【摘要】 目的:观察车前子水提物对肿瘤化疗药物环磷酰胺引起的大鼠肝损伤的保护作用,并探究基于FXR-MRP2/BSEP通路探究车前子水提物发挥保护作用的机制。方法:将70只雌雄各半的SD大鼠,随机分为空白对照组、肝损模型组、优思弗组(阳性对照,100 mg/kg)、车前子水提物10g生药/kg、5g生药/kg、2.5生药/kg剂量组、京尼平苷酸200mg/kg等7组,每组10只。空白对照组和肝损伤模型组灌胃给予0.5%的羧甲基纤维素钠,其他组灌胃给予相应药物,连续给药10天,除空白对照组,其余各组第3天腹腔注射环磷酰胺200mg/kg 1次。末次给药后,分离肝组织和腹主动脉取血,测定血清谷丙转氨酶(GPT)、谷草酶(GOT)和碱性磷酸酶(ALP)活性以及总胆红素(TB)、直接胆红素(DB)和总胆汁酸(TBA)的含量; Western Blot检测肝组织法尼醇-X受体(FXR)、多药耐药蛋白2(MRP2)、胆盐输出泵(BSEP)的表达; RT-PCR法检测FXR、MRP2、BSEP的基因表达量;苏木素伊红(HE)染色进行肝组织病理组织形态学观察。结果:与肝损伤模型组相比,车前子水提物10g生药/kg、5g生药/kg剂量组、京尼平苷酸200mg/kg明显对抗环磷酰胺引起的大鼠血清中GOT、GPT和ALP的升高,明显改善肝损伤引起的血清中TB、DB、和TBA的含量升高,并缓解环磷酰胺引起的肝组织病变,肝组织中FXR、BSEP和MRP2的蛋白表达量明显升高,肝组织中FXR、BSEP和MRP2的mRNA的表达量显著升高。结论:车前子水提物对环磷酰胺引起大鼠肝损伤具有保护作用,其活性物质可能是京尼平苷酸,其发挥作用的机制可能与上调核受体FXR来改善胆汁酸微循环有关。更多还原

【Abstract】 Objective:To investigate the protective effect and mechanism of the aqueous extract of the semen plantaginis on rat liver injury induced by cyclophosphamide(CTP) in rats,and explore the mechanism of FXR-mediated regulation of BSEP and MRP2.Methods:60 SD rats were randomly divided into 6 groups,including the control group,liver injury model group,positive control group(Ursofalk,100 mg/kg),geniposidic acid(200 mg/kg),crude drug groups of 10 g/kg,5 g/kg and 2.5 g/kg doses.In the control group and liver injury model group,0.5% of sodium carboxymethyl cellulose was administered while rats in other groups were given the corresponding dose of aqueous extract,for continuously 10 days.On the third day,cyclophosphamide(200 mg/kg) was intraperitoneally injected into rats,except for the control group.After the last administration,the liver tissue was isolated,blood was take from abdominal aorta,the activities of serum Alanine Aminotransferase(GPT),Glutamic Transaminase(GOT) and Alkaline Phosphatase(ALP) were determined,and the contents of total bilirubin(TB),direct bilirubin(DB),and total bile acid(TBA) were measured.The protein and mRNA expression levels of Farnesoid X receptor(Fxr),bile salt export pump(BSEP),multidrug resistance associated protein2(MRP2),were evaluated by Western Blot and RT-PCR,and liver was stained with hematoxylin and observed through Lecia microscope.Results:Compared with the liver injury model group,different doses of aqueous extract and geniposidic acid(200 mg/kg) significantly enhanced the enzyme activities of ALT、AST and ALP,the serum contents of TB,DB,and TBA induced by cyclophosphamide,and also significantly increased the protein and mRNA expressions of FXR,BSEP and MRP2 in liver tissues.Conclusion:The aqueous extract of the semen plantaginis improves the rat liver injury induced by cyclophosphamide,and its active substance may be geniposidic acid.The mechanism of its action may be related to the improvement of bile acid microcirculation through FXR mediated regulation of MRP2/BSEP pathway.更多还原