MOLECULAR-BASIS OF PATHOPHYSIOLOGY OF INDIAN CHILDHOOD CIRRHOSIS - ROLE OF NUCLEAR COPPER ACCUMULATION IN LIVER

Indian Childhood Cirrhosis (ICC) is a disease of abnormal copper metab olism commonly characterized by swelling and degeneration of liver cel ls along with the presence of orcein staining deposits of copper. Hepa tic copper content of ICC patients was about 43 fold higher than those of control subjects. The data on sub-cellular distribution of copper revealed massive accumulation of Copper (73%) of total cell copper) in the nuclear fraction (455 mu g Cu/g tissue nuclei). On further distri bution of copper in nuclear fraction, the enrichment of copper in hete rochromatin and euchromatin of ICC nuclei was found to be 48 and 15 fo ld higher over control fractions respectively. The ultra-violet spectr a of heterochromatin and euchromatin isolated from ICC nuclear fractio n showed a broad absorption maxima as compared to controls. Further, A 260/A280 ratio was markedly lower in heterochromatin and euchromatin o f ICC liver in comparison to controls. An antioxidant enzyme, catalase activity was also significantly reduced in ICC liver as compared to c ontrol. Further, DNA fragmentation studies indicated that there was si gnificantly increased DNA fragmentation in ICC liver. Collectively, th ese findings suggest that massive accumulation of copper in nucleus an d decrease in catalase activity was associated with DNA fragmentation in hepatocyte of ICC disease.