SAMe对雌激素诱导的肝内胆汁淤积症孕鼠的胎盘多药耐药相关蛋白-谷胱甘肽共转运体系的影响

目的:探讨S-腺苷蛋氨酸(SAMe)对雌激素诱导的肝内胆汁淤积症(ICP)孕鼠的胎盘多药耐药相关蛋白(MRP)-谷胱甘肽(GSH)共转运体系的影响。方法:将妊娠第13天的大鼠随机分成对照组(孕15～19天腹腔注射生理盐水)、EE(孕15～19天皮下注射17-α-乙炔雌二醇溶液)组、EE+SAMe组(孕15～19天皮下注射17-α-乙炔雌二醇溶液,孕17～19天腹腔注射SAMe溶液)。17-α-乙炔雌二醇诱导孕鼠发生肝内胆汁淤积,建立ICP模型,测定3组血清总胆酸(TBA)、甘胆酸(CG)、血清丙氨酸转氨酶(ALT)、门冬氨酸转氨酶(AST);ELISA检测GSH,逆转录实时荧光定量PCR和免疫组化法检测MRP1、MRP2、MRP5的表达。结果:EE组的TBA、CG、ALT、AST水平显著增高,胚胎存活率显著降低(P0.001);经SAMe治疗,TBA、CG、ALT、AST水平显著下降,增加了胚胎存活率(P0.01)。EE组胎盘的MRP1 mRNA和蛋白表达显著上调(P0.05),而胎盘MRP2、MRP5 mRNA和蛋白的表达显著下调(P0.01),GSH显著下降(P0.001);经SAMe治疗,胎盘MRP1 mRNA和蛋白表达显著下调(P0.05),胎盘MRP2、MRP5 mRNA和蛋白的表达显著上调(P0.05),GSH显著上升。结论:胎盘存在MRP-GSH共转运体系;SAMe可通过调节胎盘MRP-GSH共转运体系影响胆汁酸的转运,从而治疗大鼠妊娠期ICP。

Effects of S-adenosine methionineon on MRP-GSH transportation system in rats with ethinylestradiol induced intrahepatic cholestasis of pregnancy.

Objective：To study the effects of S-adenosine methionineon on MRP-GSH transportation system in rats with ethinylestradiol induced intrahepatic cholestasis of pregnancy. Methods：Day 13 pregnant rats were divided into control group,EE group,EE＋SAMe group. ICP rat model was established with 17-α-ethinyl estradiol. The serum TBA,CG,ALT and AST were detected. GSH was detected by ELISA. MRP1,MRP2 and MRP5 were detected by realtime RT-PCR and immunohistochemical examination. Results：TBA,CG,ALT and AST levels of EE group significantly increased,embryo survival rate significantly decreased （P〈0. 001）. After SAMe treatment,TBA,CG,ALT and AST levels dropped significantly,and the embryo survival rate increased （ P〈0 . 01 ） . Placenta MRP1 mRNA and protein expression of EE group was significantly raised （P〈0. 05）. However,MRP2 and MRP5 mRNA and protein expression was significantly reduced （P〈0. 01）,and GSH decreased significantly （P〈0. 001）. After the SAMe treatment,placenta MRP1 expression of mRNA and protein was significantly down-regulated （ P 〈0. 05）,while placenta MRP2 and MRP5 mRNA and protein expression was significantly upregulated （P〈0. 05）,and GSH increased noticeably. Conclusion：MRP-GSH transportation system exists in the placenta. SAMe affects the bile transport to treat rat intrahepatic cholestasis disease of pregnancy by regulating the placenta MRP-GSH transportation system.