Mutational analysis of the liver, colon and kidney of Big Blue rats treated with 2-amino-3-methylimidazo[4,5-f]quinoline.
The heterocyclic aromatic amine (HAA) 2-amino-3-methylimidazo[4, 5-f]quinoline (IQ) induces intestinal tumours and hepatocellular carcinomas in rats, but no tumourigenic effects have been identified in the kidney. The tissue-specific mutagenicity of IQ was studied at the lacI locus in the liver, colon and kidney of Big Blue transgenic rats. At the highest dosing regime of IQ (20 mg/kg for 5 consecutive days) the mean mutant frequencies were significantly increased above background (P < 0.05) and were highest in the liver (12.9 +/- 6.2 x 10(-5)), followed by colon (7.4 +/- 1.4 x 10(-5)) and kidney (5.9 +/- 0.8 x 10(-5)). The mutational spectra from the livers of IQ-treated rats was statistically significantly different to that from the livers of control rats (P < 0.01). The lacI mutation spectra of the liver, colon and kidney from IQ-treated rats were similar. These were characterized by an increase in GC transversions in the liver and colon and an increase in the proportion of 1 bp G:C deletions in the liver and kidney. A single G deletion in the sequence 5'-CGGGA-3', characteristic of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine exposure, was detected in the liver and colon. A 2 bp GC deletion was identified at an identical position in the liver, colon and kidney. The colon was the only organ to contain two larger deletions of 13 and 33 bp. A preference was observed for base substitution mutations at guanine in the sequence 5'-CGC/T-3' and for 1 bp deletions at the guanine doublet in the sequence 5'-CGGA-3', especially in the liver and colon. Using the lacI gene as marker in the Big Blue rat model, the mutations identified in the IQ spectra have similarities to those identified for other HAAs studied in the same experimental system, but not to mutations identified in IQ-induced tumours.
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Nestlé Research Centre, Nestec Ltd, PO Box 44, Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland.
Horlbeck
J
J
Markovic
J
J
de Boer
J G
JG
Turesky
R J
RJ
Constable
A
A
D000818:Animals; D030801:Animals, Genetically Modified; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D003106:Colon / Q000187:drug effects*; D018736:DNA Adducts / Q000032:analysis; D029968:Escherichia coli Proteins; D007093:Imidazoles / Q000633:toxicity; D007668:Kidney / Q000187:drug effects*; D056968:Lac Repressors; D008099:Liver / Q000187:drug effects*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D009928:Organ Specificity; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics
D001426:Bacterial Proteins; D002273:Carcinogens; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D007093:Imidazoles; D056968:Lac Repressors; D009153:Mutagens; D011804:Quinolines; D012097:Repressor Proteins; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine