ABNORMAL ACCUMULATION OF COPPER IN LEC RAT-LIVER INDUCES EXPRESSION OF P53 AND NUCLEAR MATRIX-BOUND P21(WAF1 CIP1)/

The LEC rat is an inbred mutant strain which spontaneously develops li ver injury and subsequent liver cancer, Liver injury in LEC rats has r ecently been shown to be closely related to abnormal copper accumulati on in the liver. Previously, we reported that LEC rat hepatocytes lose their growth potential, probably allowing selective growth of preneop lastic cells, In this study, to elucidate the effects of copper accumu lation on the growth activity of LEC rat hepatocytes, we examined the growth activity and the expression of p53 and p21(waf1/cip1) in the li vers of LEC rats fed on either a control or a low-copper diet, Potenti al for cell proliferation of hepatocytes obtained from normal diet fed LEC rats was almost comparable to that of the cells from age-matched Sprague-Dawley (SD) rats, Northern blot analysis showed that the expre ssion of p53 and p21(waf1/cip1) was significantly high in the livers o f LEC rats fed a control diet, while the expression of p53 and p21(waf 1/cip1) in the LEC rats fed a low-copper diet was as low as that of SD rat livers, Western blot analysis consistently showed that the amount of p21(waf1/cip1) bound to the nuclear matrix scaffold of the LEC rat liver was reduced by feeding a low-copper diet, These findings sugges t that abnormal accumulation of copper induced the expression of p53 a nd p21(waf1/cip1), resulting in the inhibition of cell proliferation o f LEC rat hepatocytes.