Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma.
- 20 December 1994
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 91 (26), 12808-12812
- https://doi.org/10.1073/pnas.91.26.12808
Abstract
A transgenic mouse strain that expresses the hepatitis B virus (HBV) large envelope protein in the liver was used to determine the extent of oxidative DNA damage that occurs during chronic HBV infection. This mouse strain develops a chronic necroinflammatory liver disease that mimics the inflammation, cellular hyperplasia, and increased risk for cancer that is evident in human chronic active hepatitis. When perfused in situ with nitroblue tetrazolium, an indicator for superoxide formation, the liver of transgenic mice displayed intense formazan deposition 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 damage, genomic DNA from the livers of transgenic mice and nontransgenic controls was isolated and examined for 8-oxo-29-deoxyguanosine, an oxidatively modified adduct of deoxyguanosine. Results showed a significant, sustained accumulation in steady-state 8-oxo-29-deoxyguanosine that started early in life exclusively in the transgenic mice and increased progressively with advancing disease. The most pronounced increase occurred in livers exhibiting microscopic nodular hyperplasia, adenomas, and hepatocellular carcinoma. Thus, HBV transgenic mice with chronic active hepatitis display greatly increased hepatic oxidative DNA damage. Moreover, the DNA damage occurs in the presence of heightened hepatocellular proliferation, increasing the probability of fixation of the attendant genetic and chromosomal abnormalities and the development of hepatocellular carcinoma.Keywords
This publication has 41 references indexed in Scilit:
- Involvement of inflammatory reactions and elevated cell proliferation in the development of bladder cancer in schistosomiasis patientsMutation Research, 1994
- Low frequency of allelic loss in the cyclin A gene in human hepatocellular carcinomas: a study based on PCRLiver International, 1993
- p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell linesCarcinogenesis: Integrative Cancer Research, 1993
- Enumeration of S-phase cells in normal rat liver by immunohistochemistry using bromodeoxyuridine-antibromodeoxyuridine systemDigestive Diseases and Sciences, 1991
- The hepatitis B virus and the host responseJournal of Hepatology, 1990
- Expression of oncogenes in human liver diseaseLiver International, 1988
- Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNACarcinogenesis: Integrative Cancer Research, 1987
- Delta agent and the etiology of hepatocellular carcinomaInternational Journal of Cancer, 1987
- Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repairCarcinogenesis: Integrative Cancer Research, 1986
- Significance of schistosomiasis japonica in the development of cancer of the large intestineDiseases of the Colon & Rectum, 1976