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

龙-埃文斯肉桂大鼠（LEC）和龙-埃文斯阿古提大鼠（LEA）是从一个封闭的龙-埃文斯大鼠群体中分离出来的两个近交系。LEC大鼠在4月龄左右自发发展为急性黄疸肝炎。其中一半死于肝炎，存活下来的则表现为慢性肝炎、胆管纤维化，最终发展为肝细胞癌（HCC）。遗传分析表明，一种单一的自体隐性基因（hts）是导致肝炎的原因。然而，hts基因与肝炎和HCC发展的联系尚未确定。我们最近发现，在LEC大鼠的肝脏中有异常高的铜积累，并在血清铜和铜蛋白酶水平中降低。这些发现与人类威尔逊氏病的特征非常相似，其发病机制尚未明确。虽然铜是金属酶多种生物和生化功能的必需元素，但它，特别是自由形态的铜，在过氧化氢存在下会引起DNA损伤。我们研究了氧化DNA损伤产物8-羟基鸟嘌呤（8-oh-Gua）在LEC大鼠HCC发展过程中的变化。结果表明，LEC大鼠肝脏DNA中8-oh- gua水平在4月龄大部分LEC大鼠出现急性肝炎时升高，8月龄后仍维持在肝炎慢性期较高水平。这表明过量的有毒铜，即非蛋白结合铜，将导致肝坏死，最终导致HCC。

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.