Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library.
Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library.
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从Tox21化合物文库的筛选鉴定的人胆甾烷X受体活化剂的表征。
DOI：
10.1016/j.bcp.2020.114368
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发表时间：
2021-03
影响因子：
5.8
通讯作者：
Xia, Menghang
中科院分区：
文献类型：
--
作者：
Lynch, Caitlin;Sakamuru, Srilatha;Huang, Ruili;Niebler, Jake;Ferguson, Stephen S.;Xia, Menghang
孕烷X受体（PXR; NR1I2）是一种重要的核受体，其主要功能是调节药物代谢中的酶。由PXR调控的主要药物代谢酶细胞色素P450 (CYP) 3A4占所有上市药物代谢的近50%。最近，PXR也被发现在能量稳态、免疫反应和癌症中发挥作用。由于它与这些重要角色的相互作用，以及它的药物-药物相互作用功能，鉴定可以调节PXR的化合物是必要的。在这项研究中，我们使用稳定的hPXR- luc HepG2细胞系筛选Tox21 10,000化合物集合以鉴定hPXR激动剂。在PXR拮抗剂存在的情况下进行药理学研究，以确认所选择的潜在hPXR激动剂在相同细胞中的活性。最后，利用代谢能力细胞系HepaRG和HepaRG-PXR敲除（KO）进一步确认潜在的PXR激活剂。我们确定了一组结构簇和单一化合物，其中包括潜在的新型hPXR激动剂。在21种选定的化合物中，11种潜在的PXR激活剂显著诱导了HepaRG细胞中CYP3A4 mRNA的表达。当处理HepaRG-PXR-KO细胞时，所有这些化合物都失去了诱导作用，证实了它们的PXR激活。依托咪多啉是一种潜在的选择性PXR激动剂。总之，目前的研究已经确定了11种化合物作为潜在的新型或尚未充分表征的PXR激活剂。由于作为PXR激动剂的巨大意义，这些化合物对药物代谢和药物相互作用的潜在影响应该进一步研究。
The pregnane X receptor (PXR; NR1I2) is an important nuclear receptor whose main function is to regulate enzymes within drug metabolism. The main drug metabolizing enzyme regulated by PXR, cytochrome P450 (CYP) 3A4, accounts for the metabolism of nearly 50% of all marketed drugs. Recently, PXR has also been identified as playing a role in energy homeostasis, immune response, and cancer. Due to its interaction with these important roles, alongside its drug-drug interaction function, it is imperative to identify compounds which can modulate PXR. In this study, we screened the Tox21 10,000 compound collection to identify hPXR agonists using a stable hPXR-Luc HepG2 cell line. A pharmacological study in the presence of a PXR antagonist was performed to confirm the activity of the chosen potential hPXR agonists in the same cells. Finally, metabolically competent cell lines - HepaRG and HepaRG-PXR-Knockout (KO) - were used to further confirm the potential PXR activators. We identified a group of structural clusters and singleton compounds which included potentially novel hPXR agonists. Of the 21 selected compounds, 11 potential PXR activators significantly induced CYP3A4 mRNA expression in HepaRG cells. All of these compounds lost their induction when treating HepaRG-PXR-KO cells, confirming their PXR activation. Etomidoline presented as a potentially selective agonist of PXR. In conclusion, the current study has identified 11 compounds as potentially novel or not well-characterized PXR activators. These compounds should further be studied for their potential effects on drug metabolism and drug-drug interactions due to the immense implications of being a PXR agonist.
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影响因子：
7.4
作者：
Attene-Ramos, Matias S.;Miller, Nicole;Huang, Ruili;Michael, Sam;Itkin, Misha;Kavlock, Robert J.;Austin, Christopher P.;Shinn, Paul;Simeonov, Anton;Tice, Raymond R.;Xia, Menghang
通讯作者：
Xia, Menghang
DOI：
10.1007/978-1-4939-6346-1_12
发表时间：
2016-01-01
期刊：
HIGH-THROUGHPUT SCREENING ASSAYS IN TOXICOLOGY
影响因子：
--
作者：
Huang, Ruili
通讯作者：
Huang, Ruili
影响因子：
4.6
作者：
Huang R;Sakamuru S;Martin MT;Reif DM;Judson RS;Houck KA;Casey W;Hsieh JH;Shockley KR;Ceger P;Fostel J;Witt KL;Tong W;Rotroff DM;Zhao T;Shinn P;Simeonov A;Dix DJ;Austin CP;Kavlock RJ;Tice RR;Xia M
通讯作者：
Xia M
影响因子：
5.6
作者：
Lee, Heejin;Kim, Jun Woo;Min, Sang-Hyun
通讯作者：
Min, Sang-Hyun
影响因子：
7.8
作者：
Kohonen, Teuvo
通讯作者：
Kohonen, Teuvo