DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver

Abstract

Aging is associated with reduced liver function that may increase the risk for adverse drug reactions in older adults. We hypothesized that age-related changes to epigenetic regulation of genes involved in drug metabolism may contribute to this effect. We reviewed published epigenome-wide studies of human blood and identified the cytochrome P450 2E1 (CYP2E1) gene as a top locus exhibiting epigenetic changes with age. To investigate potential functional changes with age in the liver, the primary organ of drug metabolism, we obtained liver tissue from mice aged 4-32 months from the National Institute on Aging. We assayed global DNA methylation (5-methylcytosine, 5mC), hydroxymethylation (5hydroxymethylcytosine, 5hmC), and locus-specific 5mC and histone acetylation changes around mouse Cyp2e1. The mouse livers exhibit significant global decreases in 5mC and 5hmC with age. Furthermore, 5mC significantly increased with age at two regulatory regions of Cyp2e1 in tandem with decreases in its gene and protein expressions. H3K9ac levels also changed with age at both regulatory regions of Cyp2e1 investigated, while H3K27ac did not. To test if these epigenetic changes are associated with varying rates of drug metabolism, we assayed clearance of the CYP2E1-specific probe drug chlorzoxazone in microsome extracts from the same livers. CYP2E1 intrinsic clearance is associated with DNA methylation and H3K9ac levels at the Cyp2e1 locus but not with chronological age. This suggests that age-related epigenetic changes may influence rates of hepatic drug metabolism. In the future, epigenetic biomarkers could prove useful to guide dosing regimens in older adults.

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

“…For example, histone H3K14, H4K8, and H4K12 acetylation were increased during postovulatory aging of mouse oocytes [ 284 ]. In rat liver, histone H3K9 acetylation decreased slightly with aging [ 285 ], but some gene enhancers such as those for the gene CYP2E1, the major enzyme in brain that detoxifies ethanol to acetaldehyde [ 286 ], showed increased hepatic histone H3K9 acetylation with aging [ 287 ]. Measurements of total HAT activity in isolated rat liver nuclei showed a three-fold decrease with aging that was driven by the decline of the relatively strong activity of histone H4 acetylation in young rats, while the smaller hepatic histone H3 HAT activity increased by roughly 40% with aging [ 288 ].…”

Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation

“…In mouse primary hepatocytes, HDAC5 plays a role in integrating the fasting state and ER stress signals to regulate hepatic fatty acid oxidation. This suggests HDAC5 could be a target for the treatment of obesity-associated hepatic steatosis (20). Taken together, these studies indicate central roles for class II HDACs in metabolic processes, including glucose homeostasis, energy metabolism, and lipogenesis.…”

“…Alcohol-induced histone 3 acetylation has been extensively studied in alcoholic liver disease and it appears to play a role in the progression of fibrosis (18,19). HDAC5 changes have also been implicated in liver damage when C57Bl/6 mice were fed a high fat diet (20). Acetylated H3K9 (H3K9ac) and 5-methylcytosine levels were altered at regulatory loci of agingassociated genes in mouse livers (21).…”

Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging

“…We obtained livers from 20 male CB6F1 mice from the National Institute on Aging (NIA) rodent tissue bank. Each of four age groups (4,18,24, and 32 months) comprised five subjects. We used the AllPrep DNA/RNA kit (Qiagen, Hilden, Germany) to extract DNA and RNA from the same liver samples.…”

“…Many a-DMRs have functional consequences 2,3 , leading us to seek out a-DMRs at genes encoding drug metabolizing enzymes to determine if they affect regulation of these genes. Previously, we reported that a-DMRs at the cytochrome P450 2E1 gene, which encodes a phase I drug metabolizing enzyme, showed significant changes with age that were associated with CYP2E1 function 4 . In the current study, we extend this work to consider genes encoding phase II (conjugation) drug metabolizing enzymes.…”