The Fenton degradation as a nonenzymatic model for microsomal denitrosation of N-nitrosodimethylamine.
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 degrees 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Heur
Y H
YH
Chemistry Section, National Cancer Institute, Frederick Cancer Research Facility, Maryland 21701.
Streeter
A J
AJ
Nims
R W
RW
Keefer
L K
LK
D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000378:metabolism*; D007097:Imines / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008861:Microsomes / Q000378:metabolism*; D008954:Models, Biological; D009603:Nitroso Compounds / Q000378:metabolism*
D007097:Imines; D009603:Nitroso Compounds; D003577:Cytochrome P-450 Enzyme System; D004128:Dimethylnitrosamine