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目的 探讨人ATP7B基因对Wilson病动物模型LEC(Long EvansCinnamon)大鼠肝硬化及肝癌的治疗效果。 方法 将 7 1kb含有鸡 β肌动蛋白启动子的人正常ATP7BcDNA ,经显微注射法导入Wilson病动物模型LEC大鼠受精卵 ,建立转基因功能恢复大鼠模型。以无转基因大鼠及正常野生型LEA大鼠为对照 ,对 17～ 30周龄的转基因大鼠的血清AST、ALT水平进行连续测定 ,同时取 30和 6 0周龄转基因大鼠的肝脏进行病理组织学和组织化学分析。 结果 17～ 30周龄 ,转基因大鼠的血清丙氨酸氨基转移酶 (AST)、天门冬氨酸氨基转移酶 (ALT)保持在较低的水平。至 6 0周龄 ,雄性转基因大鼠肝组织未见胆管纤维化。在所有被检的转基因大鼠个体未见肝细胞癌性病变。转基因大鼠的存活率达 95 7%。此外 ,30和 6 0周龄的转基因大鼠肝细胞内铜着色颗粒的分布及数量无明显变化。 结论 人ATP7B的导入有效的延缓了Wilson病动物模型LEC大鼠肝硬化的形成、抑制了肝癌的发生。Wilson病的肝硬化及肝癌的发生可能与铜的蓄积无直接关系。
Objective To investigate the therapeutic effect of human ATP7B on liver cirrhosis and hepatocellular carcinoma in an animal model of Wilson ’s disease (LEC). Methods Human normal ATP7B cDNA containing chicken β-actin promoter was introduced into the fertilized egg of LEC rat model of Wilson’s disease by microinjection to establish a rat model of transgenic functional recovery. The levels of AST and ALT in serum of 17 to 30-week-old transgenic rats were measured continuously in non-transgenic rats and normal wild-type LEA rats. At the same time, the liver of 30 and 60-week old transgenic rats Histological and histochemical analysis. Results Serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT) were maintained at lower levels in transgenic rats from 17 to 30 weeks of age. To 60 weeks of age, no bile duct fibrosis was found in the liver of male transgenic rats. No hepatocellular carcinoma was observed in all the transgenic rats tested. Survival rate of transgenic rats reached 95 7%. In addition, there was no significant change in the distribution and number of copper colored particles in the liver cells of 30 and 60 weeks old transgenic rats. Conclusions The introduction of human ATP7B can effectively delay the formation of liver cirrhosis and inhibit the occurrence of liver cancer in the animal model of Wilson’s disease. Wilson’s disease cirrhosis and liver cancer may not have a direct relationship with the accumulation of copper.