ArticleEpilepsia2017
Overexpression of pregnane X and glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells.
Article in Epilepsia, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 56 citations in OpenAlex.
- Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.Signal transduction and targeted therapy · 2025Review
- How Uremic Toxins Alter Atorvastatin Disposition: Molecular Mechanisms of Inhibition of the Enzyme CYP3A4.Balkan medical journal · 2025Article
- Hypothalamic-Pituitary-Adrenal Axis and Epilepsy.Journal of clinical neurology (Seoul, Korea) · 2024Review
- Review
- The role of molecular chaperones in the mechanisms of epileptogenesis.Cell stress & chaperones · 2023Review
- Pregnane X receptor (PXR) deficiency protects against spinal cord injury by activating NRF2/HO-1 pathway.CNS neuroscience & therapeutics · 2023Article
- Association of ABCB1 Polymorphisms with Efficacy and Adverse Drug Reactions of Valproic Acid in Children with Epilepsy.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Article
- The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy.Epilepsia open · 2022Review
- Glucocorticoid Receptor β Isoform Predominates in the Human Dysplastic Brain Region and Is Modulated by Age, Sex, and Antiseizure Medication.International journal of molecular sciences · 2022Article
- Factors affecting interictal unilateral and bilateral discharges and ictal diffusion patterns of scalp electroencephalogram in temporal lobe epilepsy.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2022Article
- Genetic Analysis of CYP2C9 with Reference to Drug Response in Epilepsy Patients of Pakistan.Genetics research · 2022Article
- A novel biomimetic nanomedicine system with anti-inflammatory and anti-osteoporosis effects improves the therapy efficacy of steroid-resistant nephrotic syndrome.Journal of nanobiotechnology · 2021Article
- Drug Delivery Challenges in Brain Disorders across the Blood-Brain Barrier: Novel Methods and Future Considerations for Improved Therapy.Biomedicines · 2021Review
- Multiple hurdle mechanism and blood-brain barrier in epilepsy: glucocorticoid receptor-heat shock proteins on drug regulation.Neural regeneration research · 2021Review
- Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview.Pharmaceutics · 2021Review
- Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease.International journal of molecular sciences · 2021Review
- Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances.Frontiers in pharmacology · 2021Review
- Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resistant Epilepsy.Molecular neurobiology · 2020Article
- The constitutive androstane receptor and pregnane X receptor in the brain.British journal of pharmacology · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveRecent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples.
methodsPXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures. We used primary cultures of endothelial cells obtained from epileptic brain tissues (EPI-ECs; n = 8), commercially available human brain microvascular endothelial cells (HBMECs; n = 8), and human hepatocytes (n = 3). PXR/GR messenger RNA (mRNA) levels in brain ECs was initially determined by complementary DNA (cDNA) microarrays. The expression of PXR/GR proteins was quantified by Western blot. PXR and GR silencing was performed in EPI-ECs (n = 4), and the impact on downstream CYP expression was determined.
resultsPXR/GR expression was detected by immunofluorescence in ECs and neurons in the human temporal lobe samples analyzed. Elevated mRNA and protein levels of PXR and GR were found in EPI-ECs versus control HBMECs. Hepatocytes, used as a positive control, displayed the highest levels of PXR/GR expression. We confirmed expression of PXR/GR in cytoplasmic-nuclear subcellular fractions, with a significant increase of PXR/GR in EPI-ECs versus controls. CYP3A4, CYP2C9, and CYP2E1 were overexpressed in EPI-ECs versus control, whereas CYP2D6 and CYP2C19 were downregulated or absent in EPI-ECs. GR silencing in EPI-ECs led to decreased CYP3A4, CYP2C9, and PXR expression. PXR silencing in EPI-ECs resulted in the specific downregulation of CYP3A4 expression. SIGNIFICANCE: Our results indicate increased PXR and GR in primary ECs derived from human epileptic brains. PXR or GR may be responsible for a local drug brain metabolism sustained by abnormal CYP regulation.
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