| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Masakazu Sasaki Institute, Sasaki Foundation, Department of Pathology, Chief Researcher, 病理部, 主任研究員 (50132767)
MASUMURA Ken-ichi National Institute of Health Sciences, Division of Genetics and Mutagenesis, Chief Researcher, 変異遺伝部, 主任研究官 (40291116)
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| Research Abstract |
The present study assessed possible involvement of gene mutation in the early stage hepatocarcinogenesis, using gpt delta rats with a reporter transgene. In the study, 6-week-old male gpt delta rats originated from either Fischer 344 (F344) or Sprague-Dawley (SD) strains were used. Two rat hepatocarcinogenesis models were featured, an endogenous one with a choline-deficient L-amino acid-defined (CDAA) diet and an exogenous one with N-nitrosodiethylamine (DEN). Phenyl N-tert-butyl nitrone (PBN) was chosen as a negative modifier of hepatocarcinogenesis. The experiment was conducted by 15 groups each consisting of 6 animals (F344 for groups 1-8 and SD for groups 9-15). Groups 1, 2, 3 and 4 received the CDAA diet, CDAA+PBN (0.13% in drinking water), a choline-supplemented L-amino acid-defined (CSAA) diet and CSAA+PBN, respectively, from the end of week 2 for 16 weeks. Groups 5 and 6 received DEN of 2 weekly intraperitoneal doses of 100mg/kg body weight at the beginning. Only group 6 receiv
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ed PBN from the end of week 2 for 16 weeks. Groups 7 and 8 received vehicle in place of DEN and were similarly treated to groups 5 and 6, respectively. Groups 9-13, 14 and 15 were treated similarly to groups 1-5, 7 and 8, respectively. At the end of week 18, all animals were killed to obtain the liver for the examination for the development of preneoplastic lesion, oxidative DNA injury (8-oxoguanine, 8-oxoG) and gene mutation (gpt assay). In the endogenous model, the CDAA diet induced preneoplastic lesions only in F344. The 8-oxoG levels increased by the CDAA diet in both strains, F344 being higher than SD. The gene mutation increased by both the CDAA and CSAA diets with the same extent, only in F344. The CSAA diet predominantly caused GC/AT transition and deletion, while the CDAA diet caused those in association with GC/TA transversion, specific to 8-oxoG. PBN inhibited all changes caused by the CDAA diet but not gene mutation caused by the CSAA diet. In the exogenous model, DEN induced preneoplastic lesions more but smaller in F344 and more as well as larger in SD than the CDAA diet. The lesions were more in SD than in F344. The 8-oxoG levels increased by DEN in both strains, lower and higher than the CDAA case, respectively. The gene mutation increased by DEN, higher than the CDAA case, in both strains, higher in SD than in F344. PBN did not exert any influence on changes caused by DEN. These results indicate that the gene mutation is involved in both endogenous and exogenous rat hepatocarcinogenesis at its early stage but in different manners, and plays roles in the mechanisms underlying the strain difference. Less
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