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Table of contents
1. Table of Contents
1. Table of Contents
2. Acknowledgements
3. Funding Sources
4. List of Tables
5. List of Figures
6. List of Abbreviations
7. Chapter I: Introduction to Retinoic Acid Signaling and Cytochrome P450
7.1. Introduction
7.2. Retinoic Acid Signaling
7.3. Cytochrome P450
7.4. Role of CYP26
7.5. CYP26 Pharmacology
7.6. CYP26 Homology Modeling
8. Aims and Scope
9. Chapter II: Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1
9.1. Introduction
9.2. Materials and Methods
9.2.1. Materials
9.2.2. Sequence Verification and Expression of CYP26B1
9.2.3. IC50 Determination for Retinoic Acid Receptor Agonists
9.2.4. Homology Modeling
9.2.5. Metabolic Profiling
9.2.6. Enzyme Kinetics
9.2.7. Tazarotenic Acid Phenotyping
9.2.8. LC-MS/MS Analysis
9.2.9. Data Analysis
9.3. Results
9.3.1. Homology Modeling
9.3.2. Metabolic Profile
9.3.3. In Vitro Enzyme Kinetics
9.3.4. Tazarotenic Acid Phenotyping
9.4. Discussion
10. Chapter III: Comparison of the Ligand Binding Site of CYP2C8 with CYP26A1 and CYP26B1: A Structural Basis for the Identification of New Inhibitors of the Retinoic Acid Hydroxylases
10.1. Introduction
10.2. Materials and Methods
10.2.1. Materials
10.2.2. Homology Modeling and Computational Docking Simulations
10.2.3. In Vitro Inhibition Assays
10.2.4. Spectral Binding Determination
10.2.5. Assessment of In Vitro Free Fraction
10.2.6. In Vitro Stability of Candesartan Cilexetil
10.2.7. Calculation of Cmax,u / IC50
10.2.8. Liquid Chromatography – Mass Spectrometry Analysis
10.3. Results
10.3.1. Evaluation of tazarotenic acid sulfoxide formation as a probe substrate of CYP26
10.3.2. In Vitro Inhibition Screening and IC50 Determination
10.3.3. Computational Docking Simulations
10.3.4. Spectral Binding Studies
10.3.5. Calculation of Cmax,u / IC50
10.4. Discussion
11. Chapter IV: Contribution of CYP26 to the Metabolism and Clearance of Retinoic Acid Receptor Agonists and Antagonists
11.1. Introduction
11.2. Materials and Methods
11.2.1. Materials
11.2.2. In Vitro Clearance of Retinoic Acid Receptor Agonists and Antagonists by Recombinant CYP26s, CYP2C8 and CYP3A4
11.2.3. Adapalene Phenotyping
11.2.4. Metabolite Identification of Adapalene and Des-Adamantyl Adapalene in Recombinant CYP26s
11.2.5. Computational Docking of Adapalene and Des-Adamantyl Adapalene in CYP26A1, CYP26B1 and CYP26C1 homology models
11.2.6. LC-MS/MS Analysis
11.2.7. Data Analysis
11.3. Results
11.3.1. In Vitro Clearance of Retinoic Acid Receptor Agonists and Antagonists by Recombinant CYP26s, CYP2C8 and CYP3A4
11.3.2. Metabolite Identification of Adapalene and Des-Adamantyl Adapalene in Recombinant CYP26s
11.3.3. Computational Docking of Adapalene and Des-Adamantyl Adapalene in CYP26A1, CYP26B1 and CYP26C1 homology models
11.3.4. Adapalene Phenotyping
11.4. Discussion
12. Chapter V: General Conclusions
13. References
14. Vita
