Variation in the expression of cytochrome P450-related miRNAs and transcriptional factors in human livers: Correlation with cytochrome P450 gene phenotypes
Variation in the expression of cytochrome P450-related miRNAs and transcriptional factors in human livers: Correlation with cytochrome P450 gene phenotypes
复制标题
人类肝脏中细胞色素 P450 相关 miRNA 和转录因子表达的变化：与细胞色素 P450 基因表型的相关性
DOI：
10.1016/j.taap.2020.115389
复制
发表时间：
2021-01-03
影响因子：
3.8
通讯作者：
Qiao，Hai-ling
中科院分区：
文献类型：
--
作者：
Zhang，Hai-feng;Zhu，Li-li;Qiao，Hai-ling
细胞色素 P450 (CYP) 基因表达表现出巨大的个体差异，这归因于多种调控因素，包括 microRNA (miRNA) 和肝转录因子 (TF)。我们对 106 个人类肝脏样本使用实时 qPCR 来测量 7 个 miRNA 和 4 个 TF 的表达和个体间变异，据报道这些 miRNA 和 TF 可以调节 CYP 的表达；我们还确定了影响其表达的因素。结果显示，7个miRNA和4个TF的表达呈现非正态分布，并且表达变异性很高（miRNA为89至618倍，TF为12至85倍）。年龄导致 miR-148a、miR-27b 和 miR-34a 的个体间变异，而吸烟和饮酒则显着降低 HNF4α mRNA 水平。关联分析显示 7 个 miRNA 以及 4 个 TF 之间存在显着相关性。此外，我们系统地评估了 7 个 miRNA 和 4 个 TF 对 10 个 CYP 的蛋白质含量、mRNA 水平、翻译效率和活性的影响。结果表明，7 个 miRNA 或 4 个 TF 与 10 个 CYP 表型（如 mRNA、蛋白质和活性所示）之间存在大量关联（正关联和负关联）；具体来说，miR-27b、miR-34a 和所有四种 TF 在 CYP 的个体间变异中发挥着关键作用。我们的结果扩展了之前的发现，并表明 miR-27b 和 miR-34a 可能是 CYP 表达的潜在直接或间接主调节因子，从而导致 CYP 介导的药物代谢的个体间差异。
Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.