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Epigenetic Regulation of Drug Metabolizing Enzymes in Normal Aging Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2020 Epigenetic Regulation of Drug Metabolizing Enzymes in Normal Aging Mohamad M. Kronfol Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Molecular Genetics Commons, Other Pharmacy and Pharmaceutical Sciences Commons, and the Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/6351 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Mohamad M. Kronfol 2020 All Rights Reserved i EPIGENETIC REGULATION OF DRUG METABOLIZING ENZYMES IN NORMAL AGING A dissertation submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. By Mohamad Maher Kronfol PhD Candidate, School of Pharmacy, Virginia Commonwealth University, Virginia, USA Bachelor of Pharmacy, Beirut Arab University, Lebanon, 2013 Director: Joseph L. McClay, Ph.D. Assistant Professor, Department of Pharmacotherapy and Outcomes Science Virginia Commonwealth University Richmond, Virginia April 2020 ii Dedication This is for you mom iii Acknowledgments This dissertation would not have been achievable without the support of many people. I am unreservedly thankful to my PhD advisor, Dr. Joseph McClay for providing me with his constant support and advice. You are a great mentor whose outstanding intellect and rigor shaped my independence as a scientist. I want to thank my PhD committee members, Drs. Patricia Slattum, Mikhail Dozmorov, Elvin Price, Matthew Halquist, and MaryPeace McRae. I am grateful to and humbled by your advisory that helped me complete my PhD. Dr. Patricia Slattum for your continuous support and professional advice. Dr. Elvin Price for your professionalism and career advice. Dr. Matthew Halquist for your continuous support and feedback. Dr. Mikhail Dozmorov for your seminal literature, encouragement, and advice. Dr. MaryPeace McRae for your guidance through the program. Ms. Fay Jahr for your support in the laboratory. The Deans Office and the Department of Pharmacotherapy and Outcomes Science (DPOS) for the academic, administrative, and financial support. Ms. Sha-kim Craft for your undying willingness to help in administrative aspects of my PhD. My friends at DPOS that have kept me motivated to pursue my studies. Mr. Walid Jamaleddine, for being my American father figure. Finally, my parents Maher and Mona, for your sacrifice, I am forever in your debt. iv Table of Contents Acknowledgements ...................................................................................................................... iii Table of Contents ......................................................................................................................... iv List of Tables ............................................................................................................................... vii List of Figures ............................................................................................................................. viii List of Abbreviation .......................................................................................................................x Abstract ........................................................................................................................................ xii Chapter 1: The role of epigenomics in personalized medicine: a literature review ................1 1.1. Introduction ...............................................................................................................................1 1.2. Epigenetics Overview ...............................................................................................................3 1.2.1. Epigenetic modifications to chromatin ............................................................................5 1.2.2. Epigenetic effects on gene expression and regulation .....................................................7 1.2.3. Individual differences in epigenetic states and developmental plasticity .......................8 1.3. Epigenetic Applications in Personalized Medicine ................................................................11 1.3.1. Epigenetic biomarkers of disease ..................................................................................11 1.3.2. Epigenetic drugs ............................................................................................................15 1.3.3. Epigenetic biomarkers of drug response .......................................................................24 1.3.4. Epigenetic modification of drug absorption, distribution, metabolism, and excretion (ADME) genes ..............................................................................................................26 1.4. Aging.......................................................................................................................................27 1.4.1. Aging, drug response, and adverse drug reactions ........................................................27 1.4.2. Personalized dosing in the elderly population ...............................................................28 1.4.3. Epigenetics of age .........................................................................................................28 1.5. Discussion and Conclusions ...................................................................................................29 Chapter 2: DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver .................33 2.1. Abstract ...................................................................................................................................34 2.2. Introduction .............................................................................................................................35 2.3. Methods...................................................................................................................................38 2.3.1. Mice ...............................................................................................................................38 2.3.2. DNA and RNA extraction ..............................................................................................38 2.3.3. Global 5-MethylCytosine (5mC) and 5-HydroxymethylCytosine (5hmC) ...................38 2.3.4. Selection of genomic regions of interest ........................................................................38 2.3.5. Bisulfite conversion of genomic DNA and High-Resolution Melt (HRM) analysis .....44 2.3.6. Gene expression analysis by reverse transcription – quantitative PCR (RT-qPCR) .....45 2.3.7. Western Blots .................................................................................................................45 2.3.8. Chromatin Immunoprecipitation Quantitative Polymerase Chain Reaction (ChIP- qPCR) ............................................................................................................................47 v 2.3.9. Pyrosequencing ..............................................................................................................50 2.3.10. CYP2E1 intrinsic clearance .........................................................................................51 2.3.11. Statistics .......................................................................................................................56 2.4. Results .....................................................................................................................................57 2.4.1. Global epigenetic effects in aged mouse liver ...............................................................57 2.4.2. Age-associated changes to Cyp2e1 5’UTR methylation and gene and protein expression ......................................................................................................................61 2.4.3. Base-resolution 5mC analysis of Cyp2e1 5’UTR and upstream regulatory region .......63 2.4.4. Histone acetylation analysis of Cyp2e1 5’UTR and upstream regulatory region ..........66 2.4.5. CYP2E1 pharmacokinetics, chronological age, and epigenetics ...................................68 2.5. Discussion ...............................................................................................................................73 Chapter 3: Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging ............................................................................................77 3.1. Abstract ...................................................................................................................................78 3.2. Introduction .............................................................................................................................79 3.3. Methods...................................................................................................................................84 3.3.1. Mice ...............................................................................................................................84 3.3.2. DNA and RNA extraction ..............................................................................................84
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