Metabolism of Drugs and Other Xenobiotics

Pavel Anzenbacher heads the Department of Pharmacology at Palacky University, Olomouc (Czech Republic) and is vicepresident of the Czech Society of Clinical and Experimental Pharmacology and Toxicology. 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, Vanderbilt University, Nashville, University of Connecticut, INSERM Montpellier, University of Lubeck, Technical University Berlin and Jagellonian University Cracow. Professor Anzenbacher has authored over 150 original scientific publications and has, among other honours, received the Fogarty Award of the USPHS. Ulrich M. Zanger is deputy head of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart (Germany). A chemist by training, he began to work on drug metabolism at the Biocenter of the University of Basel, Switzerland, where he obtained a PhD degree in biochemistry. 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 human drug metabolizing cytochromes P450 and in basic and clinical aspects of pharmacogenetics/genomics. Professor Zanger has authored more than 130 scientific articles and is lecturing in pharmacology and toxicology at the University of Tübingen.

Preface

PART ONE: Biochemistry and Molecular Genetics of Drug Metabolism

DRUG-METABOLIZING ENZYMES - AN OVERVIEW
Introduction: Fate of a Drug in the Human Body
Classification Systems of Drug-Metabolizing Enzymes According to Different Criteria
Overview of the Most Important Drug-Metabolizing Enzyme

CYTOCHROMES P450
Introduction and Historical Perspective
Nomenclature and Gene Organization
Regulation
Polymorphisms
Protein Structure
Catalytic Mechanisms
What Determines P450 Catalytic Selectivity?
Oxidative Stress and P450s
Relevance in Drug Metabolism and Clinical Medicine

UDP-GLUCURONOSYLTRANSFERASES
Introduction
A Simple Phenotype: Unconjugated Nonhemolytic
Hyperbilirubinemia and Glucuronidation
Organization of UGTs and the UGT1A Gene Locus
UGT1A Gene Nomenclature
Human UGT1A Gene Locus and Sequence Variability
Glucuronidation of Bilirubin
UGT1A1 Gene
Is There an Advantage or Risk Associated with UGT1A1 Variability?
UGT1A1 Gene and Pharmacogenetic Protection
UGT1A1 Gene and Pharmacogenetic Risks
UGT1A1 Variability and Cancer Risk
UGT1A3 Gene
UGT1A7 Gene
Transcriptional Regulation of UGT1A Genes
Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes
Regulation by Hepatic Nuclear Factors
Regulation by the Farnesoid X Receptor
Regulation by Nuclear Factor Erythroid 2-Related Factor 2
Regulation by Splice Variants
Animal Models to Study UGT1A Genes
Outlook

SULFOTRANSFERASES
Introduction
Background
PAPS Synthesis
SULT Enzyme Family
Assays for SULT Activity
Structure and Function of SULT
SULT Pharmacogenetics
Bioactivation and the Role of SULTs in Toxicology
Conclusions and Future Perspectives

GLUTATHIONE S-TRANSFERASES
Introduction and History
Nomenclature, Structure, and Function
Substrates
Regulation, Induction, and Inhibition
Gene Polymorphism of GSTs

HYDROLYTIC ENZYMES
Carboxylesterases
Epoxide Hydrolases
Paraoxonases
Other Hydrolases

TRANSPORTING SYSTEMS
Introduction
Classification of Drug Transporters and Transport Mechanisms
Drug Transporters of the SLC Superfamily
ABC Drug Transporters
Drug Transporters and Disease
Drug Transporters and Pharmacokinetics
Role of Drug Transporters in Chemotherapy Resistance
Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response

TRANSCRIPTIONAL REGULATION OF HUMAN DRUG-METABOLIZING CYTOCHROME P450 ENZYMES
Factors Affecting Drug-Metabolizing Cytochromes P450
Transcriptional Regulation of CYP
Regulation of Drug-Metabolizing CYPs

IMPORTANCE OF PHARMACOGENOMICS
Introduction
Pharmacogenetic Polymorphisms
Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype
Genomics Technologies and Approaches
Conclusions

PART TWO: Metabolism of Drugs

INTRODUCTION TO DRUG METABOLISM
Introduction
Historical Aspects
Diversity of Drug Metabolic Pathways
Influence of Drug Metabolism on Pharmacological Activity
Biotoxification
Extrahepatic Drug Metabolism
Factors Affecting Drug Metabolism Activity
Conclusions

CENTRAL NERVOUS SYSTEM DRUGS
Introduction
Antidepressants
Antipsychotics
Tranquillizers and Hypnotic Agents
Psychostimulants
Anticonvulsants and Mood Stabilizers
Agents for Dementia and Cognitive Enhancers
Antimigraine Drugs
Other Drugs
Conclusions

CARDIOVASCULAR DRUGS
Introduction
RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers
Adrenergic Receptor Agonists
Adrenergic Receptor Antagonists
Diuretics
Antiarrhythmics
Anticoagulants
Cholesterol-Lowering Drugs

ANTICANCER DRUGS
Introduction
Alkylating Drugs
Platinum-Containing Agents
Antimetabolites
Endocrine Therapy
Histone Deacetylase Inhibitor (Vorinostat)
Tyrosine Kinase Inhibitors
Proteasome Inhibitor (Bortezomib)

ANTIMICROBIAL AGENTS
Introduction
Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents
Pharmacogenetics
Conclusions

DRUGS AGAINST ACUTE AND CHRONIC PAIN
Introduction
Acute Pain
Chronic Pain

DRUGS OF ABUSE (INCLUDING DESIGNER DRUGS)

Introduction
Classic Drugs of Abuse
Designer Drugs of Abuse

NICOTINE METABOLISM AND ITS IMPLICATIONS
Introduction
Absorption and Distribution of Nicotine
Excretion of Nicotine
Metabolism of Nicotine
Sources of Variation in Nicotine Metabolism
Implications of Variation in Nicotine Metabolism and CYP2A6 Activity
Conclusions

METABOLISM OF ALCOHOL AND ITS CONSEQUENCES
Introduction
Properties and Sources of Ethanol
Ethanol Absorption and Elimination
Ethanol Metabolism

PART THREE: Metabolism of Natural Compounds

INTRODUCTION AND OVERVIEW
Introduction
Terpenoids: A Structurally Complex Group of Natural Products
Other Classes of Natural Products
Summary and Conclusions

FLAVONOIDS
Flavonoids - Plant Phytochemicals
Absorption and Metabolism of Flavonoids
Interactions of Flavonoids with Mammalian Proteins with Possible Implications for Drug Metabolism
Dietary Flavonoids - Health Issues
Flavonoid-Drug Interactions
Conclusion - Double-Edged Sword Properties of Flavonoids

ST JOHN'S WORT (HYPERICUM PERFORATUM L.)
The Name Hypericum
Chemical Constituents of Hypericum perforatum
Clinical Pharmacology of H. perforatum
Pharmacokinetics and Pharmacokinetic Interactions of H. perforatum
In Vitro Studies
In Vivo Studies

FOOD COMPONENTS AND SUPPLEMENTS
Introduction
Food Contaminants
Vitamins
Macronutrients
Secondary Plant Metabolites
Probiotics and Prebiotics in the Modulation of Drug Metabolism

PART FOUR: Metabolism of Unnatural Xenobiotics

ENVIRONMENTAL POLLUTANTS
Introduction - An Overview
Overview of Environmental Pollutants
Toxic and Hazardous Environmental Pollutants Interacting with Drug Metabolism
Summary

ENVIRONMENTAL ESTROGENS
Introduction
Estrogen Receptor Signaling Pathways
Agonistic/Antagonistic Effects of Xenobiotics on ERs
Effects of EDCs on Biosynthesis and Metabolism of Estrogens
Case of Polychlorinated Biphenyls
Conclusions

BIOTRANSFORMATION OF INSECTICIDES
Introduction to Insecticides
Metabolism of Insecticides
Extrahepatic Metabolism of Insecticides
Factors Affecting Metabolism
Conclusions

"Overall therefore, a book which can be read in its own right for the first half and then a valuable source of reference for the second half. A useful tome to have on the bookshelf for anyone in the field." ( British Toxicology Society , 1 July 2013)