A practice-oriented desktop reference for 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 briefly 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. Selected, well-documented case studies from the most important xenobiotics classes illustrate general principles of metabolism, making this equally useful for teaching courses on 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. INDICE: Part One Biochemistry and Molecular Genetics of Drug Metabolism 11Drug-Metabolizing Enzymes - An Overview 3Pavel Anzenbacher and Eva AnzenbacherovÃí1.1 Introduction: Fate of a Drug in the Human Body 31.2 Classifi cation Systems of Drug-Metabolizing Enzymes According to Different Criteria 41.3 Overview of the Most Important Drug-Metabolizing Enzymes 6Acknowledgments 20References 202 Cytochromes P450 27F. Peter Guengerich2.1 Introduction and Historical Perspective 272.2 Nomenclature and Gene Organization 292.3 Regulation 322.4 Polymorphisms 352.5 Protein Structure 372.6 Catalytic Mechanisms 402.7 What Determines P450 Catalytic Selectivity? 452.8 Oxidative Stress and P450s 472.9 Relevance in Drug Metabolism and Clinical Medicine 48References 533 UDP-Glucuronosyltransferases 67Christian P. Strassburg and Sandra Kalthoff3.1 Introduction 673.2 A Simple Phenotype: Unconjugated Nonhemolytic Hyperbilirubinemia and Glucuronidation 673.3 Organization of UGTs and the UGT1A Gene Locus 683.4 UGT1A Gene Nomenclature 703.5 Human UGT1A Gene Locus and Sequence Variability 713.6 Glucuronidation of Bilirubin 783.7 UGT1A1 Gene 793.8 Is There an Advantage or Risk Associated with UGT1A1 Variability? 803.9 UGT1A1 Gene and Pharmacogenetic Protection 823.10 UGT1A1 Gene and Pharmacogenetic Risks 833.11 UGT1A1 Variability and Cancer Risk 863.12 UGT1A3 Gene 873.13 UGT1A7 Gene 883.14 Transcriptional Regulation of UGT1A Genes 953.15 Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes 953.16 Regulation by Hepatic Nuclear Factors 973.17 Regulation by the Farnesoid X Receptor 973.18 Regulation by Nuclear Factor Erythroid 2-Related Factor 2 983.19 Regulation by Splice Variants 983.20 Animal Models to Study UGT1A Genes 993.21 Outlook 100Acknowledgments 101References 1014 Sulfotransferases 117Michael W. H. Coughtrie4.1 Introduction 1174.2 Background 1184.3 PAPS Synthesis 1194.4 SULT Enzyme Family 1214.5 Assays for SULT Activity 1284.6 Structure and Function of SULT 1284.7 SULT Pharmacogenetics 1324.8 Bioactivation and the Role of SULTs in Toxicology 1334.9 Conclusions and Future Perspectives 135References 1355 Glutathione S-Transferases 147Miroslav Dostalek and Anna-Katarina Stark5.1 Introduction andHistory 1475.2 Nomenclature, Structure, and Function 1485.3 Substrates 1515.4Regulation, Induction, and Inhibition 1515.5 Gene Polymorphism of GSTs 155References 1576 Hydrolytic Enzymes 165Bingfang Yan6.1 Carboxylesterases 1656.2 Epoxide Hydrolases 1786.3 Paraoxonases 1836.4 Other Hydrolases 188References 1917 Transporting Systems 199Anne T. Nies, Claudia Resch, and Tadashi Namisaki7.1Introduction 1997.2 Classification of Drug Transporters and Transport Mechanisms 1997.3 Drug Transporters of the SLC Superfamily 2007.4 ABC Drug Transporters 2087.5 Drug Transporters and Disease 2087.6 Drug Transporters and Pharmacokinetics 2127.7 Role of Drug Transporters in Chemotherapy Resistance 2147.8 Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response 215Acknowledgments 215References 2168 Transcriptional Regulation of Human Drug-Metabolizing Cytochrome P450 Enzymes 223Zdenek Dvorak8.1 Factors Affecting Drug-Metabolizing Cytochromes P450 2238.2 Transcriptional Regulation of CYP 2248.3Regulation of Drug-Metabolizing CYPs 230Acknowledgments 238References 2389 Importance of Pharmacogenomics 259Ulrich M. Zanger, Kathrin Klein, and Jessica Rieger9.1 Introduction 2599.2 Pharmacogenetic Polymorphisms 2609.3 Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype 2709.4 Genomics Technologies and Approaches 2739.5 Conclusions 276References 276Part Two Metabolism ofDrugs 28510 Introduction to Drug Metabolism 287Ulrich M. Zanger10.1 Introduction 28710.2 Historical Aspects 28710.3 Diversity of Drug Metabolic Pathways 28810.4 Infl uence of Drug Metabolism on Pharmacological Activity 28910.5 Biotoxification 29010.6 Extrahepatic Drug Metabolism 29010.7 Factors Affecting Drug Metabolism Activity 29110.8 Conclusions 296References 29611 Central Nervous System Drugs 301Pierre Baumann and Christoph Hiemke11.1 Introduction 30111.2 Antidepressants 30111.3 Antipsychotics 30611.4 Tranquillizers and Hypnotic Agents30911.5 Psychostimulants 31111.6 Anticonvulsants and Mood Stabilizers 31111.7Agents for Dementia and Cognitive Enhancers 31311.8 Antimigraine Drugs 31311.9 Other Drugs 31411.10 Conclusions 314References 31512 Cardiovascular Drugs 331Stephan Riedmaier and Ulrich M. Zanger12.1 Introduction 33112.2 RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers 33112.3 Adrenergic Receptor Agonists 33712.4 Adrenergic Receptor Antagonists 33912.5 Diuretics 34212.6 Antiarrhythmics 34912.7 Anticoagulants 35112.8 Cholesterol-Lowering Drugs 353References 35713 Anticancer Drugs 365Matthias Schwab, Elke Schaeffeler, and Hiltrud Brauch13.1 Introduction 36513.2 Alkylating Drugs 36513.3 Platinum-Containing Agents 36713.4 Antimetabolites 36713.5 Natural Products 37013.6 Endocrine Therapy 37213.7 Histone Deacetylase Inhibitor (Vorinostat) 37313.8 Tyrosine Kinase Inhibitors 37313.9 Proteasome Inhibitor (Bortezomib) 374References 37414 Antimicrobial Agents 379Chantal Csajka, Oscar Marchetti,Oriol Manuel, Laurent Decosterd, and Amalio Telenti14.1 Introduction 37914.2 Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents38014.3 Pharmacogenetics 39314.4 Conclusions 397Acknowledgments 398References39815 Drugs against Acute and Chronic Pain 403Andrew A. Somogyi and Janet K. Coller15.1 Introduction 40315.2 Acute Pain 40315.3 Chronic Pain 410References 42116 Drugs of Abuse (Including Designer Drugs) 429Markus R. Meyer and Hans H.Maurer16.1 Introduction 42916.2 Classic Drugs of Abuse 43216.3 Designer Drugsof Abuse 435References 45017 Nicotine Metabolism and its Implications 465AndyZ.X. Zhu and Rachel F. Tyndale17.1 Introduction 46517.2 Absorption and Distribution of Nicotine 46517.3 Excretion of Nicotine 46617.4 Metabolism of Nicotine 46817.5 Sources of Variation in Nicotine Metabolism 47117.6 Implications of Variation in Nicotine Metabolism and CYP2A6 Activity 48117.7 Conclusions 483Acknowledgments 483References 48418 Metabolism of Alcohol and its Consequences 493Helmut K. Seitz and Sebastian Mueller18.1 Introduction 49318.2 Properties and Sources of Ethanol 49418.3 Ethanol Absorption and Elimination 49518.4 Ethanol Metabolism 497Acknowledgments 511References 511Part Three Metabolism of Natural Compounds 51719 Introduction and Overview 519Michael Murray19.1 Introduction 51919.2 Terpenoids: A Structurally Complex Group of Natural Products 52219.3 Other Classes of Natural Products 53119.4 Summary and Conclusions 536Acknowledgments 536References 53620 Flavonoids 543Petr Hodek20.1 Flavonoids - Plant Phytochemicals 54320.2 Absorption and Metabolism of Flavonoids 54520.3 Interactions of Flavonoids with Mammalian Proteins with Possible Implications for DrugMetabolism 55420.4 Dietary Flavonoids - Health Issues 56220.5 Flavonoid-Drug Interactions 57020.6 Conclusion - Double-Edged Sword Properties of Flavonoids 573References 57421 St John’s Wort (Hypericum perforatum L.) 583Miroslav Dostalek and Anna-Katarina Stark21.1 The Name Hypericum 58321.2 Chemical Constituents of Hypericum perforatum 58321.3 Clinical Pharmacology of H. perforatum 58721.4 Pharmacokinetics and Pharmacokinetic Interactions of H. perforatum 58821.5In Vitro Studies 59121.6 In Vivo Studies 592Acknowledgments 592References 60322 Food Components and Supplements 611Alexandr Parlesak22.1 Introduction 61122.2 Food Contaminants 61222.3 Vitamins 61622.4 Macronutrients 62022.5 SecondaryPlant Metabolites 62222.6 Probiotics and Prebiotics in the Modulation of DrugMetabolism 628References 629Part Four Metabolism of Unnatural Xenobiotics 63723 Environmental Pollutants 639Marie Stiborova23.1 Introduction - An Overview 63923.2 Overview of Environmental Pollutants 64123.3 Toxic and Hazardous Environmental Pollutants Interacting with Drug Metabolism 64223.4 Summary 660References 66124 Environmental Estrogens 671Miroslav Machala and Jan VondrÃícˇek24.1 Introduction 67124.2 Estrogen Receptor Signaling Pathways 67224.3 Agonistic/Antagonistic Effects of Xenobiotics on ERs 67324.4 Effects of EDCs on Biosynthesis and Metabolism of Estrogens 67624.5 Case of Polychlorinated Biphenyls 67724.6 Conclusions 678References 67925 Biotransformation of Insecticides 685Corie A. Ellison, Alice L. Crane, and James R. Olson25.1 Introduction to Insecticides 68525.2 Metabolism of Insecticides 68825.3 Extrahepatic Metabolism of Insecticides 69325.4 Factors Affecting Metabolism 69425.5 Conclusions 697Note 697References 697Index 703
- ISBN: 978-3-527-32903-8
- Editorial: Wiley-VCH
- Encuadernacion: Cartoné
- Páginas: 753
- Fecha Publicación: 25/04/2012
- Nº Volúmenes: 1
- Idioma: Inglés