title: Organ-dependent susceptibility of p53 knockout mice to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).
abstract: p53 knockout mice are now being frequently used to identify the carcinogenic potential of chemicals, thus it is important to precisely assess the susceptibility of the animals to various test chemicals. In the present study the susceptibility of p53 nullizygous((-/-)), heterozygous((+/-)), and wild-type((+/+)) mice to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was investigated. Mice of all three genotypes were first fed a diet containing 100 or 300 p.p.m. IQ for 15 weeks in a short-term experiment. p53((+/-)) and ((+/+)) mice were then treated with IQ for 40 weeks and maintained without further treatment for an additional 12 weeks in the long-term experiment. In the forestomach, the incidence of squamous cell hyperplasia was significantly higher in p53((-/-)) than in ((+/-)) and ((+/+)) mice at 15 weeks and higher in ((+/-)) mice than ((+/+)) mice with long-term IQ treatment, indicating an elevated susceptibility of p53 knockout mice. In contrast, in the liver, various hepatocellular lesions developed mainly in female mice with long-term IQ exposure but no significant differences were evident between p53 knockout and wild-type mice, indicating a lack of elevated susceptibility in the knockout animals. Furthermore, polymerase chain reaction-single strand conformation polymorphism and sequencing analysis revealed relatively high (13/30) and low (1/15) incidences of p53 mutations (exons 5-8) in squamous cell hyperplasia and hepatocellular tumors, respectively. These results clearly indicate that the susceptibility of p53 knockout mice is organ-dependent, coinciding to some extent with the likelihood of p53 gene alteration in the induced tumors.
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirata
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Hisayo
authors.initials: H
authors.lastname: Ban
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Masegi
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D016158:Genes, p53; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009928:Organ Specificity; D011804:Quinolines / Q000008:administration & dosage / Q000633:toxicity*; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000235:genetics; D013997:Time Factors
chemical_list: D002273:Carcinogens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline