In vivo genotoxicity of 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline in lacI transgenic (Big Blue) mice.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a heterocyclic amine found in cooked meat, is a strong mutagen in the Salmonella/microsome assay and was proven to be a hepatocarcinogen in rodents. We used the lacI transgenic (Big Blue(R)) mouse to investigate MeIQx genotoxicity in vivo. lacI mutant frequencies were examined in liver and colon after single intragastric administration of MeIQx (males) or 12 weeks of feeding in the diet (males and females). Micronucleus induction was monitored in the peripheral blood and cell proliferating activity was monitored by proliferating cell nuclear antigen (PCNA) immunostaining, but only after the intragastric administration. Intragastric treatment with MeIQx (100 mg/kg) did not increase mutant frequency (MF) in liver or colon but it did induce a slight but statistically significant increase in the incidence of micronucleated reticulocytes 48 h after the treatment. No apparent increase in PCNA-positive foci was observed in any of tissues analyzed 14 days after the treatment. Administration of MeIQx (300 ppm) in diet for 12 weeks, however, caused MF increases in liver and colon in male and female mice, with greater increases in the females. An increase was also obvious after 4 weeks, but only in females. The sex difference in MF is consistent with the fact that female mice are more susceptible to MeIQx carcinogenesis. These results demonstrated that in the transgenic mouse mutation assay, long-term feeding of MeIQx was more effective than single gastric exposures in revealing the compound's mutagenicity in the target organs of carcinogenicity and that sex differences in susceptibility can also be observed.
Itoh
T
T
Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan.
Suzuki
T
T
Nishikawa
A
A
Furukawa
F
F
Takahashi
M
M
Xue
W
W
Sofuni
T
T
Hayashi
M
M
D000284:Administration, Oral; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins; D005260:Female; D007441:Intubation, Gastrointestinal; D056968:Lac Repressors; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects; D011810:Quinoxalines / Q000633:toxicity*; D012097:Repressor Proteins / Q000235:genetics; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D009153:Mutagens; D011810:Quinoxalines; D012097:Repressor Proteins; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline