The Fenton degradation as a nonenzymic model for microsomal denitrosation of N-nitrosodimethylamine

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Abstract
The microsomal metabolism of the carcinogen N-nitrosodimethylamine (NDMA) was suggested to be initiated by hydrogen atom abstraction to form an .alpha.-nitrosamino radical, which either oxidizes further to an .alpha.-hydroxy nitrosamine as the initial product of the activating dealkylation pathway or fragments to the nitric oxide radical and N-methylformaldimine as the first step of the presumably inactivating denitrosation route. To examine the chemistry of the .alpha.-nitrosamino radical in a nonenzymatic setting, we exposed NDMA to the Fenton reagent, which is known to be capable of abstracting hydrogen atoms from organic species. The products observed were those expected of a denitrosation model. Solutions containing 13 mM [14C]NDMA, 15 mM FeSO4, 15 mM H2O2, and 7.5 mM H2SO4 were kept at 4-10.degree.C for 1 h and then basified to yield methylamine (3.2 .+-. 0.5 mM, mean .+-. SD, n = 8), formaldehyde (3.1 .+-. 0.9 mM), and unreacted nitrosamine (10.2 .+-. 0.7 mM) as the only radioactive species detected, with total nitrate/nitrite also being found at a level of 2.8 .+-. 0.5 mM. N-Methylformaldiminium ion was identified as an intermediate. The parallels between these results and those seen in the microsomal reaction support the hypothesis that the .alpha.-nitrosamino radical is a common intermediate in enzymatic denitrosation versus dealkylation of NDMA. The shift from .apprx. 85% dealkylation in the microsomal metabolism to 100% denitrosation in the Fenton reaction demonstrates that the two pathways are separable and suggests that it might be possible to reduce the risk of exposure to NDMA if a means can be found to protect metabolically produced .alpha.-nitrosamino radicals from further oxidation and other activating reactions in vivo, forcing them to decompose unimolecularly along the denitrosation pathway.