Screening of a chemical library reveals novel PXR-activating pharmacologic compounds
Screening of a chemical library reveals novel PXR-activating pharmacologic compounds
复制标题
DOI：
10.1016/j.toxlet.2014.10.009
复制
发表时间：
2015-01-05
影响因子：
3.5
通讯作者：
Dastych, Jaroslaw
中科院分区：
文献类型：
--
作者：
Ratajewski, Marcin;Grzelak, Izabela;Dastych, Jaroslaw
PXR是外源性物质转化的主要调节因子之一。药理学化合物和PXR之间的相互作用经常导致药物间相互作用、药物诱导的肝毒性和癌细胞中耐药表型的发展。潜在的PXR介导的药物代谢的影响，可以预测使用高通量的方法来检测PXR的反式激活。我们使用报告细胞系nhrtox-hepg 2筛选了1120种药理物质的化合物库。使用三阶段筛选过程结合定量构效关系（QSAR）分析，我们检测到16个新的，以前未报道的PXR激活剂能够上调CYP 450表达。对于其中一些化合物，如麦考酚酸、来氟米特和曲氟尿苷，观察到的与PXR的相互作用发生在具有临床意义的浓度下，可以为观察到的药物间相互作用和药物诱导的毒性提供潜在的机制解释。一个平行的QSAR分析显示实验测量的PXR依赖的生物活性和计算的PXR激活剂的分子描述符之间的显着相关性。(C)2014爱思唯尔爱尔兰有限公司版权所有。
The pregnane X receptor (PXR) is one of the master regulators of xenobiotic transformation. Interactions between pharmacologic compounds and PXR frequently result in drug-to-drug interactions, drug-induced hepatotoxicity, and the development of drug-resistant phenotypes in cancer cells. Potential PXR-mediated effects on drug metabolism can be predicted using high-throughput methods to detect PXR transactivation. We used the reporter cell line nhrtox-hepg2 to screen an 1120-compound library of pharmacologic substances. Using a three-stage screening process combined with a quantitative structure-activity relationships (QSAR) analysis, we detected 16 novel, previously unreported PXR activators capable of upregulating CYP450 expression. For some of these compounds such as mycophenolic acid, leflunomide, and trifluridine, the observed interactions with PXR occurred at clinically significant concentrations and could provide potential mechanistic explanations for observed drug-to-drug interactions and drug-induced toxicity. A parallel QSAR analysis revealed significant correlation between the experimentally measured PXR-dependent bioactivity and the calculated molecular descriptors of the PXR activators. (C) 2014 Elsevier Ireland Ltd. All rights reserved.