DOI
https://doi.org/10.25772/Y7AP-2W53
Author ORCID Identifier
https://orcid.org/0000-0003-2757-1746
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Dr. Joseph McClay
Second Advisor
Dr. Mary Peace McRae
Third Advisor
Dr. Elvin Price
Fourth Advisor
Dr. Mikhail Dozmorov
Fifth Advisor
Dr. Dana Lapato
Abstract
Aging is considered a major risk factor for most diseases and is associated with multimorbidity and polypharmacy. Older adults aged 65 or older are considered more vulnerable to adverse drug reactions (ADRs), which may be partly due to changes in how the body processes drugs with age. Aging causes many epigenetic alterations affecting how certain genes are expressed. We reviewed the literature and found that epigenetic mechanisms can affect genes encoding phase I, II, III reactions, indicating its importance in absorption, distribution, metabolism, and excretion (ADME) processes. This dissertation is comprised of multiple projects. First, we identified genome-wide age associated differentially methylated regions (a-DMRs) in mouse livers (4- and 24-months) and showed how specific drug metabolizing enzymes are affected by epigenetic regulations. In the second project, we focused on super-agers by expanding our age range to include a super aged mice group (32-months) to represent human centenarians and an 18-months group as an intermediate group. The data revealed a marked change in DNA methylation between young (4-months) and old (18, 24 and 32-months), while the majority of xenobiotic pathways were affected in both aging pathways. In the final project, we investigated the transcription factor the aryl hydrocarbon receptor (AhR). Through data integration, we found that AhR regulates many ADME genes in liver that undergo epigenetic aging, so we hypothesized that epigenetic aging may affect AhR binding. We found that the activation of AhR by the potent ligand 2,3,7,8 -Tetrachlorodibenzo-p-dioxin (TCDD) reduces DNA methylation levels at the AhR target gene Cyp1a1, indicating the involvement of AhR in modulating DNA methylation through epigenetic dynamics. We found that DNA methylation change with age in the DMSO control group and that the DNA methylation levels were associated with the Cyp1a1 gene expression data. These findings offer valuable insights into how age-related epigenetic changes and transcription factors can affect drug metabolism molecular pathways with age.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-20-2023
Included in
Bioinformatics Commons, Molecular Genetics Commons, Other Chemicals and Drugs Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Polycyclic Compounds Commons, Translational Medical Research Commons