Heterozygous p53-deficient mice are not susceptible to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) carcinogenicity.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a very potent mutagen which induces tumors in the liver, lung and hematopoietic system of CDF1 mice and the liver, Zymbal gland and skin in F344 rats. The recent development of transgenic knockout mice allows their introduction for sensitive screening of environmental carcinogens due to the rapid development of tumors. P53 gene deficient mice (p53-/-) were found to spontaneously develop malignant lymphoma and hemangiosarcoma, whereas heterozygotes (p53+/-) mice display a high incidence of tumors of the urinary bladder when treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. In the present study, to determine whether p53 gene knockout mice can be utilized in a short-term assay model for the screening of heterocyclic amines (HCAs), the effects of MeIQx, as a representative compound, at low doses were examined. Male and female p53+/- mice and wild type littermates (p53+/+) were continuously given diets containing 0, 0.1, 1, 10 and 100 ppm MeIQx for 1 year. No significant difference in tumor induction was observed other than an increase in liver adenomas in males receiving 10 ppm MeIQx treatment. The results indicate that p53+/- mice have no practical advantages for use in short-term carcinogenicity tests of HCAs.
Park
C B
CB
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan. bpark@gan2.res.ncc.go.jp
Kim
D J
DJ
Uehara
N
N
Takasuka
N
N
Hiroyasu
B T
BT
Tsuda
H
H
D000483:Alleles; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D019337:Hematologic Neoplasms / Q000139:chemically induced / Q000235:genetics; D006579:Heterozygote; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D011804:Quinolines / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D002273:Carcinogens; D009153:Mutagens; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline