ArticleHepatology (Baltimore, Md.)2019
Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock-Induced Liver Injury.
Article in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 35 citations in OpenAlex.
- Three Thiol-Reactive Reagents drive Synergistic Lethality in Glioblastoma cells.Research square · 2026Article
- Hide and seek: targeting nuclear receptor PXR with inhibitors and PROTACs to improve drug efficacy and safety.Expert opinion on therapeutic targets · 2026Article
- Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.Structure (London, England : 1993) · 2026Article
- Pregnane X receptor (NR1I2) deficiency in mice reveals context-dependent regulation of inflammatory homeostasis.Frontiers in immunology · 2026Review
- Bisphenol F and Steatotic Liver Disease: Resolving the PXR Paradox Through Stress Pathway Mechanisms.Biomedicines · 2025Review
- Targeting Kupffer Cell Enolase 1 Attenuates Liver Inflammation and Injury in Hemorrhagic Shock.International journal of molecular sciences · 2025Article
- Exploring Adverse Event Associations of Predicted PXR Agonists Using the FAERS Database.International journal of molecular sciences · 2025Article
- First-in-Class Small Molecule Degrader of Pregnane X Receptor Enhances Chemotherapy Efficacy.Journal of medicinal chemistry · 2024Article
- CYP3A4*1B but Not CYP3A5*3 as Determinant of Long-Term Tacrolimus Dose Requirements in Spanish Solid Organ Transplant Patients.International journal of molecular sciences · 2024Article
- Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.Nature communications · 2024Article
- Ligand flexibility and binding pocket malleability cooperate to allow selective PXR activation by analogs of a promiscuous nuclear receptor ligand.Structure (London, England : 1993) · 2023Article
- Pregnane X receptor (PXR) deficiency protects against spinal cord injury by activating NRF2/HO-1 pathway.CNS neuroscience & therapeutics · 2023Article
- KDM4A, involved in the inflammatory and oxidative stress caused by traumatic brain injury-hemorrhagic shock, partly through the regulation of the microglia M1 polarization.BMC neuroscience · 2023Article
- Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- The xenobiotic receptors PXR and CAR in liver physiology, an update.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
- Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning.Cellular and molecular life sciences : CMLS · 2021Article
- PXR-mediated idiosyncratic drug-induced liver injury: mechanistic insights and targeting approaches.Expert opinion on drug metabolism & toxicology · 2020Review
- Inhibition of Estrogen Sulfotransferase (Journal of the American Society of Nephrology : JASN · 2020Article
- Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer.Medicinal research reviews · 2020Review
- CITCO Directly Binds to and Activates Human Pregnane X Receptor.Molecular pharmacology · 2020Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Hemorrhagic shock (HS) is a life-threatening condition associated with tissue hypoperfusion and often leads to injury of multiple organs including the liver. Pregnane X receptor (PXR) is a species-specific xenobiotic receptor that regulates the expression of drug-metabolizing enzymes (DMEs) such as the cytochrome P450 (CYP) 3A. Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. The goal of this study is to determine whether PXR plays a role in the regulation of DMEs in the setting of HS and whether activation of PXR is beneficial or detrimental to HS-induced hepatic injury. PXR transgenic, knockout, and humanized mice were subject to HS, and the liver injury was assessed histologically and biochemically. The expression and/or activity of PXR and CYP3A were manipulated genetically or pharmacologically in order to determine their effects on HS-induced liver injury. Our results showed that genetic or pharmacological activation of PXR sensitized wild-type and hPXR/CYP3A4 humanized mice to HS-induced hepatic injury, whereas knockout of PXR protected mice from HS-induced liver injury. Mechanistically, the sensitizing effect of PXR activation was accounted for by PXR-responsive induction of CYP3A and increased oxidative stress in the liver. The sensitizing effect of PXR was attenuated by ablation or pharmacological inhibition of CYP3A, treatment with the antioxidant N-acetylcysteine amide, or treatment with a PXR antagonist. Conclusion: We have uncovered a function of PXR in HS-induced hepatic injury. Our results suggest that the unavoidable use of PXR-activating drugs in trauma patients has the potential to exacerbate HS-induced hepatic injury, which can be mitigated by the coadministration of antioxidative agents, CYP3A inhibitors, or PXR antagonists.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.