多药耐药蛋白MRP1-MRP6（ABCC1-ABCC6）在人脑组织中的表达及免疫定位

Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain.

作者信息

Nies A T, Jedlitschky G, König J, Herold-Mende C, Steiner H H, Schmitt H-P, Keppler D

机构信息

Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

出版信息

Neuroscience. 2004;129(2):349-60. doi: 10.1016/j.neuroscience.2004.07.051.

DOI:10.1016/j.neuroscience.2004.07.051

PMID:15501592

Abstract

Multidrug resistance proteins (MRPs, symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. To identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery. Quantitative polymerase chain reaction analysis showed expression of MRP1, MRP2, MRP3, MRP4, and MRP5 mRNA, whereas MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. The proteins MRP1, MRP4, and MRP5 were clearly localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. Notably, MRP5 protein was present in pyramidal neurons. MRP proteins may, thus, contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), or glutathione (co-substrate for MRP1 and MRP4); in addition, they may play an important role in the resistance of the brain to several cytotoxic and antiviral drugs.

摘要

多药耐药蛋白（MRPs，符号ABCC）是膜糖蛋白，介导包括细胞毒性和抗病毒药物在内的有机阴离子从细胞中进行ATP依赖的外排。为了鉴定可能参与人类大脑对细胞毒性和抗病毒药物固有耐药性的MRP家族成员，我们分析了在神经外科手术中获取的成人大脑几个区域的快速冷冻病变周围样本中MRP1 - MRP6的表达和定位。定量聚合酶链反应分析显示MRP1、MRP2、MRP3、MRP4和MRP5 mRNA有表达，而MRP6 mRNA低于可检测水平。然而，人脑冰冻切片的免疫荧光显微镜检查显示MRP2或MRP3蛋白无反应性。通过共聚焦激光扫描显微镜清楚地将MRP1、MRP4和MRP5蛋白定位到脑毛细血管内皮细胞的腔侧。在皮质下白质的星形胶质细胞中也检测到了MRP4和MRP5蛋白。值得注意的是，MRP5蛋白存在于锥体细胞中。因此，MRP蛋白可能有助于内源性阴离子谷胱甘肽或葡萄糖醛酸结合物（MRP1的底物）、环核苷酸（MRP4和MRP5的底物）或谷胱甘肽（MRP1和MRP4的共底物）的细胞外排；此外，它们可能在大脑对几种细胞毒性和抗病毒药物的耐药性中起重要作用。