4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosodimethylamine (DMN) are two nitrosamines that are present in tobacco smoke.  NNK is a lung specific nitrosamine whereas DMN induces liver, respiratory tract, kidney and blood vessel tumors.  They both require hydroxylation adjacent to the nitrosamine group to exert their genotoxic effects.  The resultant a-hydroxylnitrosamine spontaneously decomposes to an alkanediazohydroxide and an aldehyde.  The alkanediazohydroxide alkylates DNA to form a spectrum of DNA adducts, some of which miscode during DNA replication.  In some cases, the aldehyde also generates miscoding adducts.  The ensuing mutations lead to tumor formation.  NNK is metabolized to both a methylating and pyridyloxobutylating agent.  Both pathways are important for lung tumor formation.  The methylation pathway generates 7-methylguanine (7-mG) and O6-methylguanine (O6-mG).  The pyridyloxobutylation pathway leads to the formation of variety of adducts, four of which are 7-[4-3-(pyridyl)-4-oxobut-1-yl]-guanine (7-pobG), O6-[4-3-(pyridyl)-4-oxobut-1-yl]-guanine (O6-pobG), O2-[4-3-(pyridyl)-4-oxobut-1-yl]thymidine (O2-pobT), and O2-[4-3-(pyridyl)-4-oxobut-1-yl]-cytosine.  While O6-mG is the major mutagenic adduct formed by the DNA methylation pathway, several of the pyridyloxobutyl DNA adducts are mutagenic; both O6-pobG and O2-pobT are mutagenic in model systems.  The principal repair route for O6-mG and O6-pobG is adduct reversal by O6-alkylguanine DNA alkyltransferase (AGT).  The mutagenic properties of the pyridyloxobutylation pathway are reduced by several repair pathways including AGT, base excision repair and nucleotide excision repair.  Oxidation of DMN generates N-nitroso(hydroxymethyl)methylamine which decomposes to methanediazohydroxide and formaldehyde.  Like NNK, DMN generates methyl DNA adducts.  Cell-based studies with model methylating agents indicate that formaldehyde may also contribute to the genotoxic properties of DMN, especially in situations where O6-mG is readily repaired.  Mechanistic studies from our lab and others indicate that the relevant contribution of each adduct to the overall genotoxic effects of the nitrosamine depends on the balance of DNA alkylation and repair pathways occurring in the target tissue.

Context matters: Contribution of specific adducts to the genotoxic properties of nitrosamines

248th National Meeting (2014)

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