Medium-term bioassay system for detection of carcinogens and modifiers of hepatocarcinogenesis utilizing the GST-P positive liver cell focus as an endpoint marker.
We have developed a medium-term bioassay system of 8 weeks duration utilizing male Fischer 344 (F344) rats for detection of liver carcinogens and modifiers of hepatocarcinogenesis. The system consists of a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg), 6-weeks-administration of test chemical beginning 2 weeks after the DEN injection, and 2/3 partial hepatectomy (PH) performed at week 3. Carcinogenic potency of test chemicals is predicted based on the results of quantitative analyses of immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive liver cell foci. At present, a total of 140 chemicals have been tested using this system, and the findings show a good correlation with reported carcinogenic activities in long-term tests. Furthermore, the reliability of the system has been extensively examined: the results from the medium-term bioassay were compared with those from long-term experiments using the same doses of selected chemicals; the data from presently-used 2-dimensional analysis were compared with calculated values utilizing mathematical formulae for three-dimensional analysis: conformity of phenotypic expression of enzymes in preneoplastic lesions was examined in relation to their growth activity. In conclusion, although the results with non-hepatocarcinogens were less than satisfactory, the present experimental protocol, which requires far fewer animals and shorter duration than a long-term carcinogenicity test, appears of advantage for rapid screening of the large number of environmental chemicals which may possess hazard potential for induction of liver cancer in man.
Ito
N
N
First Department of Pathology, Nagoya City University Medical School, Japan.
Tatematsu
M
M
Hasegawa
R
R
Tsuda
H
H
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D015197:Carcinogenicity Tests; D004052:Diethylnitrosamine; D015971:Gene Expression Regulation, Enzymologic; D005982:Glutathione Transferase / Q000032:analysis*; D008099:Liver / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D010641:Phenotype; D010920:Placenta / Q000201:enzymology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D051381:Rats
D014408:Biomarkers, Tumor; D004052:Diethylnitrosamine; D005982:Glutathione Transferase