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目的探讨古拉定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。方法用将妊娠第13 d的大鼠随机分成对照组,EE组,EE+古拉定组,17-α-乙炔雌二醇诱导建立孕鼠ICP模型,测定三组血清TBA、CG、ALT、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TBA、CG、ALT、AST水平显著增高,胚胎存活率显著降低(P<0.001),经古拉定治疗,TBA、CG、ALT、AST水平显著下降,增加了胚胎存活率(P<0.01);EE组胎盘MRP1 mRNA和蛋白的表达显著上调(P<0.05),而胎盘MRP2、MRP5 mRNA和蛋白的表达显著下调(P<0.01),GSH显著下降(P<0.001);经过古拉定治疗,下调胎盘MRP1,上调MRP2和MRP5mRNA和蛋白的表达(P<0.05),GSH显著上升。结论胎盘存在MRP-GSH共转运体系;古拉定可以通过调节胎盘MRP-GSH共转运体系影响胆汁酸的转运来治疗大鼠妊娠期肝内胆汁淤积症。
Objective To investigate the effect of gulazidine on estrogen-induced intrahepatic cholestasis of placental multidrug resistance-related protein glutathione co-transport system. Methods Pregnant rats were randomly divided into control group, EE group, EE + Gulandin group and 17-α-ethinyl estradiol. Pregnant rats were induced to establish ICP model. TBA, CG, ALT, AST ; GSH was detected by ELISA, the expression of MRP1, MRP2 and MRP5 was detected by RT-PCR and immunohistochemistry. Results The levels of TBA, CG, ALT and AST in EE group were significantly higher than those in control group (P <0.001). After Gulazine treatment, the levels of TBA, CG, ALT and AST were significantly decreased and the survival rate of embryos was increased (P < 0.01). The expression of MRP1 mRNA and protein in placenta of EE group was significantly increased (P <0.05), while the expression of MRP2 and MRP5 mRNA and protein in placenta was significantly decreased (P <0.01) and GSH was significantly decreased (P <0.001) Given treatment, down-regulation of MRP1 in the placenta, up-regulation of MRP2 and MRP5 mRNA and protein expression (P <0.05), GSH increased significantly. Conclusion Placenta exists MRP-GSH cotransporter system. Gulatin can treat intrahepatic cholestasis of pregnancy in rats by regulating the transport of bile acid in the placenta MRP-GSH cotransporter system.