Granberg Lizette, Ostergren Anna, Brandt Ingvar, Brittebo Eva B
Department of Pharmaceutical Biosciences, Biomedical Center, Uppsala University, Sweden.
Drug Metab Dispos. 2003 Mar;31(3):259-65. doi: 10.1124/dmd.31.3.259.
Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists beta-naphthoflavone (BNF), 3,3',4,4',5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [(3)H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [(3)H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [(3)H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [(3)H]DMBA. Since [(3)H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration.
免疫组织化学和放射自显影法被用于鉴定细胞色素P450酶（P450）1A1和1B1的表达位点，以及在用芳烃受体（AhR）激动剂β-萘黄酮（BNF）、3,3',4,4',5-五氯联苯或赋形剂预处理的啮齿动物大脑中7,12-二甲基苯并（a）蒽（DMBA）的活化情况。免疫组织化学显示，在AhR激动剂预处理小鼠的脉络丛内皮细胞（EC）、软脑膜静脉和脑静脉中，CYP1A1被优先诱导。脑毛细血管EC中未发生诱导。在赋形剂处理的小鼠中，未观察到CYP1A1在EC中的定位。CYP1B1在AhR激动剂处理和赋形剂处理小鼠的软脑膜动脉平滑肌细胞、脑动脉/小动脉中表达，在室管膜细胞中表达程度较低。在脉络丛的毛细血管环或脑毛细血管中未检测到CYP1B1。给BNF预处理的小鼠施用[（3）H]DMBA后，在脉络丛EC和软脑膜静脉中观察到明显的不可逆结合，但在脑毛细血管中未观察到。在赋形剂处理的小鼠中，这些部位没有[（3）H]DMBA结合。此外，在精确切割的小鼠/大鼠脑切片以及与[（3）H]DMBA孵育的离体血脑界面的这些部位的EC中，发生了高水平的不可逆结合[（3）H]DMBA。由于[（3）H]DMBA结合位点与CYP1A1诱导位点相对应，我们得出结论，啮齿动物在一些血脑界面的EC中表达组成性低但高度可诱导且有功能的CYP1A1。CYP1A1/1B1和环境污染物在脑血管疾病病因中的作用需要进一步研究。
