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 PhDdegree 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 aspectsof pharmacogenetics/genomics. Professor Zanger has authored more than 130 scientific articles and is lecturing in pharmacology and toxicology at the University of Tubingen.

• Preface PART ONE: Biochemistry and Molecular Genetics of Drug Metabolism DRUG-METABOLIZING ENZYMES -AN OVERVIEWIntroduction: Fate of a Drug in the Human BodyClassification Systems of Drug-Metabolizing Enzymes According to Different CriteriaOverview of the Most Important Drug-Metabolizing Enzyme CYTOCHROMES P450Introduction and Historical PerspectiveNomenclature and Gene OrganizationRegulationPolymorphismsProtein StructureCatalytic MechanismsWhat Determines P450 Catalytic Selectivity?Oxidative Stress and P450sRelevance in Drug Metabolism and Clinical Medicine UDP-GLUCURONOSYLTRANSFERASESIntroductionA Simple Phenotype: Unconjugated NonhemolyticHyperbilirubinemia and GlucuronidationOrganization of UGTs and the UGT1A Gene LocusUGT1A Gene NomenclatureHuman UGT1A Gene Locus and Sequence VariabilityGlucuronidation of BilirubinUGT1A1 GeneIs There an Advantage or Risk Associated with UGT1A1 Variability?UGT1A1 Gene and Pharmacogenetic ProtectionUGT1A1 Gene and Pharmacogenetic RisksUGT1A1 Variability and Cancer RiskUGT1A3 GeneUGT1A7 GeneTranscriptional Regulation of UGT1A GenesAryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A GenesRegulation by Hepatic Nuclear FactorsRegulation by the Farnesoid X ReceptorRegulation by Nuclear Factor Erythroid 2-Related Factor 2Regulation by Splice VariantsAnimal Models to Study UGT1A GenesOutlook SULFOTRANSFERASESIntroductionBackgroundPAPS SynthesisSULT Enzyme FamilyAssays for SULT ActivityStructure and Function of SULTSULT PharmacogeneticsBioactivation and the Role of SULTs in ToxicologyConclusions and Future Perspectives GLUTATHIONE S-TRANSFERASESIntroduction and HistoryNomenclature, Structure, and FunctionSubstratesRegulation, Induction, and InhibitionGene Polymorphism of GSTs HYDROLYTIC ENZYMESCarboxylesterasesEpoxide HydrolasesParaoxonasesOther Hydrolases TRANSPORTING SYSTEMSIntroductionClassification of Drug Transporters and Transport MechanismsDrug Transporters of the SLC SuperfamilyABC Drug TransportersDrug Transporters and DiseaseDrug Transporters and PharmacokineticsRole of Drug Transporters in Chemotherapy ResistancePharmacogenomics of Drug Transporters: Implications for Clinical Drug Response TRANSCRIPTIONAL REGULATION OF HUMAN DRUG-METABOLIZING CYTOCHROME P450 ENZYMESFactors Affecting Drug-Metabolizing Cytochromes P450Transcriptional Regulation of CYPRegulation of Drug-Metabolizing CYPs IMPORTANCE OF PHARMACOGENOMICSIntroductionPharmacogenetic PolymorphismsPolygenic and Multifactorial Aspects of Drug Metabolism PhenotypeGenomics Technologies and ApproachesConclusions PART TWO: Metabolism of Drugs INTRODUCTION TO DRUG METABOLISMIntroductionHistorical AspectsDiversity of Drug Metabolic PathwaysInfluence of Drug Metabolism on Pharmacological ActivityBiotoxificationExtrahepatic Drug MetabolismFactors Affecting Drug Metabolism ActivityConclusions CENTRAL NERVOUS SYSTEM DRUGSIntroductionAntidepressantsAntipsychoticsTranquillizers and Hypnotic AgentsPsychostimulantsAnticonvulsants and Mood StabilizersAgents for Dementia and Cognitive EnhancersAntimigraine DrugsOther DrugsConclusions CARDIOVASCULAR DRUGSIntroductionRAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor BlockersAdrenergic Receptor AgonistsAdrenergic Receptor AntagonistsDiureticsAntiarrhythmicsAnticoagulantsCholesterol-Lowering Drugs ANTICANCER DRUGSIntroductionAlkylating DrugsPlatinum-Containing AgentsAntimetabolitesEndocrine TherapyHistone Deacetylase Inhibitor (Vorinostat)Tyrosine Kinase InhibitorsProteasome Inhibitor (Bortezomib) ANTIMICROBIAL AGENTSIntroductionPharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial AgentsPharmacogeneticsConclusions DRUGS AGAINST ACUTE AND CHRONIC PAINIntroductionAcute PainChronic Pain DRUGS OF ABUSE (INCLUDING DESIGNER DRUGS) IntroductionClassic Drugs of AbuseDesigner Drugs of Abuse NICOTINE METABOLISM AND ITS IMPLICATIONSIntroductionAbsorption and Distribution of NicotineExcretion of NicotineMetabolism of NicotineSources of Variation in Nicotine MetabolismImplications of Variation in Nicotine Metabolism and CYP2A6 ActivityConclusions METABOLISM OF ALCOHOL AND ITS CONSEQUENCESIntroductionProperties and Sources of EthanolEthanol Absorption and EliminationEthanol Metabolism PART THREE: Metabolism of Natural Compounds INTRODUCTION AND OVERVIEWIntroductionTerpenoids: A Structurally Complex Group of Natural ProductsOther Classes of Natural ProductsSummary and Conclusions FLAVONOIDSFlavonoids -Plant PhytochemicalsAbsorption and Metabolism of FlavonoidsInteractions of Flavonoids with Mammalian Proteins with Possible Implications for Drug MetabolismDietary Flavonoids -Health IssuesFlavonoid-Drug InteractionsConclusion -Double-Edged Sword Properties of Flavonoids ST JOHN'S WORT (HYPERICUM PERFORATUM L.)The Name HypericumChemical Constituents of Hypericum perforatumClinical Pharmacology of H. perforatumPharmacokinetics and Pharmacokinetic Interactions of H. perforatumIn Vitro StudiesIn Vivo Studies FOOD COMPONENTS AND SUPPLEMENTSIntroductionFood ContaminantsVitaminsMacronutrientsSecondary Plant MetabolitesProbiotics and Prebiotics in the Modulation of Drug Metabolism PART FOUR: Metabolism of Unnatural Xenobiotics ENVIRONMENTAL POLLUTANTSIntroduction -An OverviewOverview of Environmental PollutantsToxic and Hazardous Environmental Pollutants Interacting with Drug MetabolismSummary ENVIRONMENTAL ESTROGENSIntroductionEstrogen Receptor Signaling PathwaysAgonistic/Antagonistic Effects of Xenobiotics on ERsEffects of EDCs on Biosynthesis and Metabolism of EstrogensCase of Polychlorinated BiphenylsConclusions BIOTRANSFORMATION OF INSECTICIDESIntroduction to InsecticidesMetabolism of InsecticidesExtrahepatic Metabolism of InsecticidesFactors Affecting MetabolismConclusions

“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)