Regulation mechanism of hepatodyte proliferation in LEC rats with spontaneous development of hepatitis and hepatocellular careinoma

Long-Evans Cinnamon(LEC)大鼠和Long-Evans Agti(LEA)大鼠是从封闭的Long-Evans大鼠群体中分离出来的两个近交系。LEC大鼠在4个月左右自发发展为急性肝炎伴黄疸。其中一半死于肝炎，那些幸存下来的人表现为慢性肝炎、胆管纤维化，并最终患上肝细胞癌。遗传分析表明，单个常染色体隐性基因(HTS)与肝炎有关。然而，HTS基因与肝炎和肝细胞癌的发生发展没有联系。我们最近发现LEC大鼠肝脏中铜的异常高积聚，并降低了血清铜和铜蓝蛋白的水平。这些发现与人类肝豆状核变性的特点非常相似，其发病机制尚不清楚。虽然铜是金属酶的各种生物和生化功能的必需元素，但在过氧化氢存在的情况下，它，特别是自由形式的铜，可以引起DNA损伤。我们检测了DNA氧化损伤产物8-羟基鸟嘌呤(8-oh-gua)在LEC大鼠肝细胞癌发展过程中的变化。结果表明，LEC大鼠肝脏DNA中8-OH-GUA的含量在4月龄时开始升高，大多数LEC大鼠表现为急性肝炎，8月龄后仍维持在较高水平。这表明过量的有毒铜，即非蛋白结合态铜，将导致肝脏坏死，最终导致肝细胞癌。

Long-Evans Cinnamon (LEC) rats and Long-Evans Agouti (LEA) rats are two inbred strains isolated from a closed colony of Long-Evans rats. The LEC rats spontaneously develop acute hepatitis with jaundice around the age of 4 months. Half of then die of the hepatitis, and those which have survived show chronic hepatitis, cholangio-fibrosis, and eventually hepatocellular carcinojia (HCC). Genetic analysis indicates that a single autosonal recessive gene (hts) is responsible for the hepatitis. However, no linkage of the hts gene with the development of hepatitis and HCC has been determined yet.We have recently found an abnormally high copper accumulation in the liver of LEC rats and decreases i. n the serum copper and ceruloplasain levels. These findings closely resemble the feature of human Wilson's diseases of which pathogenesis has not been clarified yet. Although copper is an essential element for a variety of biological and biochemical functions of metalloenzymes, it, in particular free-form copper, can induce DNA damage in the presence of hydrogen peroxide. We have examined the changes of an oxidative DNA damage product, 8-hydroxyguanine (8-oh-Gua) during the development of HCC in LEC rats. As the results, the levels of 8-oh-Gua in the DNA of the LEC rat liver were increased at the age of 4 months when most LEC rats showed acute hepatitis, which maintained still high in the chronic phase of hepatitis after 8 months of age. This suggest that an excess of toxic-forn copper, i. e., non-protein-bound copper, will cause hepatic necrosis, and HCC in the end.