Rx-TGx: Toxicogenomic Study Of Pharmaceuticals Using RNA-Seq

The robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 95 different compounds, many of which are known to be associated with clinical risk for drug induced liver injury (DILI) by diverse mechanisms.肝脏经由异生物受体（xenobiotic receptors）介导的强大转录可塑性，是其能够快速且高效响应各类化学应激源的核心基础。因此，肝脏中药物诱导的基因表达变化，不仅可作为肝损伤的生物标志物，同时亦可作为代谢、解毒及化学物诱导组织保护过程中适应性反应的机制性预警标志物。现代RNA测序技术为我们提供了前所未有的契机，可同时定量监测上述过程，并系统阐释药物处理诱导的肝脏剂量依赖性应激、适应性反应、保护效应与损伤应答的完整谱式及其情境关联。本研究采用该技术，对每日经口给药95种不同化合物后大鼠肝脏的转录组变化开展了谱式分析；其中多数化合物已被证实可通过多种机制与药物性肝损伤（Drug-Induced Liver Injury, DILI）的临床风险相关联。