Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism, 1st Edition (Hardback) book cover

Cytochrome P450 2D6

Structure, Function, Regulation and Polymorphism, 1st Edition

By Shufeng Zhou

CRC Press

508 pages | 30 Color Illus. | 182 B/W Illus.

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Description

Cytochromes are proteinsthat 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

About the Author

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.

Subject Categories

BISAC Subject Codes/Headings:
MED031000
MEDICAL / Gastroenterology
MED071000
MEDICAL / Pharmacology
SCI017000
SCIENCE / Life Sciences / Cytology