EXTENSIVE OXIDATIVE DNA-DAMAGE IN HEPATOCYTES OF TRANSGENIC MICE WITHCHRONIC ACTIVE HEPATITIS DESTINED TO DEVELOP HEPATOCELLULAR-CARCINOMA

A transgenic mouse strain that expresses the hepatitis B virus (HBV) l arge envelope protein in the liver was used to determine the extent of oxidative DNA damage that occurs during chronic HBV infection. This m ouse strain develops a chronic necroinflammatory liver disease that mi mics the inflammation, cellular hyperplasia, and increased risk for ca ncer that is evident in human chronic active hepatitis, When perfused in situ with nitroblue tetrazolium, an indicator for superoxide format ion, the liver of transgenic mice displayed intense formazan depositio n in Kupffer cells, indicating oxygen radical production, and S-phase hepatocytes were commonly seen adjacent to the stained Kupffer cells. Similar changes were not observed in nontransgenic control livers. To determine whether these events were associated with oxidative DNA dama ge, genomic DNA from the livers of transgenic mice and nontransgenic c ontrols was isolated and examined for 8-oxo-2'-deoxyguanosine, an oxid atively modified adduct of deoxyguanosine. Results showed a significan t, sustained accumulation in steady-state 8-oxo-2'-deoxyguanosine that started early in life exclusively in the transgenic mice and increase d progressively with advancing disease. The most pronounced increase o ccurred in livers exhibiting microscopic nodular hyperplasia, adenomas , and hepatocellular carcinoma. Thus, HBV transgenic mice with chronic active hepatitis display greatly increased hepatic oxidative DNA dama ge. Moreover, the DNA damage occurs in the presence of heightened hepa tocellular proliferation, increasing the probability of fixation of th e attendant genetic and chromosomal abnormalities and the development of hepatocellular carcinoma.