Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Autor: Jun Shen, Vishal S. Narang, Clinton F. Stewart, Christopher M. Waters, Narendra Kumar, Charles H. Fraga, Stacy L. Throm
Rok vydání: 2008
Předmět:
Male
Pregnenolone Carbonitrile
Receptors
Steroid
medicine.medical_specialty
ATP Binding Cassette Transporter
Subfamily B
Abcg2
Physiology
Blotting
Western
Gene Expression
Pharmacology
Blood–brain barrier
Dexamethasone
Rats
Sprague-Dawley
Receptors
Glucocorticoid
Glucocorticoid receptor
Downregulation and upregulation
Vascular Biology
Internal medicine
medicine
ATP Binding Cassette Transporter
Subfamily G
Member 2
Animals
ATP Binding Cassette Transporter
Subfamily B
Member 1
Glucocorticoids
Cells
Cultured
P-glycoprotein
Pregnane X receptor
biology
Reverse Transcriptase Polymerase Chain Reaction
Multidrug resistance-associated protein 2
Pregnane X Receptor
Brain
Endothelial Cells
Cell Biology
Rats
Up-Regulation
Mifepristone
Endocrinology
medicine.anatomical_structure
Indenes
Blood-Brain Barrier
biology.protein
ATP-Binding Cassette Transporters
Multidrug Resistance-Associated Proteins
medicine.drug
Zdroj: American Journal of Physiology-Cell Physiology. 295:C440-C450
ISSN: 1522-1563
0363-6143
Popis: 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.
Databáze: OpenAIRE
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