Cytochrome P450 2D6 : Structure, Function, Regulation and Polymorphism book cover
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Cytochrome P450 2D6
Structure, Function, Regulation and Polymorphism




ISBN 9781466597877
Published March 9, 2016 by CRC Press
508 Pages 30 Color & 182 B/W Illustrations

 
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Book Description

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.

Table of Contents

Introduction to Human Cytochrome P450 Superfamily
The Cytochrome P450s in Nature
Human CYP Superfamily
Human CYP1 Family
Human CYP2ABFGST Cluster: CYP2A6, 2A7, 2A13, 2B6, 2F1, and 2S1
Human CYP2C Cluster: CYP2C8, 2C9, 2C18, and 2C19
Other Human CYP2 Family Members
Human CYP3A Cluster: CYP3A4, 3A5, 3A7, and 3A43
Human CYP4ABXZ Cluster: CYP4A11, 4A22, 4B1, 4X1, and 4Z1
Human CYP4F Cluster: CYP4F2, 4F3, 4F8, 4F11, 4F12, and 4F22
Other Human CYP4 Family Members
Human CYP5 Family
Human CYP7 Family
Human CYP8 Family
Human CYP11 Family
Human CYP17 Family
Human CYP19 Family
Human CYP20 Family
Human CYP21 Family
Human CYP24 Family
Human CYP26 Family
Human CYP27 Family
Human CYP39A1, 46A1, and 51A1
Human CYP46 Family
Human CYP51 Family
Highlights of This Book
References

Mammalian CYP2D Members: A Comparison of Structure, Function, and Regulation
Introduction
Rat Cyp2d Subfamily: Cyp2d1, 2d2, 2d3, 2d4, and 2d5
Mouse Cyp2d Subfamily: Cyp2d9–2d13, 2d22, 2d26, 2d34, and 2d40
Bovine CYP2D14
Dog CYP2D15
Guinea Pig Cyp2d16
Macaque CYP2D17, 2D29, 2D42, and 2D44
Marmoset CYP2D8, 2D19, and 2D30
Rabbit CYP2D23 and CYP2D24
Pig CYP2D25
Syrian Hamster Cyp2d27
Chicken CYP2D49
Horse CYP2D50
Conclusions and Future Perspectives
References

Substrates of Human CYP2D6
Introduction
Probes of CYP2D6
Therapeutic Drugs as Substrates of CYP2D6
Drugs of Abuse as Substrates of CYP2D6
Fluorescent Probes as Substrates of CYP2D6
Plant Alkaloids, Toxicants, and Environmental Compounds as Substrates of CYP2D6
Endogenous Compounds as Substrates of CYP2D6
Structure–Activity Relationships of CYP2D6 Substrates
Conclusions and Future Directions
References

Inhibitors of Human CYP2D6
Introduction
Selective Inhibitors of CYP2D6
Reversible and Mixed-Type Inhibitors of CYP2D6
Structure–Activity Relationships of CYP2D6 Inhibitors
Conclusions and Future Directions
References

Regulation of Human CYP2D6
Introduction
Effects of Physiological Factors on CYP2D6 Activity
Effects of Environmental Factors on CYP2D6 Activity
Human CYP2D6 Is Largely Uninducible by Prototypical Inducers of CYPs
Transcriptional and Posttranscriptional Regulation of CYP2D6 by HNF-4α and FXR
Posttranslational Regulation of CYP2D6
Genome-Wide Association Studies on the Regulation of CYP2D6
Effects of Diseases on CYP2D6 Expression and Activity
Conclusions and Future Directions
References

Structure and Function of Human CYP2D6
Introduction
Pharmacophore Models and Structural Requirements of CYP2D6 Ligands
Homology Modeling Studies of Human CYP2D6
Site-Directed Mutagenesis Studies of CYP2D6
Studies Using Aryldiazene Probes
Antibody Studies of Human CYP2D6
Other Molecular Modeling Studies
X-ray Crystallographic Study of Human CYP2D6 and Functional Implications
Bindings Modes of the Substrates and Inhibitors with CYP2D6
Conclusions and Future Directions
References

Clinical Pharmacogenomics of Human CYP2D6
Introduction
Interindividual Variability in CYP2D6 Expression and Activity
Alleles of the CYP2D6 Gene
Ethnic Variation in the Distribution of CYP2D6 Polymorphisms
Antianginal Drugs
Antiarrhythmic Drugs
Antidepressants
Antipsychotics
Centrally Acting Cholinesterase Inhibitors
Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder
Drugs for the Treatment of Senile Dementia
Antimuscarinic Drugs
Antiemetics
Antihistamine
β-Blockers
Opioids
Oral Hypoglycemic Drugs
Selective Estrogen Receptor Modulators
Other Drugs
Conclusions and Future Perspectives
References

General Discussion about Human CYP2D6
References

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Author(s)

Biography

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.