Aflatoxin B1 induced lacI mutation in liver and kidney of transgenic mice C57BL/6N: effect of phorone.
Transgenic C57BL/6N mice containing a lambda shuttle vector carrying a lacI target and an alpha-lacZ reporter gene have been used to study the modulating effect of phorone, a glutathione-depleting agent, on the mutagenic activity of aflatoxin B1 (AFB1) in vivo. Animals were treated with AFB1 (8 mg/kg) for four consecutive days and the animals sacrificed 21 days after the last treatment. Treatment with AFB1 alone did not result in a significant increase in mutation frequency in the liver and kidney. When the animals were treated with phorone 4 h prior to treatment with AFB1 a significant increase in mutation frequency was observed in the liver (4-fold) and kidney (1.5-fold). Phorone treatment did not increase the AFB1-induced mutation frequency in the lung and intestine. DNA sequence analyses of 30 independent clones isolated from the liver of AFB1-treated animals showed that G:C --> T:A transversion (60%) was the predominant mutational event. Mutations within the lacI gene could not be detected in seven of 30 mutants. The mutations were randomly distributed throughout the coding sequences of the lacI gene and no hotspots for the mutations were observed. However, codons 86 and 928 appeared to be major sites for mutation. The study shows that the transgenic mouse in vivo mutagenesis model can be used to study the influence of effect-modifying compounds on the mutagenic activity of known carcinogens.
Autrup
H
H
Department of Environmental and Occupational Medicine, University of Aarhus, Denmark.
Jørgensen
E C
EC
Jensen
O
O
D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D010582:Bacteriophage lambda / Q000235:genetics; D001483:Base Sequence; D004274:DNA, Recombinant / Q000235:genetics; D004357:Drug Synergism; D029968:Escherichia coli Proteins; D017930:Genes, Reporter; D005822:Genetic Vectors; D005978:Glutathione / Q000378:metabolism; D007659:Ketones / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007763:Lac Operon; D056968:Lac Repressors; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D012097:Repressor Proteins / Q000235:genetics*; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*
D001426:Bacterial Proteins; D004274:DNA, Recombinant; D029968:Escherichia coli Proteins; D007659:Ketones; D056968:Lac Repressors; D009153:Mutagens; D012097:Repressor Proteins; D012997:Solvents; C018637:phorone; D016604:Aflatoxin B1; D005978:Glutathione