Effects of α-deuterium substitution on the mutagenicity of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)1

Stephen S. Hecht, Dorothy Lin, Andre Castonguay

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155 Scopus citations


4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic tobacco specific nitrosamine, can be converted to electrophilic diazohydroxide intermediates by metabolic hydroxylalion of either the methylene carbon (carbon 4) or the methyl carbon attached to the nitrosamine group. To investigate the relative importance of these two processes in NNK mutagenesis, we synthesized 4,4-dideutero-4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone([4,4,-D2]NNK) and 4-(trideuteromethylnitrosamino)-1-(3-pyridyl)-1-butanone ([CD3] NNK), and evaluated their mutagenic activities in Salmonella typhimurium tester strains. In the presence of Aroclor induced rat liver 9000 g supernatant, NNK and [4,4-D2]NNK had comparable mutagenic activities towards S. typhimurium TA 1535 and TA 100, but [CD3]NNK was inactive in both strains. These results suggest that hydroxylation of the methyl group of NNK is more important than hydroxylation of carbon 4 in its activation to a mutagen. To test the inherent mutagenicity of 4-oxo-4-(3-pyridyl)butyldiazohydroxide and methyldiazohydroxide which would be formed by methyl hydroxylation or carbon 4 hydroxylation, respectively, we compared the mutagenicities, without activation, of the corresponding model compounds, 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone and carbethoxynitrosaminomethane (methylnitrosourethane). Both compounds were highly mutagenic toward S. typhimurium TA 1535 and TA 100, but at doses of 4 × 10-3 to 4 × 10-4μmol/plate, only 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone was mutagenic. These results are consistent with those obtained with the deuterium substituted compounds and indicate the importance of 4-oxo-4-(3-pyridyl)butylation of DNA in NNK mutagenesis.

Original languageEnglish (US)
Pages (from-to)305-310
Number of pages6
Issue number3
StatePublished - 1983

Bibliographical note

Funding Information:
This study was supported by NCI Grant CA-21393. We thank Dr. Tomiko Shimada and Ms. Albertina Swanson for carrying out the mulagenicity assays and Mr. Joseph Camanzo for obtaining m.s.


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