Abstract
Phase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. We examined published epigenome-wide studies of human blood and identified the SULT1A1 and UGT1A6 genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologs Sult1a1 and Ugt1a6 in liver tissue from mice aged 4-32 months obtained from the National Institute on Aging rodent tissue bank. Our sample shows significant loss of 5mC at Sult1a1, mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age at Sult1a1, but no change to histone 3 lysine 27 acetylation (H3K27ac). Sult1a1 gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant changes at Ugt1a6. We conclude that Sult1a1 expression is under epigenetic influence in normal aging and that this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug metabolizing pathways. In future, epigenetic biomarkers could prove useful to inform dosing in older adults.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflicts of Interest: The authors declare no material or financial conflicts of interest.
Funding Information: MMK was partially funded through a graduate studentship from Virginia Commonwealth University (VCU) School of Pharmacy. This study was completed in partial fulfillment of the doctoral requirements in Pharmaceutical Sciences at VCU. This work was funded through R15 AG061649 from the US National Institute on Aging to JLM.