Mechanisms potentially responsible for formation, activation, and detoxication of carcinogenic N-nitroso compounds in the human body are under intense investigation. Further evidence supporting the involvement of the alpha-nitrosamino radical as the critical intermediate in both activation and inactivation of the potent carcinogen, N-nitrosodimethylamine (NDMA), has been obtained by designing a non-enzymatic model for the latter process. The Fenton degradation of NDMA produced formaldehyde, methylamine, and nitrate, each equimolar to nitrosamine consumed, suggesting that the presumably inactivating metabolic pathway of similar course (denitrosation) could be elevated from its normally minor role (- 15%) in the overall metabolism to become the major or even exclusive fate of NDMA if a means can be found to protect the initial radical from further oxidation by cytochrome P-450 and other scavenging reactions. A non-enzymatic reaction that parallels the macrophage-induced oxidative activation of reduced nitrogen species to ultimate nitrosating agents in several key respects has also been devised; oxidation of coordinated ammonia in the presence of secondary amines produced novel complexes of the carcinogenic N-nitroso derivatives. The dissociation constant for N-protonated NDMA in aqueous acid has been estimated and a novel complex of an O-protonated nitrosamine has been characterized in which each acidic proton is strongly, symmetrically, and collinearly hydrogen-bonded with two nitrosamine molecules rather than one in a structure reminiscent of the bifluoride (F-H-F-) and bihydroxide (HO-H-OH-) ions. The clearance of N-nitrosomethyl(2- hydroxyethyl)amine proved faster in female rats than in males, suggesting a pharmacokinetic origin for the greater susceptibility of females to its hepatocarcinogenic action.
