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

532 Pages·2016·33.157 MB·English

by  Zhou, Shufeng

LIFE SCIENCE

Cytochrome

Cytochrome

P450 2D6

P450 2D6

Structure, Function, Regulation,

Structure, Function, Regulation,

and Polymorphism

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 pharma-
cological 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.
Shufeng Zhou
K20857
ISBN: 978-1-4665-9787-7
90000
9 781466 597877
K20857_Cover_mech.indd All Pages 1/29/16 2:06 PM
Cytochrome
P450 2D6
Structure, Function, Regulation,
and Polymorphism

Cytochrome
P450 2D6
Structure, Function, Regulation,
and Polymorphism
Shufeng Zhou
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2016 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20160210
International Standard Book Number-13: 978-1-4665-9788-4 (eBook - PDF)
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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
1.2.1 Members of the CYP Superfamily: Family, Subfamily, Clan, and Motif.......................................3
1.2.2 Subcellular Location of CYPs .......................................................................................................15
1.2.3 CYP-Mediated Metabolism of Xenobiotics and Endogenous Compounds ..................................16
1.2.4 Structural Features of CYPs .........................................................................................................17
1.2.5 Inhibition of CYPs ........................................................................................................................19
1.2.6 Regulation of CYPs via Nuclear Receptors, miRNAs, Inflammation, and Cytokines.................19
1.2.7 Phenotypes and Polymorphisms of CYPs .....................................................................................21
1.2.8 CYP-Related Diseases...................................................................................................................22
1.3 Human CYP1 Family .................................................................................................................................22
1.3.1 CYP1A1 (Aryl Hydrocarbon Hydroxylase) ..................................................................................23
1.3.2 CYP1A2 (Aryl Hydrocarbon Hydroxylase) ..................................................................................24
1.3.3 CYP1B1 (Aryl Hydrocarbon Hydroxylase) ...................................................................................25
1.4 Human CYP2ABFGST Cluster: CYP2A6, 2A7, 2A13, 2B6, 2F1, and 2S1 ..............................................26
1.4.1 CYP2A6 (Coumarin 7-Hydroxylase) ............................................................................................26
1.4.2 CYP2A7 ........................................................................................................................................28
1.4.3 CYP2A13 ......................................................................................................................................28
1.4.4 CYP2B6 ........................................................................................................................................29
1.4.5 CYP2F1 .........................................................................................................................................31
1.4.6 CYP2S1 .........................................................................................................................................31
1.5 Human CYP2C Cluster: CYP2C8, 2C9, 2C18, and 2C19 .........................................................................32
1.5.1 CYP2C8 ........................................................................................................................................32
1.5.2 CYP2C9 ........................................................................................................................................33
1.5.3 CYP2C18 (S-Mephenytoin Hydroxylase) .....................................................................................35
1.5.4 CYP2C19 .......................................................................................................................................35
1.6 Other Human CYP2 Family Members.......................................................................................................36
1.6.1 CYP2D6 ........................................................................................................................................36
1.6.2 CYP2E1 .........................................................................................................................................37
1.6.3 CYP2J2 .........................................................................................................................................37
1.6.4 CYP2R1 ........................................................................................................................................38
1.6.5 CYP2U1 ........................................................................................................................................39
1.6.6 CYP2W1 .......................................................................................................................................39
1.7 Human CYP3A Cluster: CYP3A4, 3A5, 3A7, and 3A43 ...........................................................................40
1.7.1 CYP3A4 ........................................................................................................................................40
1.7.2 CYP3A5 ........................................................................................................................................43
1.7.3 CYP3A7.........................................................................................................................................43
1.7.4 CYP3A43.......................................................................................................................................44
1.8 Human CYP4ABXZ Cluster: CYP4A11, 4A22, 4B1, 4X1, and 4Z1 .........................................................44
1.8.1 CYP4A11 (20-Hydroxyeicosatetraenoic Acid Synthase, Fatty Acid ϖ-Hydroxylase,
and Lauric Acid ϖ-Hydroxylase) ..................................................................................................44
1.8.2 CYP4A22 (Fatty Acid ϖ-Hydroxylase and Lauric Acid ϖ-Hydroxylase) ....................................45
1.8.3 CYP4B1 .........................................................................................................................................45
1.9 Human CYP4F Cluster: CYP4F2, 4F3, 4F8, 4F11, 4F12, and 4F22 ..........................................................45
1.9.1 CYP4F2 (20-Hydroxyeicosatetraenoic Acid Synthase, Arachidonic Acid ϖ-Hydroxylase,
and Leukotriene-B4 ϖ-Hydroxylase 1) .........................................................................................45
1.9.2 CYP4F3 .........................................................................................................................................46
1.9.3 CYP4F8 .........................................................................................................................................46
v
vi Contents
1.9.4 CYP4F11 (Phylloquinone ϖ-Hydroxylase and 3-Hydroxy Fatty Acid ϖ-Hydroxylase) ...............46
1.9.5 CYP4F12 .......................................................................................................................................46
1.9.6 CYP4F22 .......................................................................................................................................47
1.10 Other Human CYP4 Family Members .......................................................................................................47
1.10.1 CYP4V2 (Docosahexaenoic Acid ϖ-Hydroxylase) .......................................................................47
1.10.2 CYP4X1.........................................................................................................................................47
1.10.3 CYP4Z1 .........................................................................................................................................47
1.11 Human CYP5 Family .................................................................................................................................48
1.11.1 CYP5A1 (Thromboxane A Synthase 1, TBXAS1) .......................................................................48
1.12 Human CYP7 Family .................................................................................................................................48
1.12.1 CYP7A1 (Cholesterol 7α-Hydroxylase) ........................................................................................48
1.12.2 CYP7B1 (Oxysterol 7α-Hydroxylase 1) ........................................................................................49
1.13 Human CYP8 Family .................................................................................................................................49
1.13.1 CYP8A1 (Prostaglandin I Synthase, PGIS/PTGIS) ....................................................................49
2
1.13.2 CYP8B1 (Sterol 12α-Hydroxylase) ...............................................................................................50
1.14 Human CYP11 Family ...............................................................................................................................50
1.14.1 CYP11A1 (Cholesterol Side-Chain Cleavage Enzyme) ................................................................50
1.14.2 CYP11B1 (Steroid 11β-Hydroxylase) ............................................................................................51
1.14.3 CYP11B2 (Aldosterone Synthase/Steroid 11β/18-Hydroxylase) ...................................................51
1.15 Human CYP17 Family ...............................................................................................................................52
1.15.1 CYP17A1 (Steroid 17α-Monooxygenase, 17α-Hydroxylase, 17,20 Lyase, and 17,20 Desmolase)....52
1.16 Human CYP19 Family ...............................................................................................................................53
1.16.1 CYP19A1 (Aromatase) ..................................................................................................................53
1.17 Human CYP20 Family ...............................................................................................................................54
1.17.1 CYP20A1 ......................................................................................................................................54
1.18 Human CYP21 Family ...............................................................................................................................54
1.18.1 CYP21A2 (Steroid 21-Hydroxylase)..............................................................................................54
1.19 Human CYP24 Family ...............................................................................................................................54
1.19.1 CYP24A1 (1,25-Dihydroxyvitamin D 24-Hydroxylase, Vitamin D 24-Hydroxylase/
3
Vitamin D 24-Hydroxylase) .........................................................................................................54
3
1.20 Human CYP26 Family ...............................................................................................................................55
1.20.1 CYP26A1 (Retinoic Acid 4-Hydroxylase) ....................................................................................56
1.20.2 CYP26B1 .......................................................................................................................................56
1.20.3 CYP26C1 ......................................................................................................................................57
1.21 Human CYP27 Family ...............................................................................................................................57
1.21.1 CYP27A1 (Sterol 27-Hydroxylase) ................................................................................................57
1.21.2 CYP27B1 (Mitochondrial 25-Hydroxyvitamin D 1α-Hydroxylase) .............................................58
1.21.3 CYP27C1 .......................................................................................................................................58
1.22 Human CYP39A1, 46A1, and 51A1 ...........................................................................................................59
1.22.1 CYP39A1 (Oxysterol 7α-Hydroxylase 2) ......................................................................................59
1.23 Human CYP46 Family ...............................................................................................................................59
1.23.1 CYP46A1 (Cholesterol 24-Hydroxylase) ......................................................................................59
1.24 Human CYP51 Family ...............................................................................................................................59
1.24.1 CYP51A1 (Lanosterol 14α-Demethylase/Sterol 14α-Demethylase) .............................................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: Cyp2d1, 2d2, 2d3, 2d4, and 2d5 ..........................................................................102
2.2.1 Tissue Distribution of Rat Cyp2ds ..............................................................................................102
2.2.2 Substrates of Rat Cyp2ds .............................................................................................................112
2.2.3 Differences in Rat Cyp2d-Dependent Metabolism ......................................................................113
2.2.4 Dark Agouti Rats as a Cyp2d2-Deficient Model..........................................................................114
2.2.5 Regulation of Rat Cyp2ds ............................................................................................................117
2.2.6 Inhibitors of Rat CYP2ds and Cyp2d-Mediated Drug–Drug Interactions ..................................118
Contents vii
2.3 Mouse Cyp2d Subfamily: Cyp2d9–2d13, 2d22, 2d26, 2d34, and 2d40 ...................................................119
2.3.1 Tissue Distribution of Mouse Cyp2ds ..........................................................................................119
2.3.2 Substrate Specificity of Mouse Cyp2ds ......................................................................................120
2.3.3 Cyp2d Knockout and CYP2D6 Transgenic Mouse Model ..........................................................120
2.4 Bovine CYP2D14 .....................................................................................................................................121
2.5 Dog CYP2D15 ..........................................................................................................................................121
2.5.1 Cloning and Purification of Dog CYP2D15 ................................................................................122
2.5.2 Tissue Distribution of Dog CYP2D15 .........................................................................................122
2.5.3 Substrate Specificity of Dog CYP2D15 ......................................................................................122
2.5.4 Induction of Dog CYP2D15 ........................................................................................................124
2.5.5 Inhibitors of Dog CYP2D15 ........................................................................................................125
2.6 Guinea Pig Cyp2d16 .................................................................................................................................125
2.6.1 Tissue Distribution of Guinea Pig Cyp2d16 ................................................................................125
2.6.2 Substrate Specificity of Guinea Pig Cyp2d16 .............................................................................125
2.6.3 Regulation of Guinea Pig Cyp2d16 .............................................................................................125
2.7 Macaque CYP2D17, 2D29, 2D42, and 2D44 ...........................................................................................126
2.7.1 Cynomolgus Monkey CYP2D17 and 2D44 ................................................................................126
2.7.2 Japanese Monkey CYP2D29 .......................................................................................................127
2.8 Marmoset CYP2D8, 2D19, and 2D30 ......................................................................................................127
2.9 Rabbit CYP2D23 and CYP2D24 .............................................................................................................128
2.10 Pig CYP2D25 ...........................................................................................................................................128
2.10.1 Cloning and Purification of Pig CYP2D25 .................................................................................128
2.10.2 Catalytic Activity of 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
3.2.1 Sparteine and Debrisoquine ........................................................................................................139
3.2.2 Dextromethorphan ......................................................................................................................140
3.2.3 Bufuralol and Tramadol ..............................................................................................................140
3.3 Therapeutic Drugs as Substrates of CYP2D6 ...........................................................................................141
3.3.1 Drugs Acting on the Central Nervous System .............................................................................141
3.3.1.1 Tricyclic Antidepressants..............................................................................................141
3.3.1.2 Selective Serotonin Reuptake Inhibitors .....................................................................146
3.3.1.3 Other Antidepressants .................................................................................................151
3.3.1.4 Antipsychotics..............................................................................................................153
3.3.1.5 Hypnotics .....................................................................................................................162
3.3.1.6 Opioids and Opioid Receptor Antagonists ..................................................................162
3.3.1.7 Antiemetics ..................................................................................................................165
3.3.1.8 Antimigraine Drugs .....................................................................................................169
3.3.1.9 Antiparkinsonism Agents .............................................................................................170
3.3.1.10 Centrally Acting Cholinesterase Inhibitors ..................................................................171
3.3.1.11 Drugs for Senile Dementia ...........................................................................................175
3.3.1.12 Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder .........................175
3.3.1.13 Nonnarcotic Analgesics ................................................................................................175
3.3.1.14 Drugs for Huntington’s Disease Chorea .......................................................................176
3.3.2 Cardiovascular Drugs ..................................................................................................................177
3.3.2.1 Antianginal Drugs .......................................................................................................177
3.3.2.2 Antiarrhythmics ...........................................................................................................180
3.3.2.3 Antiplatelet Agents ......................................................................................................190
viii Contents
3.3.2.4 β-Blockers ....................................................................................................................193
3.3.2.5 Calcium Channel Blockers ..........................................................................................198
3.3.3 Antihistamines ............................................................................................................................202
3.3.3.1 Azelastine ....................................................................................................................203
3.3.3.2 Chlorpheniramine ........................................................................................................203
3.3.3.3 Cinnarizine and Flunarizine ........................................................................................203
3.3.3.4 Diphenhydramine ........................................................................................................204
3.3.3.5 Loratadine ....................................................................................................................204
3.3.3.6 Mequitazine .................................................................................................................205
3.3.3.7 Oxatomide....................................................................................................................205
3.3.3.8 Terfenadine ..................................................................................................................207
3.3.4 Anti-HIV Agents .........................................................................................................................208
3.3.4.1 HIV Protease Inhibitors ...............................................................................................208
3.3.4.2 Nonnucleoside Reverse Transcriptase Inhibitors .........................................................210
3.3.5 Antimalarial Drugs .....................................................................................................................215
3.3.5.1 Amodiaquine ...............................................................................................................215
3.3.5.2 Chloroquine .................................................................................................................215
3.3.5.3 Halofantrine .................................................................................................................215
3.3.5.4 Phenoxypropoxybiguanides ..........................................................................................217
3.3.6 Hypolipidemic Agents ..................................................................................................................217
3.3.6.1 Fluvastatin ....................................................................................................................217
3.3.6.2 Pactimibe ......................................................................................................................218
3.3.7 Muscarinic Receptor Antagonists ................................................................................................218
3.3.7.1 Tolterodine ....................................................................................................................218
3.3.8 Nonsteroidal Anti-Inflammatory Drugs .......................................................................................218
3.3.8.1 Acetaminophen .............................................................................................................218
3.3.8.2 Indomethacin ...............................................................................................................220
3.3.9 Oral Hypoglycemic Drugs ..........................................................................................................220
3.3.9.1 Phenformin ..................................................................................................................220
3.3.10 Selective Estrogen Receptor Modulators ....................................................................................221
3.3.10.1 Tamoxifen ....................................................................................................................222
3.3.10.2 Droloxifene ..................................................................................................................226
3.3.10.3 Enclomifene .................................................................................................................226
3.3.10.4 Lasofoxifene ................................................................................................................226
3.3.11 Selective Phosphodiesterase Type 5 Inhibitors ...........................................................................227
3.3.12 Other Drugs and Compounds ......................................................................................................227
3.4 Drugs of Abuse as Substrates of CYP2D6 ...............................................................................................232
3.4.1 Amphetamine Derivatives ...........................................................................................................232
3.4.2 β-Carbolines ................................................................................................................................232
3.4.3 Designer Drugs ............................................................................................................................233
3.4.4 Indolealkylamines .......................................................................................................................234
3.5 Fluorescent Probes as Substrates of CYP2D6 .........................................................................................236
3.6 Plant Alkaloids, Toxicants, and Environmental Compounds as Substrates of CYP2D6 .........................237
3.6.1 Plant Alkaloids ............................................................................................................................237
3.6.2 Neurotoxin ...................................................................................................................................237
3.6.3 Herbicides and Pesticides ............................................................................................................238
3.7 Endogenous Compounds as Substrates of CYP2D6 ................................................................................240
3.7.1 5-Methoxyindolethylamine .........................................................................................................240
3.7.2 Tyramines ....................................................................................................................................240
3.7.3 Steroids and Neurosteroids ..........................................................................................................241
3.7.4 Endogenous Morphine ................................................................................................................244
3.7.5 Endocannabinoid Arachidonoylethanolamide (Anandamide) ....................................................244
3.8 Structure–Activity Relationships of CYP2D6 Substrates ........................................................................245
3.9 Conclusions and Future Directions ..........................................................................................................246
References ...........................................................................................................................................................256
Contents ix
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
4.3.1 Paroxetine ....................................................................................................................................299
4.3.2 Cimetidine ...................................................................................................................................299
4.3.3 Metoclopramide ..........................................................................................................................299
4.3.4 Pimozide ......................................................................................................................................300
4.3.5 Other Compounds .......................................................................................................................300
4.4 Reversible and Mixed-Type Inhibitors of CYP2D6 .................................................................................300
4.4.1 Central Nervous System Drugs ...................................................................................................300
4.4.1.1 Antipsychotics..............................................................................................................300
4.4.1.2 SSRIs ...........................................................................................................................301
4.4.1.3 Tricyclic Antidepressants.............................................................................................302
4.4.1.4 Other Antidepressants .................................................................................................302
4.4.1.5 Narcotics ......................................................................................................................302
4.4.1.6 Other Central Nervous System Drugs .........................................................................302
4.4.2 H Receptor Antagonists .............................................................................................................303
1
4.4.3 Antifungal Agents .......................................................................................................................304
4.4.4 Anti-HIV Agents .........................................................................................................................304
4.4.5 Steroids ........................................................................................................................................304
4.4.6 Other Drugs .................................................................................................................................304
4.4.7 Amphetamine Analogs................................................................................................................306
4.4.8 Natural and Herbal Compounds ..................................................................................................307
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
5.2.1 Gender ..........................................................................................................................................316
5.2.2 Developmental Changes (Ontogeny) of CYP2D6 Expression and Activity ................................316
5.2.3 Pregnancy Induces CYP2D6 ........................................................................................................317
5.2.4 Fasting ..........................................................................................................................................318
5.3 Effects of Environmental Factors on CYP2D6 Activity ...........................................................................318
5.3.1 Smoking .......................................................................................................................................318
5.3.2 Alcoholic Cirrhosis ......................................................................................................................319
5.3.3 Herbal Medicines .........................................................................................................................319
5.4 Human CYP2D6 Is Largely Uninducible by Prototypical Inducers of CYPs .........................................320
5.4.1 In Vitro Studies ...........................................................................................................................320
5.4.2 In Vivo Studies ............................................................................................................................320
5.5 Transcriptional and Posttranscriptional Regulation of CYP2D6 by HNF-4α and FXR .........................321
5.5.1 Transcriptional Regulation of CYP2D6 by HNF-4α ..................................................................321
5.5.2 Transcriptional Regulation of CYP2D6 by FXR ........................................................................322
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
5.8.1 Liver Diseases .............................................................................................................................324
5.8.2 Chronic Renal Failure .................................................................................................................326
5.8.3 Diabetes .......................................................................................................................................326
5.8.4 Rheumatoid Arthritis ..................................................................................................................327
5.8.5 Cytokines and Inflammation .......................................................................................................327
5.9 Conclusions and Future Directions ..........................................................................................................327
References ...........................................................................................................................................................327