Cytochrome P450 2D6 : structure, function, regulation, and polymorphism / Shufeng Zhou. -- Boca Raton, FL : CRC Press, Taylor & Francis Group, 2016. – (58.174359/Z63)

Contents

Preface  xiii

Author    xv

Chapter 1  Introduction to Human Cytochrome P450 Superfamily  1

1.1  The Cytochrome P450s in Nature  1

1.2  Human CYP Superfamily    3

1.3  Human CYP1 Family  22

1.4  Human CYP2ABFGST Cluster: CYP2A6, 2A7, 2A13, 2B6, 2F1, and 2S1  26

1.5  Human CYP2C Cluster: CYP2C8, 2C9, 2C18, and 2C19  32

1.6  Other Human CYP2 Family Members  36

1.7  Human CYP3A Cluster: CYP3A4, 3A5, 3A7, and 3A43  40

1.8  Human CYP4ABXZ Cluster: CYP4All, 4A22, 4B1, 4X1, and 4ZI  44

1.9  Human CYP4F Cluster: CYP4F2, 4F3, 4F8, 4Fll, 4F12, and 4F22  45

1.10  Other Human CYP4 Family Members  47

1.11  Human CYP5 Family  48

1.12  Human CYP7 Family  48

1.13  Human CYP8 Family  49

1.14  Human CYPll Family  50

1.15  Human CYP17 Family  52

1.16  Human CYP19 Family  53

1.17  Human CYP20 Family  54

1.18  Human CYP21 Family  54

1.19  Human CYP24 Family  54

1.20  Human CYP26 Family  55

1.21  Human CYP27 Family  57

1.22  Human CYP39A1, 46A1, and 51A1  59

1.23  Human CYP46 Family  59

1.24  Human CYP51 Family  59

1.25  Highlights of This Book  60

References  60

Chapter 2  Mammalian CYP2D Members: A Comparison of Structure, Function, and Regulation  101

2.1  Introduction  101

2.2  Rat Cyp2d Subfamily: Cyp2dl, 2d2, 2d3, 2d4, and 2d5  102

2.3  Mouse Cyp2d Subfamily: Cyp2d9-2d13, 2d22, 2d26, 2d34, and 2d40  119

2.4  Bovine CYP2D14  121

2.5  Dog CYP2DI5  121

2.6  Guinea Pig Cyp2dl6  125

2.7  Macaque CYP2D17, 2D29, 2D42, and 2D44  126

2.8  Marmoset CYP2D8, 2D19, and 2D30  127

2.9  Rabbit CYP2D23 and CYP2D24    128

2.10  Pig CYP2D25    128

2.11  Syrian Hamster Cyp2d27  129

2.12  Chicken CYP2D49  129

2.13  Horse CYP2D50  129

2.14  Conclusions and Future Perspectives  130

References  130

Chapter 3  Substrates of Human CYP2D6  139

3.1  Introduction  139

3.2  Probes of CYP2D6  139

3.3  Therapeutic Drugs as Substrates of CYP2D6  141

3.4  Drugs of Abuse as Substrates of CYP2D6    232

3.5  Fluorescent Probes as Substrates of CYP2D6  236

3.6  Plant Alkaloids, Toxicants, and Environmental Compounds as Substrates of CYP2D6  237

3.7  Endogenous Compounds as Substrates of CYP2D6  240

3.8  Structure-Activity Relationships of CYP2D6 Substrates  245

3.9  Conclusions and Future Directions  246

References  256

Chapter 4  Inhibitors of Human CYP2D6  289

4.1  Introduction  289

4.2  Selective Inhibitors of CYP2D6  289

4.3  Mechanism-Based Inhibitors of CYP2D6  299

4.4  Reversible and Mixed-Type Inhibitors of CYP2D6  300

4.5  Structure-Activity Relationships of CYP2D6 Inhibitors  307

4.6  Conclusions and Future Directions  308

References  308

Chapter 5  Regulation of Human CYP2D6  315

5.1  Introduction  315

5.2  Effects of Physiological Factors on CYP2D6 Activity  316

5.3  Effects of Environmental Factors on CYP2D6 Activity  318

5.4  Human CYP2D6 Is Largely Uninducible by Prototypical Inducers of CYPs  320

5.5  Transcriptional and Posttranscriptional Regulation of CYP2D6 by HNF-4α and FXR  321

5.6  Posttranslational Regulation of CYP2D6  323

5.7  Genome-Wide Association Studies on the Regulation of CYP2D6  323

5.8  Effects of Diseases on CYP2D6 Expression and Activity  324

5.9  Conclusions and Future Directions  327

References  327

Chapter 6  Structure and Function of Human CYP2D6  341

6.1  Introduction  341

6.2  Pharmacophore Models and Structural Requirements of CYP2D6 Ligands  341

6.3  Homology Modeling Studies of Human CYP2D6  343

6.4  Site-Directed Mutagenesis Studies of CYP2D6  346

6.5  Studies Using Aryldiazene Probes  358

6.6  Antibody Studies of Human CYP2D6  359

6.7  Other Molecular Modeling Studies  360

6.8  X-Ray Crystallographic Study of Human CYP2D6 and Functional Implications  360

6.9  Bindings Modes of the Substrates and Inhibitors with CYP2D6  367

6.10  Conclusions and Future Directions  407

References  407

Chapter 7  Clinical Pharamcogenomics of Human CYP2D6  415

7.1  Introduction  415

7.2  Interindividual Variability in CYP2D6 Expression and Activity  416

7.3  Alleles of the CYP2D6 Gene  416

7.4  Ethnic Variation in the Distribution of CYP2D6 Polymorphisms  430

7.5  Antianginal Drugs  431

7.6  Antiarrhythmic Drugs  431

7.7  Antidepressants  436

7.8  Antipsychotics  443

7.9  Centrally Acting Cholinesterase Inhibitors  449

7.10  Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder  449

7.11  Drugs for the Treatment of Senile Dementia  451

7.12  Antimuscarinic Drugs  451

7.13  Antiemetics  451

7.14  Antihistamine  452

7.15  β-Blockers  452

7.16  Opioids  454

7.17  Oral Hypoglycemic Drugs  458

7.18  Selective Estrogen Receptor Modulators  459

7.19  Other Drugs  460

7.20  Conclusions and Future Perspectives  460

References  463

Chapter 8  General Discussion about Human CYP2D6  483

References  489

Index    495