Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany.
Eur J Pharmacol. 2010 Feb 25;628(1-3):57-66. doi: 10.1016/j.ejphar.2009.11.051. Epub 2009 Dec 1.
Several major antiepileptic drugs, including carbamazepine, phenytoin and phenobarbital, induce xenobiotic metabolizing enzymes via activation of nuclear receptors, including pregnane X receptor (NR1I2) and constitutive androstane receptor (NR1I3). Via activation of these xenobiotic sensors, antiepileptic drugs may also induce the expression of efflux transporters such as P-glycoprotein (Pgp) in different tissues, including intestine, liver, kidney and brain. Increased expression of Pgp in brain capillary endothelial cells, which form the blood-brain barrier, could limit the penetration of antiepileptic drugs into the brain and therefore decrease their therapeutic efficacy. As a consequence, it is important to know whether antiepileptic drugs alter the expression or functionality of Pgp in endothelial cells. In the present study, we studied the effects of exposure to phenobarbital, phenytoin and carbamazepine on Pgp expression and functionality in the rat brain endothelial cell line GPNT. For comparison with drug effects on endothelial cells, a dog kidney cell line (MDCK II) was used. Furthermore, several known Pgp inducers (dexamethasone, doxorubicin, and rifampicin) were included in the study. Functionality of Pgp was determined by uptake assays, using known Pgp substrates (digoxin and vinblastine) and transport inhibitors (tariquidar, MK571). In GPNT cells, exposure to dexamethasone increased Pgp functionality, while antiepileptic drug exposure at clinically relevant concentrations did not exert any significant induction of Pgp expression or function. Similarly, antiepileptic drug exposure did not affect Pgp in MDCK cells. The lack of antiepileptic drugs to induce Pgp in brain capillary endothelial cells and kidney cells is in contrast to their known effect on Pgp expression in hepatic and intestinal cells, substantiating tissue differences in the regulation of Pgp.
几种主要的抗癫痫药物，包括卡马西平、苯妥英钠和苯巴比妥，通过激活核受体（包括孕烷 X 受体（NR1I2）和组成型雄烷受体（NR1I3））来诱导外来物质代谢酶。通过激活这些外来物质传感器，抗癫痫药物还可能在不同组织（包括肠道、肝脏、肾脏和大脑）中诱导外排转运蛋白（如 P-糖蛋白（Pgp））的表达。在形成血脑屏障的脑毛细血管内皮细胞中，Pgp 的表达增加可能会限制抗癫痫药物进入大脑的渗透，从而降低其治疗效果。因此，了解抗癫痫药物是否改变内皮细胞中 Pgp 的表达或功能非常重要。在本研究中，我们研究了苯巴比妥、苯妥英钠和卡马西平暴露对大鼠脑内皮细胞系 GPNT 中 Pgp 表达和功能的影响。为了与药物对内皮细胞的影响进行比较，使用了狗肾细胞系（MDCK II）。此外，还包括了几种已知的 Pgp 诱导剂（地塞米松、阿霉素和利福平）。通过摄取测定法确定 Pgp 的功能，使用已知的 Pgp 底物（地高辛和长春碱）和转运抑制剂（塔里奎达、MK571）。在 GPNT 细胞中，地塞米松暴露增加了 Pgp 的功能，而在临床相关浓度下暴露于抗癫痫药物并没有对 Pgp 的表达或功能产生任何显著的诱导作用。同样，抗癫痫药物暴露也没有影响 MDCK 细胞中的 Pgp。抗癫痫药物不能诱导脑毛细血管内皮细胞和肾细胞中的 Pgp，这与它们在肝和肠细胞中对 Pgp 表达的已知作用形成对比，证实了 Pgp 调节的组织差异。
