Pattern of P450 expression at the human blood-brain barrier: roles of epileptic condition and laminar flow.
Pattern of P450 expression at the human blood-brain barrier: roles of epileptic condition and laminar flow.
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DOI：
10.1111/j.1528-1167.2009.02428.x
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发表时间：
2010-08
期刊：
影响因子：
5.6
通讯作者：
Marchi N
中科院分区：
文献类型：
--
作者：
Ghosh C;Gonzalez-Martinez J;Hossain M;Cucullo L;Fazio V;Janigro D;Marchi N
P450酶（CYP）在肝脏药物代谢中起主要作用。目前尚不清楚这些酶是否由患病的人血脑屏障（BBB）功能性表达，并参与局部药物代谢或反应。我们已经评估了脑血管炎的表达和功能，假设可能的含义在耐药性癫痫。通过cDNA微阵列评估从一组脑切除物（n = 12，耐药性癫痫EPI-EC和癫痫穹隆ANE-EC）建立的原代内皮培养物中的JNP 450转录水平。人脑内皮细胞系（HBMEC）和非脑内皮细胞系（HUVEC）用作对照。评估了暴露于剪切应力对mRNA表达的影响。结果通过脑标本的Western印迹和免疫组织化学证实。通过高效液相色谱法（HPLC-UV）评估内皮药物代谢。cDNA微阵列显示分离的人原代脑内皮细胞中存在着β-淀粉酶。使用EPI-EC和HBMEC，我们发现，ESTmRNA水平显着影响暴露于剪切应力。与HBMEC相比，CYP 3A 4蛋白在EPI-EC中过表达（290 ± 30%），并通过剪切应力暴露进一步上调。CYP 3A 4在耐药癫痫脑中反应性胶质增生区域的血管室中增加。与HBMEC相比，EPI-EC中卡马西平的代谢显著升高。这些结果支持在患病的血脑屏障局部药物代谢的假设。血脑屏障相关酶与耐药表型之间的直接关系有待进一步研究。
P450 enzymes (CYPs) play a major role in hepatic drug metabolism. It is unclear whether these enzymes are functionally expressed by the diseased human blood–brain barrier (BBB) and are involved in local drug metabolism or response. We have evaluated the cerebrovascular CYP expression and function, hypothesizing possible implication in drug-resistant epilepsy. CYP P450 transcript levels were assessed by cDNA microarray in primary endothelial cultures established from a cohort of brain resections (n = 12, drug-resistant epilepsy EPI-EC and aneurism domes ANE-EC). A human brain endothelial cell line (HBMEC) and non-brain endothelial cell line (HUVEC) were used as controls. The effect of exposure to shear stress on CYP expression was evaluated. Results were confirmed by Western blot and immunohistochemistry on brain specimens. Endothelial drug metabolism was assessed by high performance liquid chromatography (HPLC-UV). cDNA microarray showed the presence of CYP enzymes in isolated human primary brain endothelial cells. Using EPI-EC and HBMEC we found that CYP mRNA levels were significantly affected by exposure to shear stress. CYP3A4 protein was overexpressed in EPI-EC (290 ± 30%) compared to HBMEC and further upregulated by shear stress exposure. CYP3A4 was increased in the vascular compartment at regions of reactive gliosis in the drug-resistant epileptic brain. Metabolism of carbamazepine was significantly elevated in EPI-EC compared to HBMEC. These results support the hypothesis of local drug metabolism at the diseased BBB. The direct association between BBB CYP enzymes and the drug-resistant phenotype needs to be further investigated.
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RLIP76，一种非ABC转运蛋白和癫痫中的耐药性。
影响因子：
2.4
作者：
Awasthi, S;Hallene, KL;Fazio, V;Singhal, SS;Cucullo, L;Awasthi, YC;Dini, G;Janigro, D
通讯作者：
Janigro, D
DOI：
10.1124/jpet.102.047530
发表时间：
2003-06-01
影响因子：
3.5
作者：
Egnell, AC;Houston, B;Boyer, S
通讯作者：
Boyer, S
影响因子：
5.8
作者：
GHERSIEGEA, JF;PERRIN, R;MINN, A
通讯作者：
MINN, A
影响因子：
10.8
作者：
Han, Zhiyi;Miwa, Yoshikazu;Sasaguri, Toshiyuki
通讯作者：
Sasaguri, Toshiyuki
影响因子：
5.6
作者：
Cucullo, Luca;Hossain, Mohammed;Janigro, Damir
通讯作者：
Janigro, Damir