Inhibition of early-phase exogenous and endogenous liver carcinogenesis in transgenic rats harboring a rat glutathione S-transferase placental form gene.

Abstract

Hepatocarcinogenesis initiated with N-nitrosodiethylamine (DEN) and that initiated by feeding of a choline-deficient, L-amino acid-defined (CDAA) diet were compared in transgenic male Wistar rats harboring a rat glutathione S-transferase placental form (GST-P) gene (GST-P-Tg rats) and non-transgenic (N-Tg) rats. Eight-week-old GST-P-Tg and N-Tg rats were administered DEN intraperitoneally at 100 mg/kg body weight, subjected to a selection procedure with 2-acetylaminofluorene and CCl4, and killed at the end of weeks 5 and 12. Other groups were fed the CDAA diet for 12 weeks and killed. Five weeks after the DEN treatment, numbers and sizes of gamma-glutamyltransferase (GGT)- or GST-P-positive lesions and 8-hydroxyguanine (8-OHG) levels in the livers were significantly less in GST-P-Tg rats than in N-Tg rats. The lesion numbers were unchanged between the ends of weeks 5 and 12 in GST-P-Tg rats, but decreased in N-Tg rats. The lesion sizes were increased in GST-P-Tg rats, but unchanged in N-Tg rats. While the proliferating cell nuclear antigen labeling indices (PCNA L.I.) in and surrounding the lesions were decreased, more prominently in GST-P-Tg rats than in N-Tg rats, the 8-OHG levels were also decreased but similarly in both cases. After 12 weeks on the CDAA diet, the lesion incidences, numbers and sizes, 8-OHG levels, PCNA L.I. in and surrounding the lesions, and liver injury were significantly less in GST-P-Tg rats than in N-Tg rats. These results indicate that insertion of a rat GST-P transgene alters the early phase of exogenous and endogenous rat hepatocarcinogenesis, presumably due to enhanced detoxification by GST-P expressed both transiently during the initiation and chronically in the altered hepatocyte populations.

• Authors: D Nakae, A Denda, Y Kobayashi, H Akai, H Kishida, T Tsujiuchi, Y Konishi, T Suzuki, M Muramatsu
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 89 Issue 11 Pg. 1118-25 (Nov 1998) ISSN: 0910-5050 [Print] Japan
• PMID: 9914780 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diethylnitrosamine
• Glutathione Transferase

Topics

• Animals
• Animals, Genetically Modified
• Choline Deficiency (complications)
• Diet
• Diethylnitrosamine (toxicity)
• Glutathione Transferase (genetics)
• Liver Neoplasms, Experimental (prevention & control)
• Male
• Placenta (enzymology)
• Precancerous Conditions (chemically induced, enzymology, genetics)
• Rats
• Rats, Wistar