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 (5-hydroxymethylcytosine, 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.

中文翻译：

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DNA 甲基化和组蛋白乙酰化在正常衰老过程中改变细胞色素 P450 2E1 的调节并影响肝脏中的药物代谢率。

衰老与肝功能下降有关，这可能会增加老年人发生药物不良反应的风险。我们假设与年龄相关的药物代谢相关基因表观遗传调控的变化可能有助于这种效应。我们回顾了已发表的人类血液表观基因组研究，并将细胞色素 P450 2E1 ( CYP2E1 ) 基因确定为随着年龄的增长而表现出表观遗传变化的顶级基因座。为了研究药物代谢的主要器官肝脏随着年龄的潜在功能变化，我们从美国国家衰老研究所获得了 4-32 个月大的小鼠的肝组织。我们检测了小鼠Cyp2e1周围的全局 DNA 甲基化（5-甲基胞嘧啶，5mC）、羟甲基化（5-羟甲基胞嘧啶，5hmC）和基因座特异性 5mC 和组蛋白乙酰化变化. 随着年龄的增长，小鼠肝脏的 5mC 和 5hmC 表现出显着的整体下降。此外，随着年龄的增长，Cyp2e1 的两个调节区域的 5mC 显着增加，同时其基因和蛋白质表达减少。在所研究的Cyp2e1的两个调节区域，H3K9ac 水平也随年龄而变化，而 H3K27ac 则没有。为了测试这些表观遗传变化是否与不同的药物代谢率相关，我们测定了来自同一肝脏的微粒体提取物中 CYP2E1 特异性探针药物氯唑沙宗的清除率。CYP2E1 内在清除与Cyp2e1的 DNA 甲基化和 H3K9ac 水平相关位点，但与实际年龄无关。这表明与年龄相关的表观遗传变化可能会影响肝脏药物代谢率。未来，表观遗传生物标志物可能有助于指导老年人的给药方案。