Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists.
Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists.
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DOI：
10.1007/s11095-009-9901-7
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发表时间：
2009-08
影响因子：
3.7
通讯作者：
Ekins, Sean
中科院分区：
文献类型：
--
作者：
Biswas, Arunima;Mani, Sridhar;Redinbo, Matthew R.;Krasowski, Matthew D.;Li, Hao;Ekins, Sean
孕烷X受体属于核激素受体超家族，参与许多基因的转录控制。最初认为它是一种控制解毒途径的外源传感器。最近的研究表明其在炎症和癌症中的作用越来越重要，支持其消除组织损伤的功能。 PXR 直系同源物和 PXR 样途径已在几种非哺乳动物物种中被发现，这证实了 PXR 在细胞解毒中的保守作用。总之，PXR 在体内具有多种作用，并且被揭示其行为类似于“Jekyll and Hyde”核激素受体。本综述的重要性在于阐明发现 PXR 拮抗剂的必要性，以进一步探讨其生物学和治疗应用。尽管已经报道了几种 PXR 激动剂，但实际上对 PXR 拮抗剂一无所知。在这里，我们建议通过化学、遗传和分子建模方法开发 PXR 拮抗剂。根据这篇综述，很明显 PXR 和 PXR 样途径的拮抗剂将在 PXR 生物学和治疗学中具有广泛的用途。
The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics.
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DOI：
10.1073/pnas.95.21.12208
发表时间：
1998-10-13
影响因子：
11.1
作者：
Bertilsson, G;Heidrich, J;Berkenstam, A
通讯作者：
Berkenstam, A
影响因子：
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作者：
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影响因子：
3.6
作者：
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影响因子：
4.5
作者：
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通讯作者：
Wright, M. C.
DOI：
10.1615/critreveukaryotgeneexpr.v12.i1.30
发表时间：
2002-01-01
影响因子：
1.6
作者：
Dussault, I;Forman, BM
通讯作者：
Forman, BM