Copper cytotoxicity impairs DNA synthesis but not protein phosphorylation upon growth stimulation in LEC mutant rat.

Long-Evans Cinnamon (LEC) mutant rat, which possesses a genetic defect of the block of copper exclusion pathway in the hepatocytes, is a good model for studying the mechanism of cellular copper toxicity. We have examined effects of copper toxicity on DNA synthesis and protein phosphorylation upon growth stimulation by treating LEC rat primary-cultured hepatocytes with EGF and insulin. The proportion of DNA-synthesizing S-phase cells in LEC rat markedly decreased when compared to that of normal rat. However, the electrophoretic pattern and the signal intensity of 32P-labeled nuclear proteins in LEC rat were indistinguishable from those of normal rat. These results suggest that a cellular event other than protein phosphorylation required for the initiation of DNA synthesis upon growth stimulation is impaired by copper cytotoxicity.