The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) generates pyridyloxobutyl DNA adducts.  The pyridyloxobutyl adducts O6-[4-3-(pyridyl)-4-oxobut-1-yl]deoxyguanosine (O6-pobdG) and O2-[4-3-(pyridyl)-4-oxobuty 1-yl]deoxythymidine (O2pobdT) are thought to contribute to the mutagenic and tumorigenic properties of the pyridyloxobutylation pathway.  O6-Alkylguanine-DNAalkyltransferase (AGT) is known to repair O6-pobdG, while nucleotide excision repair may be important in the repair of O2pobdT.  To determine the role of pyridyloxobutyl DNA adduct formation and repair in the tumorigenic properties of NNK, A/J mice weretreated with the model pyridyloxobutylating agent 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1-butanone.  DNA adduct levels and tumor yield weremeasured in the lung.  Our findings indicate that O2pobdT accumulates in lung DNA.  AGT depletion does not significantly affect O6-pobdG repair or tumor formation. These data suggest that O6-pobdG is repaired by pathways other than AGT, and that formation and persistence of O2pobdT may be important for tumorigenesis.  Studies are underway to investigate other possible repair pathways of O6-pobdG [Supported by CA-115309 and CA-138338].

Pyridyloxobutyl DNA adducts and their relationship to tumor formation in the A/J mouse lung model

242nd National Meeting (2011)

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