DECREASED EXPRESSION OF LIVER GLUTATHIONE-PEROXIDASE IN LONG-EVANS CINNAMON MUTANT RATS PREDISPOSED TO HEPATITIS AND HEPATOMA

The Long-Evans Cinnamon rat is a mutant strain that contracts heredita ry hepatitis and, eventually, spontaneous hepatoma. Recently, abnormal copper accumulations in Long-Evans Cinnamon rat livers were shown to be genetically linked to the development of hepatitis. Because reduced glutathione and glutathione-related enzymes are known to play importa nt roles in cellular resistance to transition metal toxicity, we deter mined the levels of reduced glutathione and glutathione-related enzyme s in seven different tissues of Long-Evans Cinnamon and control Long-E vans Agouti rats. Of the enzymes examined, only hepatic glutathione pe roxidase was markedly decreased in Long-Evans Cinnamon rats. Glutathio ne peroxidase content in the liver of Long-Evans Cinnamon rats was 39% , 53% and 58% of the control values at 9 (normal stage), 19 (acute hep atitis stage) and 27 (chronic hepatitis stage) wk of age, respectively . Northern-blot analysis revealed that messenger RNA levels of glutath ione peroxidase in the livers of Long-Evans Cinnamon rats were about 4 0% of the control levels. The activity of glutathione S-transferase wa s slightly decreased in the livers of Long-Evans Cinnamon rats. These data suggest that the liver of the Long-Evans Cinnamon rat is poorly p rotected against active oxygen species, the production of which is enh anced in the presence of excess copper. Glutathione-reductase activity in the Livers of Long-Evans Cinnamon rats increased to 166% and 148% of the control levels at 19 and 27 wk of age, respectively. No signifi cant changes were observed in the activity of gamma-glutamylcysteine s ynthetase or in the content of total reduced glutathione in the liver of the Long-Evans Cinnamon rat. The changes in activity of glutathione peroxidase and glutathione reductase in the Long-Evans Cinnamon rat l ivers resembled those observed during chemical hepatocarcinogenesis.