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

Journal Article · Fri Dec 31 23:00:00 EST 1982 · Carcinogenesis (N.Y.); (United States)

DOI:https://doi.org/10.1093/carcin/4.3.305· OSTI ID:5974279

Hecht, S S; Lin, D; Castonguay, A

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic tobacco specific nitrosamine, can be converted to electrophilic diazohydroxide intermediates by metabolic hydroxylation 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-(methylnitrosamino)-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 x 10(-3) to 4 x 10(-4) mumol/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.

• Research Organization: Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention, Valhalla, NY
• OSTI ID: 5974279
• Journal Information: Carcinogenesis (N.Y.); (United States), Journal Name: Carcinogenesis (N.Y.); (United States) Vol. 4:3; ISSN CRNGD
• Country of Publication: United States
• Language: English

Related Subjects

560302* -- Chemicals Metabolism & Toxicology-- Microorganisms-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINES
BACTERIA
DEUTERIUM COMPOUNDS
DNA
HYDROGEN COMPOUNDS
HYDROXYLATION
METABOLIC ACTIVATION
MICROORGANISMS
MUTAGEN SCREENING
NITROSAMINES
NITROSO COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
SALMONELLA
SALMONELLA TYPHIMURIUM
SCREENING