Fan Yilin, Liu Xiaodong
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Pharmaceutics. 2018 Jul 23;10(3):102. doi: 10.3390/pharmaceutics10030102.
Liver failure is often associated with hepatic encephalopathy, due to dyshomeostasis of the central nervous system (CNS). Under physiological conditions, the CNS homeostasis is precisely regulated by the blood-brain barrier (BBB). The BBB consists of brain microvessel endothelial cells connected with a junctional complex by the adherens junctions and tight junctions. Its main function is to maintain brain homoeostasis via limiting the entry of drugs/toxins to brain. The brain microvessel endothelial cells are characterized by minimal pinocytotic activity, absent fenestrations, and highly expressions of ATP-binding cassette (ABC) family transporters (such as P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated proteins). These ABC transporters prevent brain from toxin accumulation by pumping toxins out of brain. Accumulating evidences demonstrates that liver failure diseases altered the expression and function of ABC transporters at The BBB, indicating that the alterations subsequently affect drugs' brain distribution and CNS activity/neurotoxicity. ABC transporters also mediate the transport of endogenous substrates across the BBB, inferring that ABC transporters are also implicated in some physiological processes and the development of hepatic encephalopathy. This paper focuses on the alteration in the BBB permeability, the expression and function of ABC transporters at the BBB under liver failure status and their clinical significances.
肝功能衰竭常与肝性脑病相关，这是由于中枢神经系统（CNS）内环境稳态失调所致。在生理条件下，CNS的内环境稳态由血脑屏障（BBB）精确调节。血脑屏障由通过黏附连接和紧密连接与连接复合体相连的脑微血管内皮细胞组成。其主要功能是通过限制药物/毒素进入脑来维持脑内环境稳态。脑微血管内皮细胞的特点是胞饮活性极低、无窗孔以及ATP结合盒（ABC）家族转运蛋白（如P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白）高度表达。这些ABC转运蛋白通过将毒素泵出脑来防止脑内毒素蓄积。越来越多的证据表明，肝功能衰竭疾病会改变血脑屏障处ABC转运蛋白的表达和功能，这表明这些改变随后会影响药物在脑内的分布以及中枢神经系统的活性/神经毒性。ABC转运蛋白还介导内源性底物跨血脑屏障的转运，这意味着ABC转运蛋白也与某些生理过程以及肝性脑病的发生发展有关。本文重点关注肝功能衰竭状态下血脑屏障通透性的改变、血脑屏障处ABC转运蛋白的表达和功能及其临床意义。
