PXR Assays
Overview of Pregnane X Receptor (PXR)
PXR is a ligand-dependent nuclear receptor that binds many structurally diverse molecules and is intimately involved in the regulation of multiple metabolisms. Notably, PXR is closely related to regulating metabolism through genes that control glucose, lipid, bile acid, and bilirubin homeostasis. What's more, growing evidence for the role of PXR in tumor cell proliferation indicates that PXR is implicated in cancer. Moreover, scientists have discovered that PXR may be a promising target for pharmacological interventions, including hepatic steatosis, osteoporosis, hyperbilirubinemia, and inflammatory diseases.
Fig.1. Functions of PXR. (Skandalaki, 2021)
Distributions of PXR
PXR is mainly found in the liver. Additionally, PXR is also expressed in other tissues including specific regions of the intestine, kidney, lung, stomach, ovary, heart, bone marrow, and brain. The widespread distribution of PXR in the system suggests that PXR can be used as part of a protection system.
Mechanisms of PXR
Studies revealed that the renoprotective effect of PXR involves multiple critical signaling pathways, especially the PI3K/AKT pathway.
| Receptor | Gene | Mechanism | Agonists | Antagonists |
| Pregnane X Receptor | NR1I2 |
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Published Data
| Paper Title | Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer |
| Journal | Medicinal research reviews |
| Published | 2020 |
| Abstract | PXR is a major regulator of exogenous detoxification. It is involved in regulating the expression of drug-metabolizing enzymes and transporters to regulate the metabolism of endogenous and xenobiotic substances. Since many drugs can bind and activate PXR, PXR antagonists have potential therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and resistance. In addition, PXR is now known to be closely linked to cell proliferation as well as glucose and lipid metabolism. Therefore, PXR may be involved in cancer and metabolic diseases. This article focuses on the development of PXR antagonists hampered by the disordered binding of PXR ligands. However, in recent years there has been increasing evidence indicating that it is feasible to develop selective PXR antagonists. |
| Result |
To gain a comprehensive understanding of PXR antagonism, the development of PXR antagonists that can be used as chemical probes is imperative. In some cases, selective inhibition of PXR downstream target activity may be more feasible. PXR has now emerged as a promising target for drug discovery. To effectively address the challenges associated with PXR antagonist development, several issues need to be addressed. At the compound level, hybrid compounds based on existing selective PXR antagonists can be developed to engage intramolecular sites for enhanced potency. At the methodological level, newer technologies and computer methods will provide more information.
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Fig.2. Strategies and considerations in the development of PXR antagonists. (Chai, 2020)
References
- Skandalaki, A.; et al. Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment. Biomolecules. 2021; 11(8): 1142.
- Chai, S.C.; et al. Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer. Medicinal Research Reviews. 2020; 40(3): 1061-1083.
