Narang Vishal S, Fraga Charles, Kumar Narendra, Shen Jun, Throm Stacy, Stewart Clinton F, Waters Christopher M
Dept. of Physiology, Univ. of Tennessee Health Science Center, 894 Union Ave., Nash 426, Memphis, TN 38163, USA.
Am J Physiol Cell Physiol. 2008 Aug;295(2):C440-50. doi: 10.1152/ajpcell.00491.2007. Epub 2008 Jun 4.
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.
脑水肿是导致原发性脑肿瘤发病和死亡的一个重要因素。地塞米松是一种合成糖皮质激素，常与抗肿瘤药物联合使用，以减轻化疗相关疼痛并降低颅内压。我们研究了地塞米松治疗是否会增加血脑屏障处多药耐药（MDR）转运蛋白的表达和活性。用亚微摩尔浓度的地塞米松处理原代大鼠脑微血管内皮细胞，结果显示，如通过蛋白质和mRNA水平以及功能活性所表明的，乳腺癌耐药蛋白（ABCG2）、P-糖蛋白（P-gp；ABCB1A/ABCB1B）和多药耐药蛋白2（Mrp2；ABCC2）等药物外排转运蛋白的水平显著升高。地塞米松对转运蛋白功能的影响在治疗后6小时内显著，呈剂量依赖性且可逆。糖皮质激素受体（GR）拮抗剂RU486部分消除了地塞米松诱导的Bcrp和P-gp表达及功能上调。相比之下，RU486对地塞米松诱导的Mrp2上调没有影响，这表明Mrp2存在不依赖GR的调节，而P-gp和Bcrp存在依赖GR的调节。除了地塞米松诱导的MDR转运蛋白上调外，我们还检测到核转录因子孕烷异生素受体（PXR）的表达呈剂量依赖性且可逆性增加。给大鼠注射地塞米松会在24小时内导致脑微血管中PXR表达增加。这些结果表明，在脑肿瘤治疗中使用地塞米松等糖皮质激素进行辅助治疗可能通过涉及GR和PXR的途径增加血脑屏障处MDR转运蛋白的表达。
