The goal of this study is to determine the role of metallothionein (MT) in the development and prevention of hepatocellular carcinoma (HCC). The model to be used for these proposed studies is the Long-Evans Cinnamon (LEC) rat, a mutant breed of rats wit inherited copper toxicosis which spontaneously develop HCC. MT, by virtue of this multifunctional role in copper metabolism where it serves as a metal transporter, donor and detoxifier, is key to understanding the pathogenesis and prevention of HCC in these animals. The proposed studies focus on copper-MT metabolism in the LEC rat. Specific aspects of Cu-MT metabolism to be evaluated include the timetable for its induction, the subcellular distribution of MT and copper, and the possible defect in lysosomal metabolism of Cu-MT. Analysis of the efficacy of in-vivo treatment of copper toxicosis for preventing the progression to HCC in LEC rats and its effect on the cellular metabolism of copper-Mt will help further define MT's role in cellular trans-formation. Other studies will focus on the underlying cellular defect in copper and MT metabolism which leads to the accumulation of hepatic copper-MT in LEC hepatocytes. These studies are made possible by newly developed temperature dependent immortalized cell lines derived from LEC and control rats. Further study of the role of lysosomes in hepatocellular MT metabolism will be achieved by development of in-vitro assays for the lysosomal import of MT. Study of this unique model of aberrant copper metabolism will help elucidate the role of copper and MT in the process of hepatic carcinogenesis, and provide information from which future therapies for the prevention and treatment of HCC may be formulated.
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