Comprehensive toxicity study of safrole using a medium-term animal model with gpt delta rats.
In order to investigate a medium-term animal model using reporter gene transgenic rodents in which general toxicity, genotoxicity and carcinogenicity are evaluated, F344 gpt delta rats were given a diet containing 0.1% and 0.5% (a carcinogenic dose) safrole for 13 weeks. Serum biochemistry and histopathological examinations revealed overt hepatotoxicity of safrole, in line with previous reports. In the current study, safrole treatment possibly resulted in renal toxicity in male rats. In the in vivo mutation assays, an increase or a tendency to increase of the gpt mutant frequencies (MFs) was observed in both sexes at the carcinogenic dose. The number and area of foci of glutathione S-transferase placental form (GST-P) positive hepatocytes, ratio of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and 8-hydroxydeoxyguanosine (8-OHdG) levels in liver DNA were significantly increased in both sexes of the 0.5% group. The overall data suggested that the present model might be a promising candidate for investigating comprehensive toxicities of the agents. In addition, data demonstrating the base modification and cell proliferation due to exposure to safrole could contribute to understanding safrole-induced hepatocarcinogenesis, which imply expanding in application of this model.
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
M
M
Jin
A
A
Kijima
Y
Y
Suzuki
D
D
Hibi
T
T
Inoue
Y
Y
Ishii
T
T
Nohmi
A
A
Nishikawa
K
K
Ogawa
T
T
Umemura
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins / Q000235:genetics*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D010430:Pentosyltransferases / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D012451:Safrole / Q000008:administration & dosage / Q000633:toxicity*; D012737:Sex Factors
D029968:Escherichia coli Proteins; D018809:Proliferating Cell Nuclear Antigen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D012451:Safrole