PREVENTION OF SPONTANEOUS HEPATOCELLULAR-CARCINOMA IN LONG-EVANS CINNAMON RATS WITH HEREDITARY HEPATITIS BY THE ADMINISTRATION OF D-PENICILLAMINE

Acute hepatitis spontaneously develops in the Long-Evans Cinnamon rat at the age of 4 mo, and eventually hepatocellular carcinoma develops a fter the chronic hepatitis that persists for over a year. Previously, abnormal copper accumulation was found in the livers of Long-Evans Cin namon rats from birth, and it was reported that short-term administrat ion of D-penicillamine, a copper-chelating agent, prevented acute hepa titis in Long-Evans Cinnamon rats. In this study we investigated wheth er long-term administration of D-penicillamine could also prevent chro nic hepatitis and subsequent hepatocellular carcinoma in Long-Evans Ci nnamon rats. During long-term observation, which was continued from 11 to 70 wk after birth, no elevation of serum transaminase levels was o bserved in the Long-Evans Cinnamon rats treated with D-penicillamine. Moreover, no histological changes characteristic of the chronic hepati tis were observed in D-penicillamine-treated Long-Evans Cinnamon rats, which were killed at 70 wk of age. Furthermore, placental glutathione S-transferase-positive foci, described as a marker for preneoplastic lesions in the liver, were not detected, and thus hepatocarcinogenesis was completely prevented in D-penicillamine-treated Long-Evans Cinnam on rats. We also found that the amount of 8-hydroxy-deoxyguanosine, on e of oxidative DNA damage products in the liver, was decreased in the Long-Evans Cinnamon rats treated with D-penicillamine. These findings suggest that a process of the prolonged liver-cell injury and regenera tion was essential for spontaneous development of hepatocellular carci noma in Long-Evans' Cinnamon rats with abnormal copper metabolism.