Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier
- 1 August 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 295 (2), C440-C450
- https://doi.org/10.1152/ajpcell.00491.2007
Abstract
Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone, a synthetic glucocorticoid, is routinely prescribed with antineoplastic agents to alleviate pain associated with chemotherapy and reduce intracranial pressure. We investigated whether dexamethasone treatment increased the expression and activity of multidrug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with submicromolar concentrations of dexamethasone induced significantly higher levels of drug efflux transporters such as breast cancer resistance protein (abcg2), P-glycoprotein (P-gp; abcb1a/abcb1b), and MDR protein 2 (Mrp2; abcc2) as indicted by protein and mRNA levels as well as by functional activity. The effect of dexamethasone on transporter function was significant within 6 h of treatment, was dose dependent, and was reversible. Dexamethasone-induced upregulation of Bcrp and P-gp expression and function was partially abrogated by the glucocorticoid receptor (GR) antagonist RU486. In contrast, RU486 had no effect on the dexamethasone-induced upregulation of Mrp2, suggesting a GR-independent regulation of Mrp2, and a GR-dependent regulation of P-gp and Bcrp. In addition to the dexamethasone-induced upregulation of MDR transporters, we measured a dose-dependent and reversible increase in the expression of the nuclear transcription factor pregnane xenobiotic receptor (PXR). Administering dexamethasone to rats caused increased expression of PXR in brain microvessels within 24 h. These results suggest that adjuvant therapy with corticosteroids such as dexamethasone in the treatment of brain tumors may increase the expression of MDR transporters at the blood-brain barrier through pathways involving GR and PXR.Keywords
This publication has 43 references indexed in Scilit:
- Dexamethasone induces the expression of metalloproteinase inhibitor TIMP‐1 in the murine cerebral vascular endothelial cell line cENDJournal Of Physiology-London, 2007
- Ketoconazole and Miconazole Are Antagonists of the Human Glucocorticoid Receptor: Consequences on the Expression and Function of the Constitutive Androstane Receptor and the Pregnane X ReceptorMolecular Pharmacology, 2006
- THE ROLE OF PREGNANE X RECEPTOR IN 2-ACETYLAMINOFLUORENE-MEDIATED INDUCTION OF DRUG TRANSPORT AND -METABOLIZING ENZYMES IN MICEDrug Metabolism and Disposition, 2005
- Differential regulation of the human MRP2 and MRP3 gene expression by glucocorticoidsThe Journal of Steroid Biochemistry and Molecular Biology, 2005
- Rapid Regulation of P-Glycoprotein at the Blood-Brain Barrier by Endothelin-1Molecular Pharmacology, 2004
- Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in ratsXenobiotica, 2004
- Cancer Statistics, 2003CA: A Cancer Journal for Clinicians, 2003
- Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated EffluxThe Journal of pharmacology and experimental therapeutics, 2002
- Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.JCI Insight, 1995
- Regulation by dexamethasone of P‐glycoprotein expression in cultured rat hepatocytesFEBS Letters, 1993