Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f ]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21(Cip / WAF1).
The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into seven groups and administered with IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 p.p.m. in the diet for 16 weeks. We found that IQ doses of 1 p.p.m. and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 p.p.m. induced preneoplastic lesions in both of these organs. These results demonstrate the presence of no-effect levels of IQ for both liver and colon carcinogenicity in rats. The finding that p21(Cip/WAF1) was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects suggests that induction of p21(Cip/WAF1) is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01-10 p.p.m., but administration of 100 p.p.m. IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results suggest the existence of no-effect levels for the carcinogenicity of this genotoxic compound.
Department of Pathology, Osaka City University Medical School, Osaka. Japan.
Min
M
Wei
Hideki
H
Wanibuchi
Dai
D
Nakae
Hiroyuki
H
Tsuda
Satoru
S
Takahashi
Masao
M
Hirose
Yukari
Y
Totsuka
Masae
M
Tatematsu
Shoji
S
Fukushima
D058739:Aberrant Crypt Foci / Q000139:chemically induced; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D018736:DNA Adducts / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000502:physiology; D051549:Glutathione S-Transferase pi / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000502:physiology; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D000097642:GADD45 Proteins
D002273:Carcinogens; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018736:DNA Adducts; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D051549:Glutathione S-Transferase pi; D009687:Nuclear Proteins; D011804:Quinolines; C493958:Cdkn1a protein, rat; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C496558:Gstp1 protein, rat