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 after the chronic hepatitis that persists for over a year. Previously, abnormal copper accumulation was found in the livers of Long-Evans Cinnamon rats from birth, and it was reported that short-term administration of D-penicillamine, a copper-chelating agent, prevented acute hepatitis in Long-Evans Cinnamon rats. In this study we investigated whether long-term administration of D-penicillamine could also prevent chronic hepatitis and subsequent hepatocellular carcinoma in Long-Evans Cinnamon rats. During long-term observation, which was continued from 11 to 70 wk after birth, no elevation of serum transaminase levels was observed in the Long-Evans Cinnamon rats treated with D-penicillamine. Moreover, no histological changes characteristic of the chronic hepatitis 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 Cinnamon rats. We also found that the amount of 8-hydroxy-deoxyguanosine, one 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 regeneration was essential for spontaneous development of hepatocellular carcinoma in Long-Evans Cinnamon rats with abnormal copper metabolism.
Laboratory of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
K
K
Jong-Hon
Y
Y
Togashi
H
H
Kasai
M
M
Hosokawa
N
N
Takeichi
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000517:prevention & control*; D003300:Copper / Q000097:blood; D004247:DNA / Q000302:isolation & purification; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005260:Female; D006505:Hepatitis / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D010396:Penicillamine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D016588:Anticarcinogenic Agents; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003849:Deoxyguanosine; D010396:Penicillamine