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© 1993 Oxford University Press

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SHORT COMMUNICATION: G to A transitions and G to T transversions in codon 12 of the Ki-ras oncogene isolated from mouse lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and relati DNA methylating and pyridyloxobutylating agents

Zeev A. Ronai, Scott Gradia, Lisa A. Peterson and Stephen S. Hecht

American Health Foundation 1 Dana Road, Valhalla, NY 10595, USA

Lung tumors were induced in A/J mice by the tobacco-specific nitrosamine 4Kmethylnitrosaniino)-1-(3-pyridyI)-1-butanone (NNK) and the related compounds acetoxymethylmethyl-nitrosamine (AMMN) and 4-acetoxymethylnitrosamino)-1-(3-pyridyI)-1-butanone (NNKOAc). NNK both methylates and pyridyloxobutylates DNA while AMMN and NNKOAc only methylate or pyridyloxobutylate DNA, respectively. The lung tumors were analyzed for mutations in the Ki-ras oncogene by PCR amplification followed by either restriction fragment length polymorphism, hybridization, or sequencing procedures. NNK induced GGT to GAT mutations in codon 12 (26 of 28 samples analyzed). AMMN induced GGT to GAT mutations in 18 of 18 samples. In contrast, NNKOAc induced a variety of changes including GGT to GAT (8/21), GGT to TGT (5/21) and GGT to GTT (4/21) mutations. These results demonstrate that DNA methylation causes mainly G to A transitions in the Ki-ras gene of A/J mouse lung tumors, consistent with previous results and a role for O6-methyl-guanine, while DNA pyridyloxobutylation induces G to A transitions as well as G to T transversions, perhaps due to the steric bulk of the adducts which are formed. The results are discussed with respect to mutations observed in rodent and human lung tumors.


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