Hecht S S, Lin D, Castonguay A
Carcinogenesis. 1983;4(3):305-10. doi: 10.1093/carcin/4.3.305.
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.
4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）是一种致癌的烟草特有亚硝胺，可通过亚甲基碳（4位碳）或与亚硝胺基团相连的甲基的代谢羟基化作用转化为亲电重氮氢氧化物中间体。为了研究这两个过程在NNK诱变中的相对重要性，我们合成了4,4-二氘代-4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（[4,4,-D2]NNK）和4-（三氘代甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（[CD3]NNK），并评估了它们在鼠伤寒沙门氏菌测试菌株中的诱变活性。在存在艾氏剂诱导的大鼠肝脏9000g上清液的情况下，NNK和[4,4-D2]NNK对鼠伤寒沙门氏菌TA 1535和TA 100具有相当的诱变活性，但[CD3]NNK在这两种菌株中均无活性。这些结果表明，NNK甲基的羟基化在其活化为诱变剂的过程中比4位碳的羟基化更重要。为了测试分别由甲基羟基化或4位碳羟基化形成的4-氧代-4-（3-吡啶基）丁基重氮氢氧化物和甲基重氮氢氧化物的固有诱变性，我们比较了相应模型化合物4-（乙氧羰基亚硝胺基）-1-（3-吡啶基）-1-丁酮和乙氧羰基亚硝胺甲烷（甲基亚硝基脲）在无激活情况下的诱变性。两种化合物对鼠伤寒沙门氏菌TA 1535和TA 100均具有高度诱变性，但在剂量为4×10⁻³至4×10⁻⁴μmol/平板时，只有4-（乙氧羰基亚硝胺基）-1-（3-吡啶基）-1-丁酮具有诱变性。这些结果与用氘取代化合物获得的结果一致，并表明4-氧代-4-（3-吡啶基）丁基化DNA在NNK诱变中的重要性。
