1300 187 187
A practice-oriented desktop reference for medical professionals, toxicologists and pharmaceutical researchers, this handbook provides
systematic coverage of the metabolic pathways of all major classes of xenobiotics in the human body. The first part comprehensively reviews
the main enzyme systems involved in biotransformation and how they are orchestrated in the body, while parts two to four cover the three
main classes of xenobiotics: drugs, natural products, environmental pollutants. The part on drugs includes more than 300 substances from
five major therapeutic groups (central nervous system, cardiovascular system, cancer, infection, and pain) as well as most drugs of abuse
including nicotine, alcohol and ?designer? drugs. Selected, well-documented case studies from the most important xenobiotics classes illustrate general principles of metabolism, making this equally useful for teaching courses on pharmacology, drug metabolism or molecular
toxicology.
Of particular interest, and unique to this volume is the inclusion of a wide range of additional xenobiotic compounds, including food supplements, herbal preparations, and agrochemicals.
1 Drug-Metabolizing Enzymes – An Overview 3
Pavel Anzenbacher and Eva Anzenbacherová
1.1 Introduction: Fate of a Drug in the Human Body 3
1.2 Classifi cation Systems of Drug-Metabolizing Enzymes According to Different Criteria 4
1.3 Overview of the Most Important Drug-Metabolizing Enzymes 6
Acknowledgments 20
References 20
2 Cytochromes P450 27
F. Peter Guengerich
2.1 Introduction and Historical Perspective 27
2.2 Nomenclature and Gene Organization 29
2.3 Regulation 32
2.4 Polymorphisms 35
2.5 Protein Structure 37
2.6 Catalytic Mechanisms 40
2.7 What Determines P450 Catalytic Selectivity? 45
2.8 Oxidative Stress and P450s 47
2.9 Relevance in Drug Metabolism and Clinical Medicine 48
References 53
3 UDP-Glucuronosyltransferases 67
Christian P. Strassburg and Sandra Kalthoff
3.1 Introduction 67
3.2 A Simple Phenotype: Unconjugated Nonhemolytic Hyperbilirubinemia and Glucuronidation 67
3.3 Organization of UGTs and the UGT1A Gene Locus 68
3.4 UGT1A Gene Nomenclature 70
3.5 Human UGT1A Gene Locus and Sequence Variability 71
3.6 Glucuronidation of Bilirubin 78
3.7 UGT1A1 Gene 79
3.8 Is There an Advantage or Risk Associated with UGT1A1 Variability? 80
3.9 UGT1A1 Gene and Pharmacogenetic Protection 82
3.10 UGT1A1 Gene and Pharmacogenetic Risks 83
3.11 UGT1A1 Variability and Cancer Risk 86
3.12 UGT1A3 Gene 87
3.13 UGT1A7 Gene 88
3.14 Transcriptional Regulation of UGT1A Genes 95
3.15 Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes 95
3.16 Regulation by Hepatic Nuclear Factors 97
3.17 Regulation by the Farnesoid X Receptor 97
3.18 Regulation by Nuclear Factor Erythroid 2-Related Factor 2 98
3.19 Regulation by Splice Variants 98
3.20 Animal Models to Study UGT1A Genes 99
3.21 Outlook 100
Acknowledgments 101
References 101
4 Sulfotransferases 117
Michael W. H. Coughtrie
4.1 Introduction 117
4.2 Background 118
4.3 PAPS Synthesis 119
4.4 SULT Enzyme Family 121
4.5 Assays for SULT Activity 128
4.6 Structure and Function of SULT 128
4.7 SULT Pharmacogenetics 132
4.8 Bioactivation and the Role of SULTs in Toxicology 133
4.9 Conclusions and Future Perspectives 135
References 135
5 Glutathione S-Transferases 147
Miroslav Dostalek and Anna-Katarina Stark
5.1 Introduction and History 147
5.2 Nomenclature, Structure, and Function 148
5.3 Substrates 151
5.4 Regulation, Induction, and Inhibition 151
5.5 Gene Polymorphism of GSTs 155
References 1576
Hydrolytic Enzymes 165
Bingfang Yan
6.1 Carboxylesterases 165
6.2 Epoxide Hydrolases 178
6.3 Paraoxonases 183
6.4 Other Hydrolases 188
References 191
7 Transporting Systems 199
Anne T. Nies, Claudia Resch, and Tadashi Namisaki
7.1 Introduction 199
7.2 Classification of Drug Transporters and Transport Mechanisms 199
7.3 Drug Transporters of the SLC Superfamily 200
7.4 ABC Drug Transporters 208
7.5 Drug Transporters and Disease 208
7.6 Drug Transporters and Pharmacokinetics 212
7.7 Role of Drug Transporters in Chemotherapy Resistance 214
7.8 Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response 215
Acknowledgments 215
References 216
8 Transcriptional Regulation of Human Drug-Metabolizing Cytochrome P450 Enzymes 223
Zdenek Dvorak
8.1 Factors Affecting Drug-Metabolizing Cytochromes P450 223
8.2 Transcriptional Regulation of CYP 224
8.3 Regulation of Drug-Metabolizing CYPs 230
Acknowledgments 238
References 238
9 Importance of Pharmacogenomics 259
Ulrich M. Zanger, Kathrin Klein, and Jessica Rieger
9.1 Introduction 259
9.2 Pharmacogenetic Polymorphisms 260
9.3 Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype 270
9.4 Genomics Technologies and Approaches 273
9.5 Conclusions 276
References 276
Part Two Metabolism of Drugs 285
10 Introduction to Drug Metabolism 287
Ulrich M. Zanger
10.1 Introduction 287
10.2 Historical Aspects 287
10.3 Diversity of Drug Metabolic Pathways 288
10.4 Infl uence of Drug Metabolism on Pharmacological Activity 289
10.5 Biotoxification 290
10.6 Extrahepatic Drug Metabolism 290
10.7 Factors Affecting Drug Metabolism Activity 291
10.8 Conclusions 296
References 296
11 Central Nervous System Drugs 301
Pierre Baumann and Christoph Hiemke
11.1 Introduction 301
11.2 Antidepressants 301
11.3 Antipsychotics 306
11.4 Tranquillizers and Hypnotic Agents 309
11.5 Psychostimulants 311
11.6 Anticonvulsants and Mood Stabilizers 311
11.7 Agents for Dementia and Cognitive Enhancers 313
11.8 Antimigraine Drugs 313
11.9 Other Drugs 314
11.10 Conclusions 314
References 315
12 Cardiovascular Drugs 331
Stephan Riedmaier and Ulrich M. Zanger
12.1 Introduction 331
12.2 RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers 331
12.3 Adrenergic Receptor Agonists 337
12.4 Adrenergic Receptor Antagonists 339
12.5 Diuretics 342
12.6 Antiarrhythmics 349
12.7 Anticoagulants 351
12.8 Cholesterol-Lowering Drugs 353
References 357
13 Anticancer Drugs 365
Matthias Schwab, Elke Schaeffeler, and Hiltrud Brauch
13.1 Introduction 365
13.2 Alkylating Drugs 365
13.3 Platinum-Containing Agents 367
13.4 Antimetabolites 367
13.5 Natural Products 370
13.6 Endocrine Therapy 372
13.7 Histone Deacetylase Inhibitor (Vorinostat) 373
13.8 Tyrosine Kinase Inhibitors 373
13.9 Proteasome Inhibitor (Bortezomib) 374
References 374
14 Antimicrobial Agents 379
Chantal Csajka, Oscar Marchetti, Oriol Manuel, Laurent Decosterd, and Amalio Telenti
14.1 Introduction 379
14.2 Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents 380
14.3 Pharmacogenetics 393
14.4 Conclusions 397
Acknowledgments 398
References 398
15 Drugs against Acute and Chronic Pain 403
Andrew A. Somogyi and Janet K. Coller
15.1 Introduction 403
15.2 Acute Pain 403
15.3 Chronic Pain 410
References 421
16 Drugs of Abuse (Including Designer Drugs) 429
Markus R. Meyer and Hans H. Maurer
16.1 Introduction 429
16.2 Classic Drugs of Abuse 432
16.3 Designer Drugs of Abuse 435
References 450
17 Nicotine Metabolism and its Implications 465
Andy Z.X. Zhu and Rachel F. Tyndale
17.1 Introduction 465
17.2 Absorption and Distribution of Nicotine 465
17.3 Excretion of Nicotine 466
17.4 Metabolism of Nicotine 468
17.5 Sources of Variation in Nicotine Metabolism 471
17.6 Implications of Variation in Nicotine Metabolism and CYP2A6 Activity 481
17.7 Conclusions 483
Acknowledgments 483
References 484
18 Metabolism of Alcohol and its Consequences 493
Helmut K. Seitz and Sebastian Mueller
18.1 Introduction 493
18.2 Properties and Sources of Ethanol 494
18.3 Ethanol Absorption and Elimination 495
18.4 Ethanol Metabolism 497
Acknowledgments 511
References 511
Part Three Metabolism of Natural Compounds 517
19 Introduction and Overview 519
Michael Murray
19.1 Introduction 519
19.2 Terpenoids: A Structurally Complex Group of Natural Products 522
19.3 Other Classes of Natural Products 531
19.4 Summary and Conclusions 536
Acknowledgments 536
References 536
20 Flavonoids 543
Petr Hodek
20.1 Flavonoids – Plant Phytochemicals 543
20.2 Absorption and Metabolism of Flavonoids 545
20.3 Interactions of Flavonoids with Mammalian Proteins with Possible Implications for Drug Metabolism 554
20.4 Dietary Flavonoids – Health Issues 562
20.5 Flavonoid–Drug Interactions 570
20.6 Conclusion – Double-Edged Sword Properties of Flavonoids 573
References 574
21 St John’s Wort (Hypericum perforatum L.) 583
Miroslav Dostalek and Anna-Katarina Stark
21.1 The Name Hypericum 583
21.2 Chemical Constituents of Hypericum perforatum 583
21.3 Clinical Pharmacology of H. perforatum 587
21.4 Pharmacokinetics and Pharmacokinetic Interactions of H. perforatum 588
21.5 In Vitro Studies 591
21.6 In Vivo Studies 592
Acknowledgments 592
References 603
22 Food Components and Supplements 611
Alexandr Parlesak
22.1 Introduction 611
22.2 Food Contaminants 612
22.3 Vitamins 616
22.4 Macronutrients 620
22.5 Secondary Plant Metabolites 622
22.6 Probiotics and Prebiotics in the Modulation of Drug Metabolism 628
References 629
Part Four Metabolism of Unnatural Xenobiotics 637
23 Environmental Pollutants 639
Marie Stiborova
23.1 Introduction – An Overview 639
23.2 Overview of Environmental Pollutants 641
23.3 Toxic and Hazardous Environmental Pollutants Interacting with Drug Metabolism 642
23.4 Summary 660
References 661
24 Environmental Estrogens 671
Miroslav Machala and Jan Vondrácˇek
24.1 Introduction 671
24.2 Estrogen Receptor Signaling Pathways 672
24.3 Agonistic/Antagonistic Effects of Xenobiotics on ERs 673
24.4 Effects of EDCs on Biosynthesis and Metabolism of Estrogens 676
24.5 Case of Polychlorinated Biphenyls 677
24.6 Conclusions 678
References 679
25 Biotransformation of Insecticides 685
Corie A. Ellison, Alice L. Crane, and James R. Olson
25.1 Introduction to Insecticides 685
25.2 Metabolism of Insecticides 688
25.3 Extrahepatic Metabolism of Insecticides 693
25.4 Factors Affecting Metabolism 694
25.5 Conclusions 697
Note 697
References 697
Index 703
ISBN: 9783527329038
ISBN-10: 352732903X
Audience:
Professional
Format:
Hardcover
Language:
English
Number Of Pages: 753
Published: 29th May 2012
Dimensions (cm): 24.7 x 17.9
x 3.851
Weight (kg): 1.516
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