Microsomal denitrosation

Keefer LK, Anjo T, Wade D, et al. Concurrent generation of methylamine and nitrite during denitrosation of N-nitrosodimethylamine by rat liver microsomes. Cancer Res 1987 47(2) 447-452. 

Absorption, Distribution, Metabolism, Excretion. Examination of Section 2.6 clearly indicates that oral administration of NDMA has been the preferred route for studying its absorption, distribution, metabolism and excretion. This is not surprising since oral administration is easier to monitor when compared to other routes. The oral route seems to be the most pertinent to study since humans are most likely to be exposed to nitrosamines orally. Toxicokinetic data with regard to dermal and inhalation exposure of NDMA are clearly lacking. Furthermore, dermal and inhalation exposures may lead to different metabolic pathways and patterns of distribution and excretion, which could account for differences in the degree of toxicity exhibited by different routes of exposure. The metabolism of NDMA in isolated microsomal preparations seems to be well understood, but studies with cultured human cells could provide additional useful information. However, exploration of the denitrosation mechanism as an alternative to a-hydroxylation requires more attention. Determination of the urinary excretion of NDMA in control human volunteers and in individuals known to consume foods with high contents of nitrosamines could provide information concerning absorption and excretion of the xenobiotic. 

DMNA can be degraded chemical or microbial processes or microsomal P-450 in liver microsomes. In all cases, the decomposition is either by denitrosation or demethylation (Figure 2). Denitrosation, whidi produces nitrite, can occur by both chemical and microbial reactions, while demethylation occurs by microbial and microsomal reactions. 

A large body of information regarding metabolism of DMNA by mammalian cells is documented. Mixed-function cytochrome P-460 isozymes (MFO) in mammalian liver microsomes are involved in the metabolism of DMNA [1,6,78]. The same cytochrome P-450 isozymes are reported to be involved in both nitrite formation (denitrosation) and a-hydroxylation (demethylation) of nitrosamines [79-81]. 

Heur et al. [86] studied the Fenton degradation as a nonenzymic model for microsomal denitrosation of DMNA. 

There are two pathways of degradation of DMNA by microbial enzymes and by microsomal P-450. One is denitrosation and the other demethylation. Denitrosation is a mflin microbial process for removal of DMNA from the environment, although its degradation through demethylation also takes place by a methanotroph. The reaction catalyzed by microsomal P-450 can couple with the methylation of DNA, a central paradigm for initiation of carcinogenesis. 

Hydroxylation of NNN has been observed in vitro the rates of formation of 4 and 5 are apparently much lower than those of a-hydroxylation 186). Microsomal N-oxidation of NNN yields NNN-l-A -oxide (6) as a major in vitro metabolite. Myosmine (8) is formed from NNN by denitrosation and oxidation, or by a-hydroxylation 71). The major metabolic pathways for NNN, catalyzed... 

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