Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and University of Tuebingen, Tuebingen, Germany.
Drug Metab Dispos. 2013 Oct;41(10):1752-62. doi: 10.1124/dmd.113.052126. Epub 2013 Jun 3.
Genes that are important for the detoxification of drugs and other xenobiotics show a high degree of interindividual variation attributable to regulation by diverse genetic, nongenetic, and epigenetic mechanisms including microRNAs (miRNAs). We selected a set of 56 miRNAs predicted to target the 3'-untranslated region of absorption, distribution, metabolism, excretion (ADME) genes to assess their hepatic expression levels and interindividual variability in a well-documented human liver tissue cohort (n = 92), together with the well-known hepatic miRNAs miR-122, miR-21, miR-27b, and miR-148a. Quantification by stem-loop real-time reverse-transcription polymerase chain reaction confirmed high expression for these microRNAs and revealed particularly strong variability of expression (>1000-fold) for miR-539, miR-200c, miR-31, miR-15a, and miR-22. Association analysis revealed a high degree of correlation among various miRNAs, suggesting coregulation. Statistical analysis considering liver donor meta-data including correction for multiple testing revealed strongly elevated levels of miR-21, miR-34a, miR-130b, and miR-132 in cholestatic liver and of miR-21 and miR-130b during inflammation, as indicated by elevated C-reactive protein levels in serum. Although none of the miRNAs was strongly associated with sex, several miRNAs, including miR-34a and miR-200a/b, were positively correlated with age. Association analysis with ADME gene expression profiles and with cytochrome P450 gene expression phenotypes (mRNA, protein, enzymatic activity) revealed numerous significant correlations. Negatively affected protein and/or activity levels were observed for CYP1A1 (e.g., miR-132, miR-142-3p, miR-21), CYP2A6 (miR-142-3p, miR-21), CYP2C19 (e.g., miR-130b, miR-185, miR-34a), and CYP2E1 (miR-10a, let-7g, miR-200c). These data should be useful to further elucidate regulatory functions of miRNAs in liver pathophysiology and regulation of ADME gene expression.
对于药物和其他外源性物质的解毒至关重要的基因，由于受不同遗传、非遗传和表观遗传机制的调控，显示出高度的个体间变异性，包括 microRNAs（miRNAs）。我们选择了一组 56 个被预测靶向吸收、分布、代谢、排泄（ADME）基因 3'-非翻译区的 miRNAs，以评估它们在一个有充分文献记载的人类肝组织队列（n=92）中的肝表达水平和个体间变异性，以及众所周知的肝 miRNAs miR-122、miR-21、miR-27b 和 miR-148a。茎环实时逆转录聚合酶链反应的定量证实了这些 microRNAs 的高表达，并显示出 miR-539、miR-200c、miR-31、miR-15a 和 miR-22 的表达（>1000 倍）特别强的变异性。关联分析显示各种 miRNAs 之间具有高度相关性，表明它们是共同调控的。考虑到包括对多个测试进行校正的肝供体元数据的统计分析显示，miR-21、miR-34a、miR-130b 和 miR-132 在胆汁淤积性肝中以及 miR-21 和 miR-130b 在炎症中水平升高，血清中 C 反应蛋白水平升高表明这一点。虽然没有一个 miRNAs 与性别强烈相关，但有几个 miRNAs，包括 miR-34a 和 miR-200a/b，与年龄呈正相关。与 ADME 基因表达谱和细胞色素 P450 基因表达表型（mRNA、蛋白质、酶活性）的关联分析显示了许多显著的相关性。观察到 CYP1A1（例如，miR-132、miR-142-3p、miR-21）、CYP2A6（miR-142-3p、miR-21）、CYP2C19（例如，miR-130b、miR-185、miR-34a）和 CYP2E1（miR-10a、let-7g、miR-200c）的蛋白和/或活性水平受到负面影响。这些数据应该有助于进一步阐明 miRNAs 在肝病理生理学和 ADME 基因表达调控中的调节功能。
