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目的研究熊去氧胆酸(UDCA)对大鼠肝癌发生的抑制作用并探讨其机制。方法利用二乙基亚硝胺(DEN)诱导大鼠肝癌模型,75只雄性Wistar大鼠随机分为5组:正常对照组、UDCA对照组、DEN组、UDCA高和低剂量组。DEN组及UDCA高低剂量组均给予DEN腹腔注射(20 mg/kg),正常对照组及UDCA对照组给予等剂量的生理盐水腹腔注射。同时UDCA对照组及UDCA高低剂量组分别按30、30、15 mg/kg给予UDCA灌胃,正常对照组及DEN组给予等量生理盐水灌胃。观察大鼠肝质量、体质量及肝脏系数的变化;并检测血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)及甲胎蛋白(AFP)的含量;采用实时定量RT-PCR检测不同组间DNA损伤修复基因hMTH1在大鼠肝脏中的表达。结果与正常对照组相比,DEN组大鼠的体质量明显降低,肝质量和肝脏系数明显增加,ALT、AST及AFP的含量均明显升高(P<0.05);与DEN组相比,UDCA高低剂量组各项指标明显好转。实时定量RT-PCR显示,hMTH1在DEN组大鼠肝脏中的表达较正常对照组明显升高(P<0.05);UDCA高低剂量组大鼠肝脏中hMTH1的表达较DEN组明显降低(P<0.05);且hMTH1在UDCA高剂量组中的表达也较UDCA低剂量组明显降低(P<0.05)。UDCA对照组与正常对照组相比,各项指标无统计学差异。结论 UDCA对大鼠肝癌发生有抑制作用,并能够抑制DNA损伤修复基因hMTH1的表达,其效果和剂量呈正相关,提示UDCA对肝癌的抑制作用可能与抑制氧化应激有关。
Objective To study the inhibitory effect of ursodeoxycholic acid (UDCA) on hepatocarcinogenesis in rats and its mechanism. Methods 75 male Wistar rats were induced by diethylnitrosamine (DEN). The rats were randomly divided into 5 groups: normal control group, UDCA control group, DEN group and UDCA high and low dose groups. DEN group and UDCA high and low dose groups were given DEN intraperitoneal injection (20 mg / kg), normal control group and UDCA control group were given an equal dose of saline intraperitoneal injection. UDCA control group and UDCA high and low dose groups were given 30,30,15 mg / kg UDCA gavage, normal control group and DEN group were given the same amount of saline gavage. The changes of liver mass, body weight and hepatic coefficient of rats were observed. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alpha fetoprotein (AFP) Quantitative RT-PCR was used to detect the expression of DNA damage repair gene hMTH1 in rat liver. Results Compared with the normal control group, the body weight of rats in DEN group was significantly decreased, the liver mass and liver coefficient were significantly increased, and the levels of ALT, AST and AFP were significantly increased (P <0.05). Compared with DEN group, UDCA High and low dose groups significantly improved the indicators. The expression of hMTH1 in the liver of DEN group was significantly higher than that of the normal control group (P <0.05) by real-time quantitative RT-PCR. The expression of hMTH1 in the liver of UDCA high and low dose group was significantly lower than that of DEN group ). The expression of hMTH1 in UDCA high-dose group was also significantly lower than that in UDCA low-dose group (P <0.05). UDCA control group compared with the normal control group, the indicators were not statistically different. Conclusion UDCA can inhibit the occurrence of hepatocellular carcinoma in rats and inhibit the expression of DNA damage repair gene hMTH1. The effect of UDCA is positively correlated with the dose of UDCA, which suggests that UDCA may have an inhibitory effect on hepatocellular carcinoma in inhibiting the oxidative stress.