Nitroso mutagens

Several new facets of the chemical and physical behavior of mutagens isolated from food and pyrolysates have been noted recently. Trp-P-1, Trp-P-2, and Glu-P-1 are rapidly deaminated upon incubation with nitrite at acid pH (54). At pH 1.6, in 50 yM nitrite, the half lifetime of Trp-P-1 and Trp-P-2 is approximately 100 min, but less than 5 min for Glu-P-1. AdC is also deaminated in 1 mM sodium nitrite at pH less than four with the difference that longer incubation, for 1.5 h, leads to the formation of a directly mutagenic nitroso derivative (55). These reaction conditions approach those in the stomach (pH 1-2, 0-10 yM nitrite), but careful kinetic studies in vivo will be required... 

We have proposed that gastric cancer may be the end result of a series of mutations (or similar cell transformations) begun many years before cancer becomes clinically apparent. The mutagens could be nitroso compounds synthesized situ from nitrite and naturally-occurring nitrogen-containing compounds. 

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. 

Nelson, J., E.A. MacKinnon, H.F. Mower, and L. Wong. 1981. Mutagenicity of V-nitroso derivatives of carbofuran and its toxic metabolites. Jour. Toxicol. Environ. Health 7 519-531. 

Nitroso-/V,/V-diniclhylanilinc has been reported to be bactericidal and mutagenic to Salmonella typhimurium TA 100 tester strains. In addition, this compound has proved to... 

C-nitroso compounds Combustion products, atmospheric Mutagenic and carcinogenic... 

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. 

The relatively acidic thiol on serum albumin forms a fairly stable S-nitroso adduct with nitric oxide, which may serve to preserve and carry NO throughout the circulatory system [162,163]. Bacterial toxins released in toxic-shock syndrome induce excessive NO-synthase activity in macrophages. The resulting arterial expansion may induce the cardiovascular collapse associated with toxic shock syndrome [164]. Nitrous acid reacts with DNA to form dG-N2-dG interstrand crosslinks at the sequence 5 CG [165]. NO can also deaminate cytidine [166] and deoxyguanosine [167] and so may function as a mutagen. The rate law for NO reacting with O2 has been measured electrochemically as [168] ... 

HechL S.S., Lijinsky, W., Kovatch, R.M., Chung, F.-L. Saavedra, J.E. (1989) Comparative tumorigenicity of A-nitroso-2-hydroxymorpholine, A-nitrosodiethanolamine and N-nitrosomorpholine in A/J mice and F344 rats. Carcinogenesis, 10, 1475-1477 Heim, L, Eisenbrand, G Zankl, H. (1989) Increased mutagenicity of A-nitrosodiethanol-amine in human lymphocyte cultures after activation by alcohol dehydrogenase. J. Cancer Res. din. Oncol, 115, 445 48... 

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