脑内1,2-二氯乙烷代谢的调控及其对脑水肿形成影响的研究

Subacute poisoning of 1,2-dichloroethane (1,2-DCE) has become one of the most serious occupational diseases in China. The previous studies have disclosed that Cytochrome P450 2E1 (CYP2E1) is the primary catalyst of 1,2-DCE in experimental animals and, most likely, in humans as well. Chloroacetaldehyde and reactive oxygen species (ROS) can be generated in CYP2E1 mediated metabolism of 1,2-DCE in vivo. Moreover, metabolism of 1,2-DCE may induce upregulated expression of CYP2E1 in the body. Due to the active chemical property, both chloroacetaldehyde and ROS can combine rapidly with the intracellular proteins and DNA to form adduct. Furthermore, due to the high aldehyde dehydrogenase activity at the blood-brain barrier (BBB), although CYP2E1 is mainly expressed in the liver, chloroacetaldehyde derived from the peripheral metabolism of 1,2-DCE can not penetrate from blood into brain. the accumulated data suggested that CYP2E1 is also expressed with relatively high levels in various brain regions of animals and human beings, such as the olfactory bulbs, olfactory cortex, hippocampus, cerebellum and brainstem..In this project, concerning the contribution of CYP2E1 mediated metabolism of 1,2-DCE to brain edema formation, alteration of CYP2E1 expression in various brain regions and their regulatory mechanisms will be explored. These data would be useful for elucidating the mechanism of 1,2-DCE induced brain edema and for finding the therapeutic targets.

亚急性1,2-二氯乙烷（1,2-DCE）中毒是我国特有的职业病。研究发现，CYP2E1是1,2-DCE体内代谢的关键酶，在其催化下1,2-DCE被代谢为氯乙醛，同时产生ROS。并且1,2-DCE的代谢可诱导CYP2E1表达，以促进自身代谢。由于氯乙醛和ROS的化学性质活跃，极易与细胞内蛋白质和DNA反应形成加合物，而且BBB的内皮细胞中含有高水平醛脱氢酶，故肝脏代谢产生的氯乙醛和ROS主要引起肝细胞损伤，它们很难通过血液循环透过BBB进入脑组织。新近的研究揭示，脑内也有相对高水平CYP2E1表达。本项目拟在前期研究的基础上，围绕脑内1,2-DCE代谢对中毒性脑水肿形成的影响，探讨脑水肿形成过程中不同脑区CYP2E1表达的变化及其调控机制，为揭示亚急性1,2-DCE中毒性脑水肿的发生机制、探索其防治靶点提供依据。

亚急性1,2-二氯乙烷(1,2-DCE)中毒是我国特有的职业病。本项目在前期研究成果的基础上，围绕CYP2E1介导的1,2-DCE脑内代谢对其中毒性脑水肿形成的影响，为进一步揭示亚急性1,2-DCE中毒性脑损伤的发生机制、探索其防治靶点提供科学依据。 .体内研究结果显示：1,2-DCE染毒可明显诱导小鼠的肝和脑组织中CYP2E1表达，促进1,2-DCE的体内代谢。乙醇与1,2-DCE联合暴露可在基因水平协同作用上调CYP2E1的表达，进而促进1,2-DCE体内代谢，产生更多的活性中间代谢产物和ROS，故乙醇与1,2-DCE联合暴露可加重1,2-DCE引起的脑损伤。抑制脑组织中CYP2E1的表达，可预防小鼠1,2-DCE中毒性脑水肿的发生。进一步的研究发现，1,2-DCE染毒对小鼠不同脑区的损伤与其CYP2E1的表达水平密切相关。此外，亚急性1,2-DCE中毒可激活小鼠脑星形胶质细胞(AS)和小胶质细胞(MG)。活化的AS和MG相互作用加重脑组织的神经炎症反应，导致血脑屏障(BBB)的破坏和脑水肿的形成。 .体外研究结果显示：AS暴露1,2-DCE的体内中间代谢产物2-氯乙醇(2-CE)，CYP2E1介导的2-CE代谢可产生ROS，并通过激活ERK1/2-SP1信号通路，上调AS内CYP2E1的表达，进而导致AS氧化损伤，引起细胞凋亡。此外，生成的ROS通过p38 MAPK/NF-κB和AP-1信号通路激活AS，促进其合成IL-1β、TNF-α和iNOS等。2-CE暴露的AS通过释放IL-1β、TNF-α和NO诱导MG的促炎表型极化。.综上所述：CYP2E1介导的脑内代谢在1,2-DCE中毒性脑损伤中发挥重要作用，是1,2-DCE中毒性脑水肿形成的主要机制之一。