| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1991: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1990: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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.
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