Metabolism of Drugs and Other Xenobiotics

Description

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.

Table of Contents

Part One Biochemistry and Molecular Genetics of Drug Metabolism

• 1. Drug-Metabolizing Enzymes – An Overview
  Pavel Anzenbacher and Eva Anzenbacherová
1. Introduction: Fate of a Drug in the Human Body
2. Classifi cation Systems of Drug-Metabolizing Enzymes According to Different Criteria
3. Overview of the Most Important Drug-Metabolizing Enzymes
• Acknowledgments
• References

• 2. Cytochromes P450
  F. Peter Guengerich
1. Introduction and Historical Perspective
2. Nomenclature and Gene Organization
3. Regulation
4. Polymorphisms
5. Protein Structure
6. Catalytic Mechanisms
7. What Determines P450 Catalytic Selectivity?
8. Oxidative Stress and P450s
9. Relevance in Drug Metabolism and Clinical Medicine
• References

• 3. UDP-Glucuronosyltransferases
  Christian P. Strassburg and Sandra Kalthoff
1. Introduction
2. A Simple Phenotype: Unconjugated Nonhemolytic Hyperbilirubinemia and Glucuronidation
3. Organization of UGTs and the UGT1A Gene Locus
4. UGT1A Gene Nomenclature
5. Human UGT1A Gene Locus and Sequence Variability
6. Glucuronidation of Bilirubin
7. UGT1A1 Gene
8. Is There an Advantage or Risk Associated with UGT1A1 Variability?
9. UGT1A1 Gene and Pharmacogenetic Protection
10. UGT1A1 Gene and Pharmacogenetic Risks
11. UGT1A1 Variability and Cancer Risk
12. UGT1A3 Gene
13. UGT1A7 Gene
14. Transcriptional Regulation of UGT1A Genes
15. Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes
16. Regulation by Hepatic Nuclear Factors
17. Regulation by the Farnesoid X Receptor
18. Regulation by Nuclear Factor Erythroid 2-Related Factor 2
19. Regulation by Splice Variants
20. Animal Models to Study UGT1A Genes
21. Outlook
• Acknowledgments
• References

• 4. Sulfotransferases
  Michael W. H. Coughtrie
1. Introduction
2. Background
3. PAPS Synthesis
4. SULT Enzyme Family
5. Assays for SULT Activity
6. Structure and Function of SULT
7. SULT Pharmacogenetics
8. Bioactivation and the Role of SULTs in Toxicology
9. Conclusions and Future Perspectives
• References

• 5. Glutathione S-Transferases
  Miroslav Dostalek and Anna-Katarina Stark
1. Introduction and History
2. Nomenclature, Structure, and Function
3. Substrates
4. Regulation, Induction, and Inhibition
5. Gene Polymorphism of GSTs
• References

• 6. Hydrolytic Enzymes
  Bingfang Yan
1. Carboxylesterases
2. Epoxide Hydrolases
3. Paraoxonases
4. Other Hydrolases
• References

• 7. Transporting Systems
  Anne T. Nies, Claudia Resch, and Tadashi Namisaki
1. Introduction
2. Classification of Drug Transporters and Transport Mechanisms
3. Drug Transporters of the SLC Superfamily
4. ABC Drug Transporters
5. Drug Transporters and Disease
6. Drug Transporters and Pharmacokinetics
7. Role of Drug Transporters in Chemotherapy Resistance
8. Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response
• Acknowledgments
• References

• 8. Transcriptional Regulation of Human Drug-Metabolizing Cytochrome P450 Enzymes
  Zdenek Dvorak
1. Factors Affecting Drug-Metabolizing Cytochromes P450
2. Transcriptional Regulation of CYP
3. Regulation of Drug-Metabolizing CYPs
• Acknowledgments
• References

• 9. Importance of Pharmacogenomics
  Ulrich M. Zanger, Kathrin Klein, and Jessica Rieger
1. Introduction
2. Pharmacogenetic Polymorphisms
3. Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype
4. Genomics Technologies and Approaches
5. Conclusions
• References

Part Two Metabolism of Drugs

• 10. Introduction to Drug Metabolism
  Ulrich M. Zanger
1. Introduction
2. Historical Aspects
3. Diversity of Drug Metabolic Pathways
4. Infl uence of Drug Metabolism on Pharmacological Activity
5. Biotoxification
6. Extrahepatic Drug Metabolism
7. Factors Affecting Drug Metabolism Activity
8. Conclusions
• References

• 11. Central Nervous System Drugs
  Pierre Baumann and Christoph Hiemke
1. Introduction
2. Antidepressants
3. Antipsychotics
4. Tranquillizers and Hypnotic Agents
5. Psychostimulants
6. Anticonvulsants and Mood Stabilizers
7. Agents for Dementia and Cognitive Enhancers
8. Antimigraine Drugs
9. Other Drugs
10. Conclusions
• References

• 12. Cardiovascular Drugs
  Stephan Riedmaier and Ulrich M. Zanger
1. Introduction
2. RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers
3. Adrenergic Receptor Agonists
4. Adrenergic Receptor Antagonists
5. Diuretics
6. Antiarrhythmics
7. Anticoagulants
8. Cholesterol-Lowering Drugs
• References

• 13. Anticancer Drugs
  Matthias Schwab, Elke Schaeffeler, and Hiltrud Brauch
1. Introduction
2. Alkylating Drugs
3. Platinum-Containing Agents
4. Antimetabolites
5. Natural Products
6. Endocrine Therapy
7. Histone Deacetylase Inhibitor (Vorinostat)
8. Tyrosine Kinase Inhibitors
9. Proteasome Inhibitor (Bortezomib)
• References

• 14. Antimicrobial Agents
  Chantal Csajka, Oscar Marchetti, Oriol Manuel, Laurent Decosterd, and Amalio Telenti
1. Introduction
2. Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents
3. Pharmacogenetics
4. Conclusions
• Acknowledgments
• References

• 15. Drugs against Acute and Chronic Pain
  Andrew A. Somogyi and Janet K. Coller
1. Introduction
2. Acute Pain
3. Chronic Pain
• References

• 16. Drugs of Abuse (Including Designer Drugs)
  Markus R. Meyer and Hans H. Maurer
1. Introduction
2. Classic Drugs of Abuse
3. Designer Drugs of Abuse
• References

• 17. Nicotine Metabolism and its Implications
  Andy Z.X. Zhu and Rachel F. Tyndale
1. Introduction
2. Absorption and Distribution of Nicotine
3. Excretion of Nicotine
4. Metabolism of Nicotine
5. Sources of Variation in Nicotine Metabolism
6. Implications of Variation in Nicotine Metabolism and CYP2A6 Activity
7. Conclusions
• Acknowledgments
• References

• 18. Metabolism of Alcohol and its Consequences
  Helmut K. Seitz and Sebastian Mueller
1. Introduction
2. Properties and Sources of Ethanol
3. Ethanol Absorption and Elimination
4. Ethanol Metabolism
• Acknowledgments
• References

Part Three Metabolism of Natural Compounds

• 19. Introduction and Overview
  Michael Murray
1. Introduction
2. Terpenoids: A Structurally Complex Group of Natural Products
3. Other Classes of Natural Products
4. Summary and Conclusions
• Acknowledgments
• References

• 20. Flavonoids
  Petr Hodek
1. Flavonoids – Plant Phytochemicals
2. Absorption and Metabolism of Flavonoids
3. Interactions of Flavonoids with Mammalian Proteins with Possible Implications for Drug Metabolism
4. Dietary Flavonoids – Health Issues
5. Flavonoid–Drug Interactions
6. Conclusion – Double-Edged Sword Properties of Flavonoids
• References

• 21. St John’s Wort (Hypericum perforatum L.)
  Miroslav Dostalek and Anna-Katarina Stark
1. The Name Hypericum
2. Chemical Constituents of Hypericum perforatum
3. Clinical Pharmacology of H. perforatum
4. Pharmacokinetics and Pharmacokinetic Interactions of H. perforatum
5. In Vitro Studies
6. In Vivo Studies
• Acknowledgments
• References

• 22. Food Components and Supplements
  Alexandr Parlesak
1. Introduction
2. Food Contaminants
3. Vitamins
4. Macronutrients
5. Secondary Plant Metabolites
6. Probiotics and Prebiotics in the Modulation of Drug Metabolism
• References
• Part Four Metabolism of Unnatural Xenobiotics

• 23. Environmental Pollutants
  Marie Stiborova
1. Introduction – An Overview
2. Overview of Environmental Pollutants
3. Toxic and Hazardous Environmental Pollutants Interacting with Drug Metabolism
4. Summary
• References

• 24. Environmental Estrogens
  Miroslav Machala and Jan Vondrácˇek
1. Introduction
2. Estrogen Receptor Signaling Pathways
3. Agonistic/Antagonistic Effects of Xenobiotics on ERs
4. Effects of EDCs on Biosynthesis and Metabolism of Estrogens
5. Case of Polychlorinated Biphenyls
6. Conclusions
• References

• 25. Biotransformation of Insecticides
  Corie A. Ellison, Alice L. Crane, and James R. Olson
1. Introduction to Insecticides
2. Metabolism of Insecticides
3. Extrahepatic Metabolism of Insecticides
4. Factors Affecting Metabolism
5. Conclusions
• Note
• References

• Index

Author Information

Pavel Anzenbacher heads the Department of Pharmacology at Palacky University, Olomouc (Czech Republic). Having obtained his academic degrees from Charles University, Prague and from the Academy of Sciences of the Czech Republic he joined the Faculty of Medicine at Palacky University. His scientific contacts and stays have included e.g. the Princeton University, University of Connecticut, INSERM Montpellier, University of Lubeck, Technical University Berlin and Cracow University. Professor Anzenbacher has authored over 150 original scientific publications has, among other honours, received the Fogarty Award of the USPHS.

Ulrich M. Zanger is the Deputy Head of the Margarete Fischer Bosch Institute for Clinical Pharmacology, Stuttgart (Germany). A chemist by training, Dr. Zanger began to work on drug metabolism at the Biocenter of the University of Basel, Switzerland, where he obtained a PhD degree in biochemistry in 1988. He undertook postdoctoral studies at the Southwestern Medical Center at Dallas, Texas before returning to Basel and later moving to Stuttgart. His major research interests are in drug metabolism, basic and clinical aspects of pharmacogenetics / genomics, and molecular genetics of human drug metabolizing cytochromes P450. Dr. Zanger has authored more than 130 scientific articles and is lecturing in Pharmacology and Toxicology at the University of Tübingen.