Nitrosamine enzymatic reactions

Gold and Linder (17) studied the esterase catalyzed hydrolysis of A-(-)-acetoxymethyl-(l-phenylethyl)nitrosamine. They found that the stereochemistry of 1-phenylethanol produced in the reaction was the same as that observed in the base catalyzed hydrolysis of the nitrosamine and also of N-(l-phenylethyl)nitrosocarbamate. These results indicated that the same diazotate was produced in all three reactions. The fact that no irreversible inhibition of the enzymatic hydrolysis of the nitrosamine was observed, while extensive irreversible inhibition was obtained with the nitrosocarba-mate, led these workers to conclude that the a-hydroxynitro-samine produced by the hydrolysis had sufficient stability to diffuse away from the active site of the enzyme. 

Most of the C-diazeniumdiolates are not NO donors since they hydrolyze to produce nitrous oxide directly [174]. However, it has been found that carefully selected compounds can serve as NO donors under physiological conditions via alternative reaction pathways. Many cupferron analogs release NO via enzymatic oxidation [175] as do Oi-alkylated diazeniumdiolates [176]. Several novel types of NO-releasing N-hydroxy-N-nitrosamines have been prepared. These new preparative methods have been described in earlier sections. The precursors are enamines (Scheme 3.10), phenolates (Scheme 3.12), nitriles, and N-hydroxyguanidines (Scheme 3.9). 

As has been stated above, the activation of nitrosamines is an enzymatic process. We have made some progress toward the understanding of the mechanism of this important reaction. The study is rendered extraordinarily difficult because there are apparently a number of enzymes involved in the metabolism and the principal ones seem to be membrane bound. This makes the purification of the individual enzymes very hard. Nevertheless, considerable information on the mechanism of the enzymatic processes can be obtained, even with the unpurified preparations. 

The formation of nitrosamines in the reaction of amines with nitrites under acidic conditions in the stomach can be considered as nonenzymatic activation of amines present in food. Nitrosamines undergo further metabolism, catalyzed enzymatically by cytochrome P450, involving hydroxylation (Anon., 1993). 

The A-nitrosamines develop carcinogenesis in different animal species. These compounds need a metabolic activation to become mutagens. The metabolic activation reaction of the A-nitrosamines is catalyzed for members of the enzymatic family P450. More precisely, the isoenzyme P450 2E1 (CYP2E1) is responsible for the metabolism of most A-nitrosamines. 

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