Gold B, Hines L
IARC Sci Publ. 1984(57):453-8.
The metabolic activation of N-nitrosamines to alkylating agents is mediated by the hydroxylation of the carbon adjacent to the N-nitroso moiety. The resulting N-nitroso-alpha-hydroxy-amines are unstable and decompose to an aldehyde or ketone and a syn-alkane diazotic acid, the latter species being responsible for the carbenium ion reactions associated with nitrosamine-induced alkylation of DNA. Since this chain of events is thought to be initiated in the cytoplasm, there must be a 'transportable' metabolite that can diffuse through the cytoplasm, penetrate the nuclear envelope and alkylate the DNA therein. The 'transportability' of N-nitrosomethylhydroxymethylamine, the putative proximate metabolite of N-nitrosodimethylamine, has been assessed by incubating N-nitroso- ([14C]-methyl)-methylacetoxymethylamine with intact rat liver nuclei in the presence and absence of esterase. The results obtained demonstrate the ability of the in-situ-generated N-nitroso-alpha-hydroxyamine to penetrate the nuclear envelope and confirm that these unstable metabolites are 'transportable' proximate carcinogens.
N-亚硝胺代谢活化为烷基化剂是由与N-亚硝基部分相邻的碳原子的羟基化介导的。生成的N-亚硝基-α-羟基胺不稳定，会分解为醛或酮以及顺式链烷重氮酸，后一种物质负责与亚硝胺诱导的DNA烷基化相关的碳正离子反应。由于这一系列事件被认为是在细胞质中启动的，所以必定存在一种“可转运的”代谢产物，它能够扩散穿过细胞质，穿透核膜并使其中的DNA烷基化。通过在有酯酶和无酯酶的情况下，将N-亚硝基-([14C]-甲基)-甲基乙酰氧基甲胺与完整的大鼠肝细胞核一起孵育，评估了N-亚硝基二甲基胺的假定近端代谢产物N-亚硝基甲基羟甲基胺的“可转运性”。所获得的结果证明了原位生成的N-亚硝基-α-羟基胺穿透核膜的能力，并证实这些不稳定的代谢产物是“可转运的”近端致癌物。
