Agreement of mutational characteristics of heterocyclic amines in lacI of the Big Blue mouse with those in tumor related genes in rodents.
The mutational spectra of carcinogenic heterocyclic amines (HCAs), 2-amino-3,4-dimethylimidazo[4,5-b]quinoline (MeIQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-9H-pyrido[2,3-b]indole (A alphaC) were studied in the colon of Big Blue mice. In 90, 115 and 105 lacI mutants from mice fed 300 p.p.m. MeIQ, 400 p.p.m. PhIP and 800 p.p.m. A alphaC, respectively, 92, 115 and 105 mutations were identified. G:C-->T:A transversions predominated with these HCAs. Mutational hot spots for base-substitution mutations caused by MeIQ, PhIP and A alphaC were in distinct sequence contexts; at 5'-GC-3', in runs of guanine and in 5'-CGT-3', respectively. Further, 30 of 115 (26%) PhIP-induced mutations were G:C base pair deletions, and eight of these deletions were in 5'-GGGA-3'. The mutational characteristics of MeIQ in the lacI gene coincided well with those in the Ha-ras gene of MeIQ-induced mouse forestomach tumors and rat Zymbal gland tumors. The characteristic single-base deletion induced by PhIP in the lacI gene also coincided well with those in the Apc gene of PhIP-induced rat colon tumors. These results suggest that the mutational characteristics of each chemical are conserved across different genes in different species.
Okonogi
H
H
Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Ushijima
T
T
Zhang
X B
XB
Heddle
J A
JA
Suzuki
T
T
Sofuni
T
T
Felton
J S
JS
Tucker
J D
JD
Sugimura
T
T
Nagao
M
M
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D002243:Carbolines / Q000633:toxicity*; D002455:Cell Division / Q000235:genetics; D029968:Escherichia coli Proteins; D005260:Female; D017491:Genes, APC; D011905:Genes, ras; D007093:Imidazoles / Q000633:toxicity*; D056968:Lac Repressors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics; D011804:Quinolines / Q000633:toxicity*; D012097:Repressor Proteins / Q000235:genetics*
D001426:Bacterial Proteins; D002243:Carbolines; D029968:Escherichia coli Proteins; D007093:Imidazoles; D056968:Lac Repressors; D011804:Quinolines; D012097:Repressor Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline; C017822:2-amino-9H-pyrido(2,3-b)indole