Handbook of toxicogenomics: strategies and applications
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| Format: | Buch |
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| Sprache: | English |
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Wiley-VCH
2005
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| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XXXII, 673 S. Ill., graph. Darst. |
| ISBN: | 3527303421 9783527303427 |
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| 245 | 1 | 0 | |a Handbook of toxicogenomics |b strategies and applications |c ed. by Jürgen Borlak |
| 264 | 1 | |a Weinheim |b Wiley-VCH |c 2005 | |
| 300 | |a XXXII, 673 S. |b Ill., graph. Darst. | ||
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| 650 | 4 | |a Expression génique | |
| 650 | 4 | |a Génomique | |
| 650 | 4 | |a Protéomique | |
| 650 | 4 | |a Toxicologie génétique | |
| 650 | 4 | |a Gene expression | |
| 650 | 4 | |a Genetic toxicology | |
| 650 | 4 | |a Genomics | |
| 650 | 4 | |a Proteomics | |
| 650 | 4 | |a Toxicogenetics | |
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Datensatz im Suchindex
| _version_ | 1804133414479069184 |
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| adam_text | Contents
Preface V
1 Introduction 1
Jurgen Borlak
1.1 A Shift in Paradigm 1
1.2 Enabling Technologies Lead to New Founded Knowledge
in Genomic Science 3
1.3 Translating RNAs Into Proteins 4
1.4 Toxicogenomics A Perspective 5
Technology Platforms in Toxicogenomics
2 Expression Profiling using SAGE and cDNA Arrays 9
Andreas Bosio
2.1 Introduction 9
2.2 SAGE Technology 10
2.2.1 Principles of SAGE Technology 10
2.2.2 Generation of SAGE Libraries 11
2.2.3 SAGE Bioinformatics 12
2.2.4 SAGE Applications 13
2.3 cDNA Arrays 14
2.3.1 Principles of PIQOR Technology 14
2.3.2 Selection and Annotation of Suitable cDNA Fragments 16
2.3.3 Production of Microarrays 17
2.3.4 Application of Microarrays 19
2.3.5 Array Data: Acquisition, Analysis, and Mining 20
2.4 Integrated Approaches using Microarrays 23
2.5 Combination of Microarrays and SAGE 24
References 25
Handbook of Toxicogenomics: Strategies and Applications. Edited by Jurgen Borlak
Copyright © 2005 WILEY VCH Verlag GmbH Co. KGaA, Weinheim
ISBN: 3 527 30342 1
XIV I Contents
3 Oligo Arrays, Global Transcriptome Analysis 27
Jacques Retief, Earl Hubbell, and David Finkelstein
3.1 Introduction to GeneChip® Microarray Technology 27
3.1.1 Introduction to RNA Expression Microarrays 27
3.1.2 GeneChip® RNA Expression Microarray Technology 27
3.1.3 Biological Annotations 35
3.1.4 Conclusions 43
3.1.5 Introduction to GeneChip® DNA mapping microarrays 44
3.1.6 GeneChip® DNA Mapping Microarray Technology 45
3.1.7 Conclusion 47
3.2 Experimental Design and Data Analysis 47
3.2.1 Introduction 47
3.2.2 Experimental Design 48
3.2.3 Data Assessment and Correction 66
3.2.4 Comparing Results 71
3.2.5 Conclusions 77
References 78
4 Toxicogenomics Applications of Open platform High Density
DNA Microarrays 83
Mark McCormick and Emile F. Nuwaysir
4.1 Introduction 83
4.2 Genome scale Expression Profiling 87
4.3 Multiplex Array Hybridization with NimbleScreen 12 88
4.4 NimbleScreen 4 90
4.5 Software for Open platform Array Design 92
4.6 Multiplex Array Control Elements 93
4.7 Multiplex Array Consistency 93
4.8 Conclusions 94
References 99
5 Mass Spectrometry and Proteomics: Principles and Applications 97
Uwe Rapp
5.1 Introduction 97
5.2 Analysis Tools in Proteomics 98
5.2.1 Separation Techniques 98
5.2.2 Mass Spectrometric Techniques 99
5.3 Application 100
5.3.1 Experimental Details 100
5.3.2 Results 101
5.3.3 Top Down Analysis 112
5.4 Summary and Outlook 112
References 113
Contents I XV
6 Covalent Protein Modification Analysis by Electrospray Tandem
Mass Spectrometry 115
WolfD. Lehmann
6.1 Introduction 225
6.2 Electrospray Ionization 227
6.3 Tandem Mass Spectrometry 227
6.4 Q TOF and Q FT ICR Systems 2 2 9
6.4.1 Resolution 229
6.4.2 Mass Accuracy 220
6.5 Peptide Sequencing by Electrospray Tandem Mass Spectrometry 222
6.6 Protein Modifications and their MS/MS Reactions 222
6.7 Detection of Protein Modifications by MS and MS/MS 224
6.7.1 Phosphorylation 226
6.7.2 Tyrosine Sulfation 232
6.7.3 Redox related Modifications 232
6.7.4 Myristoylation 232
6.7.5 Acetylation 233
6.7.6 Methylation 235
6.7.7 Glycosylation 235
6.7.8 Ubiquirination 235
6.7.9 Isoaspartate Formation 236
6.8 Summary and Outlook 236
References 137
7 Chromatin Immunoprecipitation based Identification of Cene
Regulatory Networks 243
Monika Niehqf andJurgen Borlak
7.1 Introduction 243
7.1.1 Importance of Identifying Transcriptional Regulatory Networks
in Toxicogenomics 243
7.1.2 Chromatin Immunoprecipitation to Analyze Target Genes 244
7.2 Description of Methods 244
7.2.1 Crosslinking Applications 244
7.2.2 Chromatin Fragmentation 246
7.2.3 Immunoprecipitation of Proteins 247
7.2.4 DNA Isolation and PCR Analyses 248
7.2.5 Cloning Strategies 248
7.2.6 Target Validation 250
7.3 Successfully Reported ChIP Cloning for New Target Identification 252
7.4 Problems and Potential Strategies 253
7.4.1 Elimination of Nonspecific DNA and Protein Protein Crosslinking 253
7.4.2 Enrichment of Target Promoters and High throughput Screening 253
7.5 Challenges for the Future 255
References 157
XVI I Contents
8 N M R Spectroscopy as a Versatile Analytical Platform for Toxicology
Research 163
Olivia Corcoran
8.1 A Role for NMR in Toxicogenomics 163
8.2 Evolution of NMR Technologies in Toxicology Research 164
8.2.1 Conventional NMR Spectroscopy 165
8.2.2 Flow NMR Methods 168
8.2.3 HRMAS NMR of Tissues 170
8.3 Metabolite Profiling by NMR 170
8.3.1 Inborn Errors of Metabolism 171
8.3.2 Reactive Metabolites 172
8.3.3 Animal Models of Toxicity 173
8.4 Biomarkers of Toxicity 173
8.4.1 Organ Toxicity 174
8.4.2 Forensic and Chemical Warfare Toxicology 175
8.4.3 Environmental Toxicity 176
8.5 Improvements in NMR Technology 177
8.5.1 Sensitivity and Throughput 177
8.5.2 Integrated NMR Chemical Analyzer 178
8.5.3 Metabolic and Genetic Profiling 179
8.6 Conclusions 179
References 180
Bioinformatic Tools in Toxicogenomics
9 Generation and Validation of a Reference System for Toxicogenomics
DNA Microarray Experiments 187
Jurgen Cox, Hans Cmunder, Andreas Hohn, and Hubert Rehrauer
9.1 Genomics and DNA Microarrays 287
9.2 Toxicogenomics 188
9.2.1 Challenges of Conventional Toxicology Approaches 188
9.2.2 Opportunities for Genomics 188
9.3 Processes and Methods for Toxicogenomics 188
9.3.1 Experimental Design 188
9.3.2 Data Quality Assessment 189
9.3.3 Reference Compendium Generation 190
9.3.4 Classification 191
9.4 Diagnosis of Microarray Data Quality 191
9.4.1 Sample Preparation 191
9.4.2 Dye Incorporation 192
9.4.3 Distortion 192
9.4.4 Impurities 193
9.4.5 Scanner Settings 193
Contents I XVII
9.4.6 Automation of Data Quality Control 193
9.4.7 Preprocessing of Microarray Data 193
9.5 Generating a Reference Compendium of Compounds 194
9.5.1 Cross Validation 195
9.6 Mechanism of Action 198
9.6.1 Alternative Structuring of Profiling Data 198
9.6.2 Promoter Analysis 199
9.6.3 Pathways 199
9.6.4 Mapping Gene Expression Profiles onto Genomes 199
9.6.5 In silico Comparative Genomics 199
9.7 Outlook 200
References 200
10 The Chemical Effects in Biological Systems (CEBS) Knowledge Base 201
Michael D. Waters, Gary Boorman, Pierre Bushel, Michael Cunningham,
Rick Irwin, Alex Merrick, Kenneth Olden, Richard Paules, James K. Selkirk,
Stanley Stasiewicz, Ben Van Houten, Nigel Walker, Brenda Weis,
Honghui Wan, and Raymond Tennant
10.1 Overview 201
10.2 NCT Intramural Research 204
10.3 Toxicogenomics Research Partnerships 206
10.4 Microarray Analysis 207
10.5 Implementation of a CEBS Prototype 208
10.6 Systems Toxicology: Bioinformatics and Interpretive Challenges 210
10.7 Understanding Functions of Biomarkers 211
10.7.1 Microarray Expression Profile Analysis 211
10.7.2 Coevolutional Profile Analysis 212
10.7.3 Domain Fusion Analysis 213
10.7.4 Structural Analysis 213
10.7.5 Text Mining in MEDLINE Based on Literature Profile Comparison 213
10.7.6 Integrative Analysis 214
10.8 Phased Development of the CEBS Knowledge Base 224
10.8.1 CEBS Phase I: Microarray/Gene Expression Data, Toxicology/Pathology
Data and Associated Analysis Tools 214
10.8.2 CEBS Phase II: Protein Expression Database and Metabolomics
Datasets 219
10.8.3 CEBS Phase III: Integrate Microarray/Gene Expression and Protein
Expression Databases using a Gene/Protein Group Strategy 220
10.8.4 CEBS Phase IV: Knowledge Technology 221
10.9 Conclusions 226
References 229
XVIII I Contents
11 Investigating the Effective Range of Agents by Using Integrative
Modelling 233
Andreas Freier, RalfHofestadt, and ThoralfToepel
11.1 Introduction 233
11.2 Mathematical Models 235
11.3 Modelling Molecular Databases 237
11.3.1 Drug Databases 237
11.3.2 Pathway Databases 238
11.3.3 Gene Expression Databases and Others 239
11.4 Integrative Modelling 240
11.4.1 Data Preprocessing 241
11.4.2 Object Oriented Models and Data Integration 241
11.4.2 Process Oriented Modelling Using Views 244
11.4.3 System Oriented Modelling and Simulation 246
11.4.4 Implementation 248
11.5 Summary 249
References 250
12 Databases and Tools for in silico Analysis of Regulation
of Gene Expression 253
Alexander Kel, Olga Kel Margoulis, and Edgar Wingender
12.1 Introduction 253
12.2 Concepts of Gene Regulation 253
12.2.1 Transcription Factors 254
12.2.2 Modern Concepts of the Structure and Function of the
Gene regulation Regions in the Genome 255
12.3 Databases Relating to Gene Regulation 260
12.3.1 TRANSFAC Database 262
12.4 Regulatory Sequence analysis Tools and Approaches 263
12.4.1 MotifAnalysis 264
12.4.2 Recognition of TF Binding Sites 266
12.4.3 Recognition of Composite Regulatory Elements 272
12.4.4 Analysis of Promoters 275
12.4.5 Functional Classification of Promoters and Prediction of
Gene Regulation 279
12.4.6 Phylogenetic Footprinting 281
12.5 Analysis of Gene Expression Data 281
12.5.1 Analysis of the Promoters of Coregulated Genes 282
References 285
Contents I XIX
13 Systems Biology Applied to Toxicogenomics 291
Klaus Prank, Matthias Hochsmann, Bjorn Oleson, Thomas Schmidt,
Leila Taher, and Dion Whitehead
13.1 Introduction to Systems Biology 291
13.1.1 System level Understanding of Biological Systems 294
13.1.2 Measurement Technology and Experimental Approaches 301
13.2 Data Mining and Reverse Engineering of Regulatory Networks 305
13.2.1 Data Mining Techniques 305
13.2.2 Inferring Gene Regulatory Networks from Gene Expression Data 307
13.2.3 Reverse Engineering of Metabolic and Signal transduction Pathways 308
13.3 Modelling and Simulation Software 310
13.3.1 Automated Model Generation 310
13.3.2 Parser 311
13.3.3 Systems Biology Workbench and Markup Languages 313
13.3.4 Parameter Estimation 317
13.3.5 Simulators 318
13.3.6 Visualization 320
13.4 Toward Predictive in silico Toxicogenomics 320
13.4.1 A Systems Biology Approach to ab initio Hepatotoxicity Testing 320
13.4.2 In silico Toxicogenomics for Personalized Medicine 321
13.4.3 Future of Predictive in silico Toxicity Testing in the R D Process 321
References 322
Application of Toxicogenomic: Case Studies
14 Regulatory Networks of Liver enriched Transcription Factors
in Liver Biology and Disease 327
Jurgen Borlak, Jurgen Klempnauer, and Harald Schrem
14.1 Introduction 327
14.2 The HNF l/HNF 4 Network for Liver specific Gene Expression 328
14.2.1 HNF 1 Regulates HNF 4alpha Expression 329
14.2.2 HNF lalpha and HNF 4 Regulate HNF lalpha Expression 329
14.2.3 Dimerization Cofactor of HNF lalpha and Liver specific
Gene Expression 331
14.2.4 Agonistic and Antagonistic Ligands for the Orphan Nuclear Receptor
HNF 4alpha 331
14.2.5 Coactivators for HNF 1 and HNF 4 and Their Network Effects in
Liver Biology 334
14.2.6 The Relevance of HNF 4alpha Splice Variants in Differential
Transcriptional Regulation 336
14.2.7 Activation and Repression by Homo and Heterodimerization
; of HNF 4alpha Proteins 336
XX I Contents
14.2.8 Posttranscriptional Modification of HNF 4 Function by Phosphorylation
and Acetylation 337
14.2.9 Cooperation and Competition between COUP TF and HNF 4 337
14.2.10 The Role of HNFs in CYP Monooxygenase Expression 338
14.3 HNF 6 and HNF 3beta in Liver specific Transcription Factor
Networks 339
14.3.1 HNF 6, OC 2, HNF 3beta, and C/EBPs Regulate HNF 3beta
Expression 339
14.3.2 Competition and Cooperation between HNF 3alpha and HNF 3beta 340
14.4 The Role of C/EBPs in Diverse Physiological Functions 340
14.4.1 C/EBP alpha in Energy Metabolism and Detoxification 340
14.4.2 C/EBP beta in Energy Metabolism 343
14.4.3 C/EBPs in the Acute phase Response 344
14.4.4 Protein Protein Interactions of C/EBP beta during the Acute phase
Response 347
14.4.5 C/EBPs in Liver Regeneration 348
14.4.6 C/EBPs and Apoptosis 349
14.4.7 C/EBPs in Liver Development 350
14.4.8 The Role of C/EBPs in CYP Monooxygenase Expression during
Development 350
14.4.9 C/EBPs and Their Role in Liver Tumour Biology 351
14.5 Involvement of C/EBP alpha and C/EBP beta in Regulation
of Cell Cycle Control 352
14.5.1 C/EBP alpha Expression and Growth Arrest 352
14.5.2 Glucocorticoid induced Gl Cell Cycle Arrest Is Mediated
by C/EBP alpha 352
14.5.3 Protein Protein Interactions between p21, cdk2, cdk4,
and C/EBP alpha 354
14.5.4 C/EBP alpha and plO7 Protein Protein Interaction Disrupts
E2F Complexes 355
14.5.5 C/EBP beta Arrests the Cell Cycle before the Gl/S Boundary 356
14.6 DBP Circadian Gene Regulation in the Liver 356
14.7 Conclusions and Outlook 358
References 360
15 Toxicogenomics Applied to Understanding Cholestasis and Steatosis
in the Liver 369
Timothy W. Cant, Peter Greaves, Andrew C. Smith, and Andreas Cescher
15.1 Introduction 369
15.2 Models of Cholestatsis and Steatosis 370
15.2.1 The Fech Mouse 370
15.2.2 Griseofulvin 371
15.2.3 ET743 371
15.2.4 Alpha napthylisothiocyanate (ANIT) 371
Contents I XXI
15.3 Pathological and Biochemical Characterization of the Models 372
15.3.1 Pathological Characterization 372
15.3.2 Protoporphyrin IX levels in Models of Ferrochelatase Inhibition 374
15.4 Microarray and Bioinformatics Methodology 375
15.5 Liver Gene Expression Altered Directly as a Response to
Griseofulvin 377
15.5.1 Genes of the Heme Synthesis and Catabolism Pathways 377
15.5.2 Monooxygenases 380
15.6 Gene Expression Changes Associated with Pathological Changes 381
15.6.1 Gene Expression Associated with Inflammation 381
15.6.2 CD24a 383
15.6.3 Annexins and Liver Damage or Maybe Cholestasis? 383
15.6.4 Fibrosis and Mallory Body Formation 383
15.7 Gleaning New Information on Pathological Changes from
Gene Expression Data 387
15.8 Conclusions 389
References 392
16 Toxicogenomics Applied to Cardiovascular Toxicity 395
Thomas Thum andjurgen Borlak
16.1 Introduction 395
16.2 Toxicogenomics Applied to Cardiovascular Toxicity 395
16.2.1 Drug induced Cardiac Arrhythmias 395
16.2.2 Drug induced Myocardial Apoptosis and Necrosis 396
16.2.3 Drug induced Cardiomyopathy and Myocardial Remodelling 398
16.2.4 Drug induced Myocarditis and Inflammation 399
16.2.5 Drug induced Effects on Cardiac Contractility 399
16.2.6 Drug induced Cardiac Hypertrophy 399
16.2.7 Drug induced Vascular Injury 400
16.3 Environmental Pollution and Cardiotoxicity: Effect of Halogenated
Aromatic Hydrocarbons 401
16.4 Importance of Single Nudeotide Polymorphisms (SNPs) and
Tissue specific Drug Metabolism in Cardiovascular Drug Therapy 402
16.4.1 Single Nudeotide Polymorphisms and Drug Treatment of
Cardiovascular Diseases 402
16.4.2 Tissue specific Metabolism in Cardiovascular Tissues 405
16.5 Conclusions 405
References 406
17 Toxicogenomics Applied to Endocrine Disruption 413
Damian C. Deavall, Jonathan C. Moggs, and George Orphanides
: 17.1 Introduction 413
; 17.1.1 Introduction to Endocrine Disruption 413
I 17.1.2 Therapeutic Endocrine Modulators 415
XXIII Contents
17.2 Molecular Mechanisms of Estrogen Signalling 416
17.2.1 Introduction to Estrogen Receptor Action 417
17.2.2 Extranudear Action of Estrogen Receptors Signalling Through Kinase
Cascades to Pleiotropic Transcriptional Effects 417
17.3 Current Methods for Assessing Endocrine disrupting Potential 418
17.3.1 Nuclear Receptor Binding Assays and Yeast Transactivation Assays 418
17.3.2 End point In vivo Assays for Potential Endocrine Disruptors 419
17.4 Value of Toxicogenomic Platforms to ED Toxicology 420
17.4.1 Genome scale Microarray Experiments Facilitate a Global View of
Gene Expression 420
17.4.2 Experimental Design 424
17.5 Data Interpretation 425
17.5.1 The Use of Hierarchical Gene Clustering to Fingerprint ED Modes
of Action Will Allow Mechanistic Determination 425
17.5.2 Pathway Analysis of ED Action 426
17.5.3 Predictive Testing of ED Potential Based on Transcript Profiling 428
17.6 Summary 429
References 430
18 Toxicogenomics Applied to Teratogenicity Studies 435
Philip C. Hewitt, Peter ]. Kramer, andjtirgen Borlak
18.1 Introduction 435
18.1.1 Current Testing Strategies: Established Procedures 438
18.1.2 Calcium Signalling and Foetal Development 439
18.1.3 Effect of Dose on Embryo Development 440
18.1.4 Effect of Time on Embryo Development 441
18.1.5 Issues Linked to the Placenta as a Barrier 442
18.1.6 Effect of Xenobiotic and Endogenous Metabolism 442
18.1.7 Mechanisms of Teratogenicity 443
18.2 Alternative Methods 443
18.2.1 Embryonic Stem Cells 443
18.2.2 Micromasses and Other Cell Culture Systems 444
18.2.3 Whole embryo Culture 444
18.2.4 Gene Expression Profiling 445
18.2.5 In Silico Studies 445
18.3 Molecular Aspects of Teratogenicity 445
18.3.1 Genes Responsible for Causing Birth Defects 445
18.3.2 Specific Genes Involved in Birth Defects 447
18.4 Case Study: Elucidation of Mechanisms of Teratogenic Toxicity
of the Developmental Drug EMD 82571 448
18.4.1 Properties of EMD 57033 and EMD 82571 448
18.4.2 Hypothesis driven Gene Expression Array 450
18.4.3 Global Expression Array (Affymetrix) 453
18.4.4 Results and Discussion 454
Contents I XXIII
18.5 Importance of Surrogate Markers for Prediction of Teratogenicity 464
18.6 Summary and Future of Gene Expression Profiling for Teratogenicity
Studies 464
References 465
19 Toxicogenomics Applied to Nephrotoxicity 471
Anke Liihe and Heinz Hildebrand
19.1 Brief Survey of Nephrotoxicity 471
19.1.1 Relevance and Occurrence of Nephrotoxic Effects 471
19.1.2 Different Modes of Nephrotoxicity 472
19.1.3 Actual Situation in Diagnosis and Mechanistic Investigation 474
19.1.4 New Perspectives Offered by Toxicogenomics 475
19.2 Toxicogenomic Approaches in Prediction of Toxicity and Mechanistic
Studies (Case Studies) 476
19.2.1 Prediction of Toxicity: Toxicogenomics Aimed at the Identification of
Markers of Renal Toxicity ( Fingerprinting ) 476
19.2.2 Mechanistic Studies: Toxicogenomics Aimed at Elucidating the Mode of
Nephrotoxic Action 478
19.3 Perspectives 483
References 484
20 Toxicogenomic Analysis of Human Umbilical Cords to Establish
a New Risk Assessment of Human Foetal Exposure to
Multiple Chemicals 487
Masatoshi Komiyama and Chisato Mori
20.1 Introduction 487
20.2 Strategy for Establishment of a New Risk assessment Method for
Human Foetal Exposure to Multiple Chemicals 488
20.3 Concentrations of Chemicals in Umbilical Cords of Neonates
in Japan 490
20.4 Gene Expression in Umbilical Cords 491
20.5 Toxicogenomic Analysis of Human Umbilical Cords 494
20.5.1 Principal Components Analysis 495
20.5.2 Hierarchical Cluster Analysis 495
20.5.3 Relation between Chemical Concentration and Gene Expression
in Umbilical Cords 497
20.5.4 Genes Contributing to Grouping of the Umbilical Cords 499
20.6 Conclusions 502
References 503
XXIV I Contents
21 Genetic Variability: Implications for Toxicogenomic Research 507
Gilbert Schonfelder, Dieter Schwarz, Thomas Cerloff,
Martin Paul, and War Roots
21.1 Introduction 507
21.2 Toxicity Due to Genetic Variability of Xenobiotic metabolizing
Enzymes 508
21.2.1 Genetic Variability in Carcinogen Activation by CYP450 Enzymes 509
21.2.2 Toxicity by Variants of Thiopurine Methyltransferase (TPMT) 517
21.2.3 Dihydropyrimidine Dehydrogenase 518
21.2.4 UDP glucuronosyl Transferase Enzymes 520
21.3 Involvement of Xenobiotic Transporter Systems in Toxicogenomics 521
21.3.1 MDR1 (ABCB1) 522
21.3.2 Multidrug Resistance related Proteins (MRPs, ABCC) 525
References 527
22 Profiling of Peripheral Blood Gene Expression to Search
for Biomarkers 535
Arno Kalkuhl and Mario Beilmann
22.1 Introduction 535
22.2 Objective 536
22.3 Methods 537
22.3.1 Animal Study 537
22.3.2 RNA Isolation 538
22.3.3 Differential Gene Expression Analysis and Statistics 539
22.4 Results and Discussion 540
22.4.1 Comparison of Analyzing Two Different Blood Cell Populations 540
22.4.2 Hemogram/Histopathology in the Animal Study 542
22.4.3 Analysis of the Number of Significantly Deregulated Genes 542
22.4.4 Analysis of Deregulated Genes in Blood after Cydosporin A
Administration 545
22.4.5 Analysis of Genes Deregulated in Blood and Target Organ 551
22.5 Summary 556
References 556
23 How Things Could Be Done Better Using Toxicogenomics:
A Retrospective Analysis 561
Laura Suter and Rodolfo Casser
23.1 Introduction 561
23.2 Case Example: Two 5 HT6 Receptor Antagonists Displaying Similar
Pharmacological Activity and Different Toxicity Profiles 562
23.2.1 Pharmacological Characteristics of the Compounds 562
23.2.2 Toxicological Findings in Rats and Dogs 563
Contents I XXV
23.3 The use of Toxicogenomics (Retrospectively) to Evaluate Hepatic
Liability 564
23.4 Classification of Compounds with the Use of a Reference
Gene Expression Database 566
23.4.1 Differentiation of Two Pharmacologically Closely Related
Compounds 567
23.4.2 Use of Gene Expression for Mechanistic Hypothesis Generation 569
23.4.3 Corroboration of the Mechanistic Hypothesis I: Validation of the
Technology 573
23.4.4 Corroboration of the Mechanistic Hypothesis II: in vitro Studies 575
23.5 Conclusions and Outlook 578
References 581
24 Toxicogenomics Applied to Hematotoxicology 583
Yoko Hirabayashi and Tohru Inoue
24.1 Introduction: Forward and Reverse Genomics 583
24.2 Hematopoietic Stem/Progenitor Cells in Hematotoxicology 585
24.3 Molecular Signature of Sternness of Hematopoietic Stem/Progenies 588
24.4 Radiation Hematotoxicity and Leukemogenesis 591
24.4.1 Radiation Effects on Hematopoietic Stem/Progenitor Cells 591
24.4.2 Radiation Exposure and Gene Expression Microarray 593
24.5 Benzene induced Hematotoxicity and Leukemogenesis 594
24.5.1 Benzene Exposure and Cell Cycle in Hematopoietic Stem/
Progenitor Cells 594
24.5.2 Gene expression Profile after Benzene Exposure in WT Mice 596
24.5.3 Cell cycle related Genes in p53 KO and WT Mice 598
24.5.4 Apoptosis related Genes in p53 KO and WT Mice 601
24.5.5 DNA repair related Genes in the p53 Gene Network 601
24.6 Summary 602
References 604
The National Toxicogenomic Program/Initiatives
25 The National Toxicogenomics Program 611
James K. Selkirk, Michael D. Waters, and Raymond W. Tennant
25.1 Introduction: The National Center for Toxicogenomics 611
25.2 Risk Assessment 613
25.3 The NCT Strategy 614
25.4 Toxicogenomics Broadly Defined 615
25.5 The Chemical Effects in Biological Systems (CEBS) Knowledge Base 617
25.6 Conclusions 618
j References 619
I
i
1
XXVII Contents
26 Toxicogenomics: Japanese Initiative 623
Tetsuro Urushidani and Taku Nagao
26.1 The Present State of Drug Development Genome Science 623
26.2 The Necessity of Toxicogenomics 625
26.3 Toxicogenomics Project 2002 2007 626
26.3.1 Planning Process and the Present Organization 626
26.3.2 Contents of the Project 627
26.3.3 Advantage and Originality of the Project 629
26.4 Future Perspectives and Conclusions 630
References 631
Point of View from Regulatory Authorities and Ethical Aspects
27 Toxicogenomics in Need of an ICH Guideline?
Experiences from the Past 635
Frauke Meyer and Cerd Bode
27.1 Introduction 635
27.2 Application Options for Toxicogenomics 636
27.2.1 Comparative/Predictive Toxicogenomics 636
27.2.2 Mechanistic Studies (Mode of Action) 637
27 .2.3 Risk Assessment 637
27.2.4 Dose dependent Toxicity 638
27.2.5 Interspecies Extrapolation 638
27.2.6 Human Biomarkers of Exposure 638
27.2.7 Regulatory Acceptance: Current Status 639
27.3 ICH Process for Harmonization of Guidelines: Experience
from the Past 640
27.3.1 Overview 640
27.3.2 ICH Carcinogenicity Guidelines as a Case Study: Experience with the
Implementation of Alternative Models in Cancer Risk Assessment 641
21A Incorporation of Toxicogenomics into Drug Development, Evaluation,
and Regulation: Benefits versus Risks 645
27.4.1 General Criteria for Successful Exploitation 645
27.4.2 Evaluation Process: Current Status 651
27.5 Summary and Outlook 653
References 655
Subject Index 657
|
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| callnumber-first | R - Medicine |
| callnumber-label | RA1224 |
| callnumber-raw | RA1224.3 |
| callnumber-search | RA1224.3 |
| callnumber-sort | RA 41224.3 |
| callnumber-subject | RA - Public Medicine |
| classification_rvk | VT 5300 VT 5350 XI 2150 |
| classification_tum | MED 950f CIT 840f CIT 972f |
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| dewey-search | 610 616.042 570 |
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| dewey-tens | 610 - Medicine and health 570 - Biology |
| discipline | Chemie / Pharmazie Biologie Chemie-Ingenieurwesen Biotechnologie Medizin |
| format | Book |
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| genre_facet | Aufsatzsammlung |
| id | DE-604.BV019883577 |
| illustrated | Illustrated |
| indexdate | 2024-07-09T20:08:20Z |
| institution | BVB |
| isbn | 3527303421 9783527303427 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-013207691 |
| oclc_num | 57637842 |
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| physical | XXXII, 673 S. Ill., graph. Darst. |
| publishDate | 2005 |
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| spelling | Handbook of toxicogenomics strategies and applications ed. by Jürgen Borlak Weinheim Wiley-VCH 2005 XXXII, 673 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Expression génique Génomique Protéomique Toxicologie génétique Gene expression Genetic toxicology Genomics Proteomics Toxicogenetics Arzneimittelentwicklung (DE-588)4143176-5 gnd rswk-swf Toxikologie (DE-588)4060538-3 gnd rswk-swf Gentoxikologie (DE-588)4338045-1 gnd rswk-swf Genomik (DE-588)4776397-8 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Gentoxikologie (DE-588)4338045-1 s DE-604 Toxikologie (DE-588)4060538-3 s Genomik (DE-588)4776397-8 s Arzneimittelentwicklung (DE-588)4143176-5 s b DE-604 Borlak, Jürgen 1958- Sonstige (DE-588)123081386 oth HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=013207691&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Handbook of toxicogenomics strategies and applications Expression génique Génomique Protéomique Toxicologie génétique Gene expression Genetic toxicology Genomics Proteomics Toxicogenetics Arzneimittelentwicklung (DE-588)4143176-5 gnd Toxikologie (DE-588)4060538-3 gnd Gentoxikologie (DE-588)4338045-1 gnd Genomik (DE-588)4776397-8 gnd |
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| title | Handbook of toxicogenomics strategies and applications |
| title_auth | Handbook of toxicogenomics strategies and applications |
| title_exact_search | Handbook of toxicogenomics strategies and applications |
| title_full | Handbook of toxicogenomics strategies and applications ed. by Jürgen Borlak |
| title_fullStr | Handbook of toxicogenomics strategies and applications ed. by Jürgen Borlak |
| title_full_unstemmed | Handbook of toxicogenomics strategies and applications ed. by Jürgen Borlak |
| title_short | Handbook of toxicogenomics |
| title_sort | handbook of toxicogenomics strategies and applications |
| title_sub | strategies and applications |
| topic | Expression génique Génomique Protéomique Toxicologie génétique Gene expression Genetic toxicology Genomics Proteomics Toxicogenetics Arzneimittelentwicklung (DE-588)4143176-5 gnd Toxikologie (DE-588)4060538-3 gnd Gentoxikologie (DE-588)4338045-1 gnd Genomik (DE-588)4776397-8 gnd |
| topic_facet | Expression génique Génomique Protéomique Toxicologie génétique Gene expression Genetic toxicology Genomics Proteomics Toxicogenetics Arzneimittelentwicklung Toxikologie Gentoxikologie Genomik Aufsatzsammlung |
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