DNA methylation dynamics in the hepatic CYP3A4 gene promoter
DNA methylation dynamics in the hepatic CYP3A4 gene promoter
复制标题
DOI：
10.1016/j.biochi.2012.07.013
复制
发表时间：
2012-11-01
期刊：
影响因子：
3.9
通讯作者：
Ingelman-Sundberg, Magnus
中科院分区：
文献类型：
--
作者：
Kacevska, Marina;Ivanov, Maxim;Ingelman-Sundberg, Magnus
编码人体主要药物代谢酶的CYP 3A 4基因在肝脏表达中表现出高度的个体间差异，这可能导致药物代谢和相关药物不良反应的个体间差异。CYP 3A 4的许多个体间变异性仍然无法解释。在本研究中，我们研究了DNA甲基化在影响个体间CYP 3A 4表达中的作用。采用亚硫酸氢盐测序法，对72例成人和7例胎儿肝脏中类似于12 kb CYP 3A 4调控区的单个CpG甲基化进行了研究。我们在成人肝脏中鉴定了高度可变的CpG甲基化位点，其对应于重要的CYP 3A 4转录因子结合位点，包括近端启动子、XREM和CLEM 4以及单独的C/EBP和HNF 4 α结合区。与成人肝脏相比，在胎儿肝脏中观察到这些调控区域内的CpG超甲基化。这些数据表明，动态DNA甲基化元件可能与关键的调控CYP 3A 4启动子区域相关，并可能有助于通常观察到的CYP 3A 4个体间表达及其表达的肝脏发育转变。这些发现为CYP 3A 4调节提供了新的见解，可能对了解药物反应的个体间差异产生影响。(C)2012年Elsevier Masson SAS。All rights reserved.
The CYP3A4 gene, encoding the major drug metabolizing enzyme in humans, exhibits a high interindividual variation in hepatic expression that can lead to interindividual differences in drug metabolism and associated adverse drug effects. Much of the interindividual variability in CYP3A4 remains unexplained. In the present study we investigated the role of DNA methylation in influencing the interindividual CYP3A4 expression. Individual CpG methylation within the similar to 12 kb CYP3A4 regulatory region was investigated in 72 adult as well as in 7 fetal human livers using bisulfite sequencing. We identified highly variable CpG methylation sites in adult livers, which correspond to important CYP3A4 transcription factor binding sites including the proximal promoter, XREM and CLEM4 as well as in separate C/EBP and HNF4 alpha binding regions. CpG hypermethylation within these regulatory regions was observed in fetal livers when compared to adult livers. This data suggests that dynamic DNA methylation elements are likely associated with key regulatory CYP3A4 promoter regions and may potentially contribute to the commonly observed interindividual expression of CYP3A4 as well as the hepatic developmental shift in its expression. The findings provide novel insight to CYP3A4 regulation with possible implications for understanding interindividual differences in drug response. (C) 2012 Elsevier Masson SAS. All rights reserved.