Kidney as a Target Organ......Page 376
3.2. Proximal Tubular Toxicity......Page 377
3.3. Renal Medullary Toxicity......Page 382
3.4. Renal Glomerular Toxicity......Page 386
3.5. Species and Strain Differences in Response to Nephrotoxins......Page 389
3.6. Direction of Metabonomic Research in Nephrotoxicity Studies......Page 390
4.1. Challenges for Assessing Vascular Toxicity......Page 391
4.2. Drug-Induced Vascular Injury......Page 392
4.3. Advantages of Metabonomics for Assessing Drug-Induced Vascular Toxicity......Page 395
4.4. Metabonomics and Vascular Toxicity: Issue of Concern......Page 397
4.5. Metabonomics and Mechanisms of Vascular Pathology......Page 401
4.6. Conclusions......Page 404
1. INTRODUCTION......Page 414
2.1. Inter-Animal Variation......Page 418
2.2. Age-Related Differences......Page 419
2.3. Gender Differences......Page 421
2.4. Species Differences......Page 425
2.5. Strain Differences......Page 430
2.6. Transgenic Models......Page 433
2.7. Hormonal Effects......Page 435
2.8. Diurnal Effects......Page 438
2.9. Water Deprivation......Page 439
2.10. Fasting......Page 440
2.11. Dietary and Gut Microfloral Influences......Page 441
2.12. Temperature Effects......Page 442
2.14. Stress and Acclimatization......Page 447
3. PHYSIOLOGICAL VARIATION IN HUMANS......Page 449
3.2. Gender......Page 450
3.3. Water Deprivation and Water Loading......Page 451
3.5. Diet......Page 452
3.7. Stress......Page 455
11 Environmental Applications of Metabonomic Profiling......Page 470
1.1. Goals......Page 471
1.3. Variation and Statistical Models......Page 473
1.5. Need for Field Validation......Page 475
2. CHARACTERIZATION OF BASELINE DATA BY NMR SPECTROSCOPY......Page 476
2.1. Terrestrial Invertebrates - Earthworms......Page 483
2.2. Marine Invertebrates......Page 487
3. TOXICOLOGICAL AND RELATED STUDIES......Page 491
3.2. Other Invertebrates......Page 496
4.1. Unusual Metabolism......Page 501
4.2. Baseline Variability......Page 503
4.3. Prior Knowledge......Page 504
4.4. Lack of Success......Page 505
1. PERSPECTIVE......Page 516
2. THE POWER OF THE METABONOMIC APPROACH IN TOXICOLOGY......Page 517
3.1. "Omics" as a Tool of Systems Biology......Page 521
3.2. The "Panomics" Approach......Page 523
4. SHORT TERM NEEDS FOR METABONOMICS AS A SCIENCE......Page 525
5. CAUTIONARY NOTE......Page 527
6. CONCLUSION......Page 529
Index......Page 534
Back cover......Page 540