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

• Published in: American Journal of Physiology: Cell Physiology 2008-08, Vol.295 (2), p.C440-C450
• Main Authors: Narang, Vishal S, Fraga, Charles, Kumar, Narendra, Shen, Jun, Throm, Stacy, Stewart, Clinton F, Waters, Christopher M
• Format: Article
• Language: English
• Subjects: Animals; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Blood-Brain Barrier - cytology; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blotting, Western; Brain; Brain - drug effects; Brain - metabolism; Breast cancer; Cells; Cells, Cultured; Dexamethasone - pharmacology; Drug resistance; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene expression; Gene Expression - drug effects; Glucocorticoids - pharmacology; Indenes - pharmacology; Male; Mifepristone - pharmacology; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Pregnenolone Carbonitrile - pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Tumors; Up-Regulation - drug effects; Vascular Biology
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00491.2007

1 Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; and 2 St. Jude Children's Research Hospital, Memphis, Tennessee Submitted 17 October 2007 ; accepted in final form 18 May 2008 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. multidrug resistance proteins; pregnane xenobiotic receptor; breast cancer resistance protein Address for reprint requests and other correspondence: C. M. Waters, Dept. of Physiology, Univ. of Tennessee Health Science Center, 894 Union Ave., Nash 426, Memphis, TN 38163 (e-mail: cwaters2{at}utmem.edu )