Mutagenicity nitrosamines

When phenolics are added to nitrosation mixtures, C-nitroso derivatives could be formed. The question must be raised as to their genotoxic or carcinogenic properties. It would be an act of folly to use phenolics as inhibitors of mutagenic nitrosamines, nitrosamides or nitrosoalkylureas and, in the course of this process, create equally or even more active C-nitroso phenolics. Only scanty information is available on this issue. The mutagenicity of p-nitrosophenol is higher than that of phenol in the S, typhi-... 

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

It appears that considerable metabolism of nitrosamines takes place in the liver, from the finding that most of them are activated by rat liver microsomes to bacterial mutagens. However, relatively few nitrosamines induce liver tumors in rats. The most common target is the esophagus and a wide variety of nitrosamines induce tumors in this organ of rats, some only tumors of the esophagus, others tumors of other organs also. 

CARCINOGENIC NITROSAMINES NOT MUTAGENIC TO SALMONELLA WHEN ACTIVATED WITH RAT LIVER S9... 

The experiments with deuterium-labeled nitrosamines illustrate two important points. One is that oxidation of nitrosamines takes place at more than one position in the molecule, and the outcome of the balance of such competing reactions probably is the determinant of carcinogenic potency. The second is that the reason for the failure of carcinogenesis to be mirrored in many cases by the microsomally activated bacterial mutagenicity is that there can be several metabolic steps leading to formation of the proximate carcinogenic agent and not all of these need necessarily involve microsomal enzymes. ... 

This far into a nitrosamine symposium it should hardly be necessary to point out that nitrosamines are technically just one of a group of Ji-nitroso compounds that also includes nitros-amides, nitrosocarbamates, nitrosoureas, etc. Or that nitrosa-table pesticides encompass all the categories just mentioned and more. Or that many diverse pesticides, including herbicides, insecticides, and fungicides have been converted to Ji-nitroso derivatives in the laboratory (a recent review contained a 3-page, probably incomplete, compilation), or that some of the Ji-nitroso compounds thus synthesized were determined to be carcinogenic in test animals or mutagenic in various assays. 

N-Nitrosamines have been shown to be inhibitors of cysteine-containing enzymes. For example, dephostatin and other N-methyl-N-nitrosoanilines (1) were found to be inhibitors of the protein tyrosin phosphatases, papain and caspase [90,91]. Inhibition results from the S-nitrosation of the critical cysteine residues in the active sites of the enzymes by the nitrosamines. Compounds 6 and 7 have been found to inhibit thrombus formation in arterioles and venules of rats [92], while N-nitrosamide 9 exhibited vasodilation and mutagenicity as a result of NO release [93]. 

As detailed by Gatehouse and Tweats (1987), the nature and concentration of solvent may have a marked effect on the test result. Dimethysolphoxide is often used as the solvent of choice for hydrophibic compounds. However, there may be unforeseen effects, such as an increase in mutagenicity of some compounds, for example, / -phcnylenediamne (Burnett et al., 1982) or a decrease in mutagenicity of others, such as simple aliphatic nitrosamines (Yahagi et al., 1977). It is essential to... 

Bartsch, H., Camus, A.-M. and Malaveille, C. (1976). Comparative mutagenicity of N-nitrosamines in a semi-solid and in a liquid incubation system in the presence of rat or human tissue fractions. Mutation Res. 37 149-162. 

Many activations involve compounds which are used as pesticides. In the case of N-nitrosation, the precursors are secondary amines and nitrate. The former are common synthetic compounds and the latter is an anion found in nearly all solid and aqueous phases. The N-nitrosation of a secondary amine [R-NH-R ] occurs in the presence of nitrite formed microbiologically from nitrate. The product is an N-nitroso compound (i.e., a nitrosamine [RR -N-N=0]). The reason for concern with nitrosamines is their potency, at low concentrations, as carcinogens, teratogens, and mutagens. 

Figure 3. Proposed relationship between metabolic and chemically activated nitrosamines for producing an ultimate carcinogen or mutagen...

The chemical activation of dibenzylnitrosamine (VI), that is the chemical conversion to the a-acetoxy derivative, would give an intermediate which on hydrolysis would yield the benzylcar-bocation. Hius on the basis of the previous report (, ) the a-acetoxydibenzylnitrosamine (VII) should be a non-mutagenic, non-carcinogenic nitrosamine. 

The importance of the stereochemistry of the nitrosamine function in the mutagenicity and carcinogenicity of these compounds has not been demonstrated and yet there is considerable indirect evidence that such a stereochemical dependence may be important. It is evident that the metabolism can be related to a stereochemical factor for unsyrametrical nitrosamines. These, of course, give either of two oxygenated metabolites, and there is evidence that only one of these is mutagenic in some cases (23, 24). Thus, the metabolism may be at least regiospecific, if not stereospecific, relative to the nitrosamine function. 

Sinskey, A.J. and Tannenbaum, S.R., "Chemical Activation of Nitrosamines into Mutagenic Agents", Tetrahedron Letters, 1976, 333-336. 

Yahagi, T., M. Nagao, Y. Seino, T. Matshushima, and T. Sugimura, Mutagenicities of jV-Nitrosamines on Salmonella, Mutat. Res.,... 

Dahl, A.R. (1985) Mutagenicity of some dialkylnitrosamines, cyclic nitrosamines and N,N-di-ethanolnitrosamine in Salmonella typhimurium with rat and rabbit nasal, lung and liver S9 homogenates. Mw/at. Res., 158,141-147... 

Kerklaan, P, Mohn, G. Bouter, S. (1981) Comparison of the mutagenic activity of dialkyl-nitrosamines in animal-mediated and in vitro assays using an Escherichia coli indicator. Carcinogenesis, 2, 909-914... 

Lethco, E.J., Wallace, W.C. Brouwer, E. (1982) The fate of V-nitrosodiethanolamine after oral and tropical administration to rats. Food chem. Toxicol, 20, 401 06 Lijinsky, W. Andrews, A.W (1983) The superiority of hamster liver microsomal fraction for activating nitrosamines to mutagens in Salmonella typhimurium. Mutat. Res., Ill, 135-144 Lijinsky, W. Kovatch, R. (1985) Induction of liver tumoms in rats by nitrosodiethanolamine at low doses. Carcinogenesis, 6, 1679-1681... 

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