steroids important to prevent swelling with brain mets--but they may decrease the

[Lani]

ability of drugs to cross the blood brain barrier and make them be metabolized (and inactivated ) sooner.

1: Am J Physiol Cell Physiol. 2008 Jun 4. [Epub ahead of print]

Dexamethasone increases expression and activity of multi-drug resistance transporters at the rat blood-brain barrier.

Narang VS, Fraga C, Kumar N, Shen J, Throm S, Stewart CF, Waters CM.
Physiology, University of Tennessee Health Science Center, 38163, Tennessee, United States.
Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone, a synthetic glucocorticoid, is routinely prescribed with anti-neoplastic agents to alleviate pain associated with chemotherapy and reduce intra-cranial pressure. We investigated whether dexamethasone treatment increased the expression and activity of multi-drug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with sub-micromolar concentrations of dexamethasone induced significantly higher levels of drug efflux transporters such as Bcrp (abcg2), P-gp (abcb1a/abcb1b), and 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 hours of treatment, was dose-dependent, and was reversible. Dexamethasone-induced up-regulation 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 up-regulation 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 up-regulation 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 hours. 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. Key words: multi-drug resistance proteins, PXR, breast cancer resistance protein.