Mechanisms potentially responsible for activation and detoxication of carcinogenic N-nitroso compounds in the human body are under intense from the investigation. In our continuing search for ways of protecting animals deleterious effects of N-nitrosodimethylamine (NDMA) by shunting its metabolism away from the activating demethylation pathway to detoxicating routes, a new metabolite has been discovered in the bile of isolated perfused rat livers. Despite the fact that N-nitrosoethylmethylamine (NEMA) undergoes an organotropic shift in its tumorigenicity from almost exclusivity for liver to an additional esophageal involvement when the beta-methyl group is deuterated, in vitro work with rat liver microsomes as well as in vivo toxicokinetic studies revealed no differences in kinetic constants, bioavailability or other relevant parameters between the deuterated and normal substrates, suggesting that localized tissue factors in the esophagus may be the important determinants of tumor formation. The biomimetic conversion of NDMA to methylamine according to the oxidative denitrosation pathway effected by the Fenton reaction has been shown to proceed with no detectable involvement of the free hydroxyl radical, the potent oxidant usually assumed to dominate Fenton reactivity; this suggests that iron-oxo species akin to those involved in cytochrome P-450 metabolism may be responsible for NDMA degradation in this nonenzymatic model system.
