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Published on: August 16, 2018
Screening of a chemical library reveals novel PXR-activating pharmacologic compounds
Marcin Ratajewski1, Izabela Grzelak2, Kamila Wiśniewska2
1Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
Abstract:
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.
Insights
This study identified 16 new compounds activating the pregnane X receptor (PXR), a key regulator of drug metabolism. These findings offer insights into drug interactions and toxicity.
Area of Science:
- Pharmacology
- Toxicology
- Molecular Biology
Background:
- The pregnane X receptor (PXR) is crucial in regulating how the body processes foreign substances (xenobiotics).
- PXR interactions with drugs can lead to adverse effects like drug-drug interactions, liver damage (hepatotoxicity), and cancer drug resistance.
- Predicting PXR activity is vital for drug development and safety assessment.
Purpose of the Study:
- To screen a large library of pharmacologic compounds for novel PXR activators.
- To identify compounds that modulate CYP450 expression via PXR transactivation.
- To correlate chemical structure with PXR-activating bioactivity.
Main Methods:
- Utilized the nhrtox-hepg2 reporter cell line for high-throughput screening.
- Employed a three-stage screening process to identify PXR activators.
- Applied quantitative structure-activity relationship (QSAR) analysis to correlate bioactivity with molecular descriptors.
Main Results:
- Screened 1120 compounds, identifying 16 novel PXR activators.
- Detected PXR activation by compounds like mycophenolic acid, leflunomide, and trifluridine at clinically relevant concentrations.
- QSAR analysis showed a strong correlation between measured PXR bioactivity and calculated molecular properties.
Conclusions:
- Identified novel PXR activators with potential to explain observed drug-drug interactions and toxicity.
- The findings provide a basis for predicting PXR-mediated drug effects using QSAR.
- This research contributes to safer drug development by understanding PXR pathway modulation.
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