Nuclear receptors in drug metabolism:
Saved in:
| Format: | Book |
|---|---|
| Language: | English |
| Published: |
Hoboken, NJ
Wiley
2009
|
| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Item Description: | Includes bibliographical references and index |
| Physical Description: | XXII, 330 S. Ill., graph. Darst. 25 cm |
| ISBN: | 0470086793 9780470086797 |
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| 245 | 1 | 0 | |a Nuclear receptors in drug metabolism |c ed. by Wen Xie |
| 264 | 1 | |a Hoboken, NJ |b Wiley |c 2009 | |
| 300 | |a XXII, 330 S. |b Ill., graph. Darst. |c 25 cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 500 | |a Includes bibliographical references and index | ||
| 650 | 4 | |a Drugs |x Metabolism | |
| 650 | 4 | |a Nuclear receptors (Biochemistry) | |
| 650 | 4 | |a Genetic regulation | |
| 650 | 4 | |a Receptors, Cytoplasmic and Nuclear |x metabolism | |
| 650 | 4 | |a Drug Delivery Systems |x methods | |
| 650 | 4 | |a Pharmaceutical Preparations |x metabolism | |
| 650 | 4 | |a Receptors, Steroid |x metabolism | |
| 700 | 1 | |a Xie, Wen |e Sonstige |4 oth | |
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Record in the Search Index
| _version_ | 1804138923327225856 |
|---|---|
| adam_text | CONTENTS
Preface xiii
Abbreviations xv
Contributors xxi
1 Drug Metabolism: Significance and Challenges 1
Chandra Prakash and Alfin D. N. Vaz
1.1 Introduction 1
1.2 Phase I Drug-Metabolizing Enzymes 3
1.2.1 Cytochrome P450 4
1.2.2 Flavin Mono-Oxygenase (FMO) 8
1.2.3 Monoamine Oxidase 8
1.2.4 Molybdenum Hydroxylases 9
1.2.5 Epoxide Hydrolase 9
1.2.6 Esterase/Amidase 9
1.3 Phase II Conjugative Enzymes 10
1.3.1 Uridine Diphosphate Glucuronosyltransferase (UGT) 10
1.3.2 Sulfotransferase 10
1.3.3 Glutathione S-Transferase 11
1.3.4 N-Acetyltransferase 11
1.3.5 Methyl Transferase (MT) 11
1.4 Drug Efflux Transporters 12
1.4.1 ABCB1 (P-Glycoprotein, MDR1) 12
1.4.2 ABCC1 (Multidrug Resistance Related Protein 1, MRP 1) 13
v
vi CONTENTS
1.4.3 ABCC2 (Multidrug Resistance Related Protein2, MRP2) 13
1.4.4 ABCG2 (Breast Cancer Resistance Protein, BCRP) 13
1.5 Drag Uptake Transporters 14
1.5.1 Organic Anion Transporter Polypeptides 14
1.5.2 Organic Cation Transporter 14
1.5.3 Organic Anion Transporter 14
1.5.4 Peptide Transporter 14
1.6 Challenges in Drug Metabolism 15
1.6.1 Prediction of Metabolism and Pharmacokinetics
in Humans 15
1.6.2 Drag-Drag Interactions 17
1.6.3 Polymorphisms 22
1.7 Summary 26
References 27
2 Establishing Orphan Nuclear Receptors PXR and CAR as
Xenobiotic Receptors 43
Tao Li, Junichiro Sonoda, and Ronald M. Evans
2.1 Introduction 43
2.2 Nuclear Receptor and Orphan Nuclear Receptor Superfamily 44
2.3 Orphan Nuclear Receptors as Xenobiotic Receptors and
Their Implications in Phase I Enzyme Regulation 47
2.3.1 Cloning of PXR as a Xenobiotic Receptor and Its
Regulation of P450s 47
2.3.2 Characterization of CAR as a Xenobiotic Receptor 51
2.4 Perspective 53
References 53
3 Nuclear Receptor-Mediated Regulation of Phase II
Conjugating Enzymes 61
Olivier Barbier
3.1 Introduction 61
3.2 Phase II Drag Metabolizing Enzymes 62
3.2.1 Glucuronidation and UGTs 62
3.2.2 Sulfonation and SULTs 64
3.2.3 Sulfonation and Glucuronidation: Two
Complementary Metabolic Pathways 67
3.2.4 Glutathione Conjugation and GSTs 68
3.2.5 Acetylation, Methylation, and EPHXs 69
3.3 The Xenosensors CAR and PXR: Two Master Regulators of
Phase II Metabolism 70
3.3.1 General Considerations 70
3.3.2 Phase II XMEs Identified as PXR and/or CAR Target Genes 71
: CONTENTS vii
3.3.3 Physiological and Pharmacological Interests of Phase
II Enzymes Regulation by PXR and/or CAR 73
3.3.4 Functional Mechanisms of Phase II Genes Regulation
by PXR and CAR: Role of the Glucocorticoid Receptor 77
3.4 AhR and Nrf2, Two Important Regulators of Phase II Enzymes 78
3.4.1 AhR and Phase II XMEs Regulation 78
3.4.2 Nrf2 and Phase II XMEs Regulation 81
3.5 PPARs and Phase II XMEs Regulation 85
3.6 FXR/LXRa and Phase II XMEs Regulation 88
3.7 HNF and Phase II XMEs Regulation 89
3.8 Regulation of Phase II Conjugating Enzymes by Steroid
and Thyroid Receptors 90
3.9 Concluding Remarks and Perspectives 91
References 92
4 Nuclear Receptor-Mediated Regulation of Drug Transporters 111
Oliver Burk
4.1 Introduction 111
4.2 Drug Transporters 112
4.2.1 ABC Efflux Transporters 113
4.2.2 SLCO/OATP Transporters 114
4.2.3 SLC22/Organic Ion Transporters 115
4.3 Induction of Drug Transporters by Activation of PXR
and CAR 116
4.3.1 Induction in Liver and Intestine 117
4.3.2 Induction in Other Organs and Tissues 127
4.4 Induction of Drug Transporters by Activation of PPARa 128
4.5 Molecular Mechanism of PXR- and CAR-Dependent Drug
Transporter Regulation 129
4.5.1 MDR1 (ABCB1) 130
4.5.2 Mrp2(Abcc2) 131
4.5.3 Mrp4(Abcc4) 132
4.5.4 Slcola4 132
4.5.5 SLCO1B1 133
4.6 Induction of Drug Transporter Expression and Drug
Disposition 133
4.7 Conclusions and Future Perspectives 134
References 135
5 Structurejind Function of PXR and CAR 147
X. Edward Zhou and H. Eric Xu
5.1 Introduction 147
5.2 Structure and Function of PXR 148
5.2.1 Crystal Structures of Human PXR LBD/Ligand Complexes 148
viii CONTENTS
5.2.2 The Flexibility of the Ligand Binding Pocket of the
PXR LBD 148
5.2.3 Coactivator Binding and Transcriptional Activity 152
5.2.4 Species Differences among LBD Sequences 152
5.2.5 Heterodimerization with RXR 154
5.3 Structure and Function of CAR 154
5.3.1 Crystal Structure of CAR 154
5.3.2 Ligand Binding and Activation of CAR 156
5.3.3 Cofactor Recruitment and Transcription Activation 162
5.3.4 Species Differences in CAR Ligand Binding and
Activation 162
5.3.5 Heterodimerization with RXR 163
5.4 Concluding Remarks 163
References 164
6 Xenobiotic Receptor Cofactors and Coregulators 167
John Y. L. Chiang
6.1 Regulation of PXR and CAR Nuclear Translation 167
6.1.1 Activation and Nuclear Translocation of CAR 167
6.1.2 Nuclear Translocation of PXR 168
6.2 Nuclear Receptor Coregulators and Epigenetic Regulation
of Gene Transcription 169
6.2.1 Ligand-Independent and Ligand-Dependent
Recruitment of Nuclear Receptor Coactivators 169
6.2.2 Nuclear Receptor Corepressor in Xenobiotic
Receptor Signaling 171
6.3 PXR and CAR Cross Talk With Other Nuclear Receptors
and Transcription Factors 171
6.3.1 PXR and CAR Interact with Other Nuclear Receptors 171
6.3.2 PXR and CAR Interact with Other Transcription Factors 172
6.4 PXR and CAR Regulation of Lipid and Glucose Homeostasis 173
6.4.1 CAR and PXR Regulation of Fatty Acid Metabolism 173
6.4.2 PXR and CAR Regulation of Bile Acid Metabolism 173
6.4.3 PXR Regulation of Cholesterol Metabolism 175
6.4.4 CAR and PXR Regulation of Glucose and Energy
Metabolism 176
6.5 Conclusion 176
References 177
7 Animal Models of Xenobiotic Nuclear Receptors and Their
Utility in Drug Development 185
Haibiao Gong and Wen Xie
7.1 Introduction 185
I
i CONTENTS ix
; 7.2 PXR and CAR Loss-of-Function (Knock-Out) Mouse Models 186
7.2.1 PXR Knock-Out Mice 186
7.2.2 Phenotype of the PXR Knock-Out Mice 188
7.2.3 Another Independently Developed PXR Null Mouse Line 188
7.2.4 CAR Knock-Out Mice 189
7.2.5 Another Independently Developed CAR Null Mouse
Line 189
7.2.6 Combined Loss of PXR and CAR 190
7.3 PXR and CAR Gain-of-Function (Transgenic) Mouse Models 191
7.3.1 Albumin Promoter-Human PXR (Alb-hPXR)
Transgenic Mice 191
7.3.2 Alb-VP-hPXR Transgenic Mice Expressing the
Activated hPXR 192
7.3.3 Fatty Acid Binding Protein Promoter-Human PXR
(FABP-hPXR) Transgenic Mice 194
7.3.4 FABP-VP-hPXR Transgenic Mice 194
7.3.5 Tetracycline-Inducible VP-CAR Transgenic Mice 196
7.4 Humanized Mouse Models 198
7.4.1 Humanized PXR Mice Carrying Human PXR cDNA 198
7.4.2 Humanized PXR Mice Carrying Human PXR
Genomic DNA 199
7.4.3 Humanized CAR Mice 200
7.4.4 Humanized PPARa Mice 200
7.4.5 Humanized AhR Mice 201
7.4.6 Cytochrome P450 Humanized Mice 201
7.5 Utility of Xenobiotic Mouse Models in Pharmaceutical
Development 202
7.6 Closing Remarks 203
References 204
8 Nuclear Receptors and Drug-Drug Interactions with
Prescription and Herbal Medicines 211
Rommel G. Tirona and Richard B. Kim
8.1 Introduction 211
8.2 Prescription Drugs/Drug Classes Involved in Inductive
Drug Interactions 213
8.2.1 Anticonvulsants 214
8.2.2 Rifamycin Antibiotics 214
8.2.3 HIV Protease Inhibitors (HIV-PI) 216
8.2.4 Non-Nucleoside Reverse Transcriptase Inhibitors 216
8.2.5 Bosentan 216
8.3 Herbal Medicines Involved in Inductive Drug Interactions 216
8.3.1 St. John s Wort 217
8.3.2 Other Herbal Medicines 218
x CONTENTS
8.4 Pharmacology of Induction 218
8.5 Clinical Aspects of Induction-Type Drug Interactions 222
8.5.1 Enzymes, Transporters, and Drugs Highly Sensitive
to Induction 222
8.5.2 Therapeutic Implications of Induction-Type Drug
Interactions 224
8.5.3 Time Course of Induction and Deinduction 225
8.6 Inhibition of Nuclear Receptors in Clinical Drug Interactions 226
8.7 Nuclear Receptor Mediated Drug Side Effects 226
8.8 Perspectives 227
References 227
9 Genetic Variants of Xenobiotic Receptors and Their
Implications in Drug Metabolism and Pharmacogenetics 241
Jatinder Lamba and Erin G. Schuetz
9.1 PXR (Pregnane X Receptor) Background 241
9.2 PXR Gene Structure 243
9.3 PXR Alternative mRNAs 243
9.4 Genetic Variants in PXR s Exons and their Functional
Consequences 246
9.5 Genetic Variants in Introns 2-8 and the 3 -UTR of PXR
and their Functional Consequences 251
9.6 Resequencing Strategy for the PXR Promoter and Intron 1 251
9.7 Genetic Variation in the PXR Promoter and 5 -UTR and Its
Functional Relevance 252
9.8 Genetic Variation in PXR s Intron 1 and Its Functional
Relevance 253
9.9 In Silico Analysis for Functional Effect of SNPs in PXR s
Promoter, 5 -UTR, and Intron 1 256
9.10 SNPs in PXR s Promoter and Intron 1 Affect Putative HNF
Binding Sites 256
9.11 PXR SNPs Have Been Associated with Intestinal and
Hepatic Inflammation and Diseases 257
9.12 PXR Structural Variation and Other Genomic Features 258
9.13 PXR Summary 259
9.14 CAR Background 259
9.15 CAR Gene Structure 260
9.16 CAR Alternatively Spliced mRNAs 261
9.17 CAR Genetic Variants (SNPs) and their Functional
Consequences 264
9.18 CAR Summary 266
References 267
CONTENTS xi
10 Beyond PXR and CAR, Regulation of Xenobiotic Metabolism
by Other Nuclear Receptors 275
Martin Wagner, Gernot Zollner, and Michael Trauner
10.1 Introduction 275
10.2 Farnesoid X Receptor 277
10.2.1 FXR-Dependent Regulation of Basolateral Drug
and Bile Acid Uptake 277
10.2.2 FXR-Dependent Regulation of Phase I and II
Metabolism 282
10.2.3 FXR-Dependent Regulation of Canalicular and
Basolateral Drug and Bile Acid Excretion 282
10.2.4 FXR-Dependent Effects on Sterol and Lipid Metabolism 283
10.3 Hepatocyte Nuclear Factor 4a 284
10.4 Vitamin D Receptor 285
10.5 Glucocorticoid Receptor 286
10.6 Peroxisome Proliferator-Activated Receptors 286
10.7 Aryl Hydrocarbon Receptor (AhR) 287
10.8 Conclusions 288
References 288
11 Emerging Role of Retinoid-Related Orphan Receptor (ROR)
and Its Cross Talk with LXR (Liver X Receptor) in the
Regulation of Drug-Metabolizing Enzymes 301
Taira Wada and Wen Xie
11.1 Introduction 301
11.2 Orphan Nuclear Receptor RORct 303
11.3 A Potential Role of RORs in Xeno- and Endobiotic Gene
Regulation 305
11.4 LXR and Its Regulation of Drug-Metabolizing Enzymes 307
11.5 A Functional Cross Talk Between RORa and LXR in the
Regulation of Xeno- and Endobiotic Genes 308
11.6 Closing Remarks 310
References 312
Index 319
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| indexdate | 2024-07-09T21:35:54Z |
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| language | English |
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| spelling | Nuclear receptors in drug metabolism ed. by Wen Xie Hoboken, NJ Wiley 2009 XXII, 330 S. Ill., graph. Darst. 25 cm txt rdacontent n rdamedia nc rdacarrier Includes bibliographical references and index Drugs Metabolism Nuclear receptors (Biochemistry) Genetic regulation Receptors, Cytoplasmic and Nuclear metabolism Drug Delivery Systems methods Pharmaceutical Preparations metabolism Receptors, Steroid metabolism Xie, Wen Sonstige oth HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017385973&sequence=000004&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Nuclear receptors in drug metabolism Drugs Metabolism Nuclear receptors (Biochemistry) Genetic regulation Receptors, Cytoplasmic and Nuclear metabolism Drug Delivery Systems methods Pharmaceutical Preparations metabolism Receptors, Steroid metabolism |
| title | Nuclear receptors in drug metabolism |
| title_auth | Nuclear receptors in drug metabolism |
| title_exact_search | Nuclear receptors in drug metabolism |
| title_full | Nuclear receptors in drug metabolism ed. by Wen Xie |
| title_fullStr | Nuclear receptors in drug metabolism ed. by Wen Xie |
| title_full_unstemmed | Nuclear receptors in drug metabolism ed. by Wen Xie |
| title_short | Nuclear receptors in drug metabolism |
| title_sort | nuclear receptors in drug metabolism |
| topic | Drugs Metabolism Nuclear receptors (Biochemistry) Genetic regulation Receptors, Cytoplasmic and Nuclear metabolism Drug Delivery Systems methods Pharmaceutical Preparations metabolism Receptors, Steroid metabolism |
| topic_facet | Drugs Metabolism Nuclear receptors (Biochemistry) Genetic regulation Receptors, Cytoplasmic and Nuclear metabolism Drug Delivery Systems methods Pharmaceutical Preparations metabolism Receptors, Steroid metabolism |
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