Cytochrome P450 2D6 Structure, Function, Regulation and Polymorphism

Cytochromes are proteins that catalyze electron transfer reactions of well-known metabolic pathways and are classified in various superfamilies. The CYP, or P450, superfamily accounts for 90% of the oxidative metabolism of clinical drugs. One member of this superfamily, P450 2D6 (or CYP2D6), singlehandedly metabolizes about 25% of all medications in the human liver. Cytochrome P450 2D6: Structure, Function, Regulation, and Polymorphism reviews the current knowledge of CYP2D6 as well as the maturing body of evidence indicating its significance to clinical and pharmacological researchers and practitioners. This book focuses on the critical role CYP2D6 plays in the human liver. It examines the genetic, epigenetic, physiological, pathological, and structural factors of the gene that govern the highly variable metabolism of a number of drugs in clinical use. It highlights the impact of the functional roles of CYP2D6 on clinical practice and drug development and also discusses implications for precise medicine, strategies to avoid adverse drug reactions, and paths for future research. Cytochrome P450 2D6 is a unique, valuable book focusing on a single but immensely powerful human gene. It provides the first single source of comprehensive information on CYP2D6 that serves as an important reference for medical, biomedical, pharmaceutical, and nursing researchers, practitioners, and students.

Introduction to Human Cytochrome P450 SuperfamilyThe Cytochrome P450s in NatureHuman CYP SuperfamilyHuman CYP1 FamilyHuman CYP2ABFGST Cluster: CYP2A6, 2A7, 2A13, 2B6, 2F1, and 2S1Human CYP2C Cluster: CYP2C8, 2C9, 2C18, and 2C19Other Human CYP2 Family MembersHuman CYP3A Cluster: CYP3A4, 3A5, 3A7, and 3A43Human CYP4ABXZ Cluster: CYP4A11, 4A22, 4B1, 4X1, and 4Z1Human CYP4F Cluster: CYP4F2, 4F3, 4F8, 4F11, 4F12, and 4F22Other Human CYP4 Family MembersHuman CYP5 FamilyHuman CYP7 FamilyHuman CYP8 FamilyHuman CYP11 FamilyHuman CYP17 FamilyHuman CYP19 FamilyHuman CYP20 FamilyHuman CYP21 FamilyHuman CYP24 FamilyHuman CYP26 FamilyHuman CYP27 FamilyHuman CYP39A1, 46A1, and 51A1Human CYP46 FamilyHuman CYP51 FamilyHighlights of This BookReferencesMammalian CYP2D Members: A Comparison of Structure, Function, and RegulationIntroductionRat Cyp2d Subfamily: Cyp2d1, 2d2, 2d3, 2d4, and 2d5Mouse Cyp2d Subfamily: Cyp2d9–2d13, 2d22, 2d26, 2d34, and 2d40Bovine CYP2D14Dog CYP2D15Guinea Pig Cyp2d16Macaque CYP2D17, 2D29, 2D42, and 2D44Marmoset CYP2D8, 2D19, and 2D30Rabbit CYP2D23 and CYP2D24Pig CYP2D25Syrian Hamster Cyp2d27Chicken CYP2D49Horse CYP2D50Conclusions and Future PerspectivesReferencesSubstrates of Human CYP2D6IntroductionProbes of CYP2D6Therapeutic Drugs as Substrates of CYP2D6Drugs of Abuse as Substrates of CYP2D6Fluorescent Probes as Substrates of CYP2D6Plant Alkaloids, Toxicants, and Environmental Compounds as Substrates of CYP2D6Endogenous Compounds as Substrates of CYP2D6Structure–Activity Relationships of CYP2D6 SubstratesConclusions and Future DirectionsReferencesInhibitors of Human CYP2D6IntroductionSelective Inhibitors of CYP2D6Reversible and Mixed-Type Inhibitors of CYP2D6Structure–Activity Relationships of CYP2D6 InhibitorsConclusions and Future DirectionsReferencesRegulation of Human CYP2D6IntroductionEffects of Physiological Factors on CYP2D6 ActivityEffects of Environmental Factors on CYP2D6 ActivityHuman CYP2D6 Is Largely Uninducible by Prototypical Inducers of CYPsTranscriptional and Posttranscriptional Regulation of CYP2D6 by HNF-4a and FXRPosttranslational Regulation of CYP2D6Genome-Wide Association Studies on the Regulation of CYP2D6Effects of Diseases on CYP2D6 Expression and ActivityConclusions and Future DirectionsReferencesStructure and Function of Human CYP2D6IntroductionPharmacophore Models and Structural Requirements of CYP2D6 LigandsHomology Modeling Studies of Human CYP2D6Site-Directed Mutagenesis Studies of CYP2D6Studies Using Aryldiazene ProbesAntibody Studies of Human CYP2D6Other Molecular Modeling StudiesX-ray Crystallographic Study of Human CYP2D6 and Functional ImplicationsBindings Modes of the Substrates and Inhibitors with CYP2D6Conclusions and Future DirectionsReferencesClinical Pharmacogenomics of Human CYP2D6IntroductionInterindividual Variability in CYP2D6 Expression and ActivityAlleles of the CYP2D6 GeneEthnic Variation in the Distribution of CYP2D6 PolymorphismsAntianginal DrugsAntiarrhythmic DrugsAntidepressantsAntipsychoticsCentrally Acting Cholinesterase InhibitorsDrugs for the Treatment of Attention-Deficit/Hyperactivity DisorderDrugs for the Treatment of Senile DementiaAntimuscarinic DrugsAntiemeticsAntihistamineß-BlockersOpioidsOral Hypoglycemic DrugsSelective Estrogen Receptor ModulatorsOther DrugsConclusions and Future PerspectivesReferencesGeneral Discussion about Human CYP2D6References

Shufeng Zhou is the associate vice president of Global Medical Development and associate dean of international research in the College of Pharmacy of the University of South Florida in Tampa. He earned his PhD in pharmacology from the University of Auckland in New Zealand. His major research interests are systems pharmacology, drug metabolism and drug transport, pharmacokinetics/pharmacometrics, pharmacogenomics, nanomedicine, and Chinese medicine. He has published more than 450 peer-reviewed papers, 20 books and book chapters, and more than 440 conference abstracts. He was one of the Highly Cited Researchers of 2014 according to Thomson Reuter and has given more than 150 invited seminars and keynote presentations to academic institutions, government agencies, and high-profile international conferences. He serves as an editor or the editor in chief of at least 21 biomedical journals and is an editorial board member of more than 75 medical and pharmacological journals. He has received several national and international awards, is a voting member of US Pharmacopeia, a consultant for the World Health Organization and the Food and Drug Administration, and a council member or chair of several national and international professional societies.