a-Hydroxynitrosamine metabolites of nitrosamines decompose to an alkanediazohydroxide and an aldehyde.  To test the hypothesis that aldehydes contribute to the harmful effects of nitrosamines, the toxic and mutagenic activity of three model methylating nitrosamines were compared in CHO cells expressing and not expressing human O6-alkylguanine DNA alkyltransferase (hAGT).  N-nitrosomethylurethane (NMU), acetoxymethylmethylnitrosamine (AMMN) and 4-(methylnitrosamino)-4-acetoxy-1-(3-pyridyl)-1-butanone (NNK-4-OAc) are activated by esterase hydrolysis to methanediazohydroxide.  NMU does not form an aldehyde, whereas AMMN and NNK-4-OAc generate formaldehyde and 4-oxo-1-(3-pyridyl)-1-butanone, respectively.  NNK-4-OAc was the most toxic and mutagenic.  hAGT protected cells against these effects, indicating the importance of O6-methylguanine in the toxicological properties of these chemicals.  Levels of 7-methylguanine and O6-methylguanine demonstrated that the activity of a methylating nitrosamine is influenced by the alkyl substitution on the other side of the nitrosamine group by increasing DNA alkylation efficiency, altering repair of mutagenic adducts or generating mutagenic aldehydes.  [Supported by CA- CA059887, CA138338 and CA-018137].   

Role of aldehydes in the toxic and mutagenic effects of nitrosamines

244th National Meeting (2012)

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