大黄素对急性淤胆型肝炎模型大鼠的治疗作用及机制探讨

Therapeutic effects of emodin on acute choiestatic hepatitis and mechanism in rats

目的探讨大黄素对急性淤胆型肝炎模型大鼠的治疗作用及其机制。方法50只SD大鼠按随机数字表法随机分为5组：正常对照组、模型组、大黄素组、熊去氧胆酸（UDCA）组、地塞米松组，除正常对照组外，其余4组均给予α-异硫氰酸萘酯（ANIT）50 mg/kg一次灌胃大鼠建立淤胆型肝炎动物模型，并给予相应的药物干预，造模后48 h留取标本，检测其肝功能和进行肝脏病理学检查。实时荧光定量PCR检测肝组织中法尼醇X受体（FXR）、小异源二聚体伴侣受体（SHP）、胆盐输出泵（BSEP）、尿苷二磷酸葡萄糖苷酸转移酶2B4（UGT2B4）mRNA表达量。全自动生化分析仪检测γ-谷氨酰转移酶（GGT）的水平。结果模型组血清总胆红素（TB）、直接胆红素（DB）、丙氨酸转氨酶（ALT）、胆汁酸（TBA）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）水平分别为（68.1±26.1） μmol/L、（46.3±20.1） μmol/L、（483±228） U/L、（159.1±57.9） μmol/L、（2.0±0.5） U/L、（996±382） U/L、（324±120） U/L，大黄素组TB、DB、ALT、TBA、AST、ALP水平分别为（15.0±8.7） μmol/L 、（10.8±3.9） μmol/L、（147±71） U/L、（60.1±22.7） μmol/L、（295±104） U/L、（222±59） U/L，均明显低于模型组，差异均有统计学意义（均P〈0.05）。大黄素组TB、DB、ALT、TBA、GGT、AST、ALP明显低于熊去氧胆酸组，差异均有统计学意义（均P〈0.05），TB、DB、ALT、TBA、GGT、AST明显低于地塞米松组，差异均有统计学意义（均P〈0.05）。大黄素组48 h肝组织FXR、SHP、BSEP、UGT2B4 mRNA表达水平分别为（1.087±0.285、0.892±0.390、0.902±0.149、1.785±0.403），均明显高于模型组（0.152±0.088、0.559±0.194、0.561±0.123、0.177±0.039），差异均有统计学意义（均P〈0.05）。结论大黄素可显著降低ANIT诱导的淤胆型肝炎大鼠中TB、DB、ALT、TBA、AST、ALP水平及减轻其肝组织病理学损害，疗效优于熊去氧胆酸及地塞米松。其作用机制可能与促进FXR及其下游分子SHP、BSEP、UGT2B4的表达有关。

ObjectiveTo investigate the therapeutic effects of emodin on acute cholestatic hepatitis and mec-hanism thereof.MethodsFifty Sprague-Dawley （SD） rats were randomly divided into 5 groups and were treated with emodin, ursodeoxycholic acid, dexamethasone, or normal saline respectively for 4 days.On the fifth day gastric perfusion of alpha-naphthylisothiocyanate（ANIT） was performed to establish models of choiestatic hepatitis.Four to six hours after the establishment of model the above mentioned agents were given continuously.Forty-eight hours after the model establishment blood samples were collected from abdominal aorta to examine the total bilirubin（TB）, direct bilirubin（DB）, alanine aminotransferase（ALT）, total bile acid（TBA）, aspartate aminotransferase（AST）, alkaline phosphatase（ALP）, gamma glutamine transferase（GGT）. Specimen of liver was collected to undergo pathological examination.Real-time PCR was used to detect the mRNA expression of farnesoid X receptor（FXR）, small heterodimer partner（SHP）, bile salt export pump（BSEP）, uridine diphosphate glucuronosyltransferase 2 family polypeptide B4（UGT2B4）.ResultsThe serum levels of total bilirubin （TB）, direct bilirubin （DB）, alanine aminotransferase （ALT）, total bile acids （TBA）, aspartate aminotransferase （AST）, and alkaline phosphatase （ALP） of the model group were respectively （68.1±26.1） μmol/L, （46.3±20.1） μmol/L, （483±228） U/L, （159.1±57.9） μmol/L, （2.0±0.5） U/L, （996±382） U/L, （324±120） U/L.The levels of TB, DB, ALT, TBA, AST, ALP of the emodin group were respectively （15.0±8.7） μmol/L, （10.8±3.9） μmol/L, （147±71） U/L, （60.1±22.7） μmol/L, （295±104） U/L, （222±59） U/L, and were all significantly lower than those of the model group （all P〈0.05）. The levels of TB, DB, ALT, TBA, AST, GGT, ALP of the emodin group were all significantly lower than those of the ursodeoxycholic acid group （all P〈0.05）. The levels of TB, DB, ALT, TBA, GGT, AST were all significantly lower than those of the dexamethasone group （all P〈0.01）. The expression levels of FXR, SHP, BSEP, UGT2B4 mRNA in the emodin group （1.087±0.285, 0.892±0.390, 0.902±0.149, 1.785±0.403） were all significantly higher than those of the model group （0.152±0.088, 0.559±0.194, 0.561±0.123, 0.177±0.039, all P〈0.05）.ConclusionsBy decreasing the levels of TB, DB, ALT, TBA, AST, ALP and reducing pathological changes, emodin has a protective effect on cholestatic hepatitis.It has better effects than ursodeoxycholic acid and dexamethasone.These effects may be due to promoting FXR, SHP, BSEP and UGT2B4 expression.