Hydroxylamines carcinogenicity

Other cases are described in Section 13.5 under the heading Lethal examples . Thus fluoroacetic acid is transformed to fluorocitric acid which blocks the enzyme aconitase. Several amines, such as benzidine and 2-aminonaph-thalene are converted to carcinogenic hydroxylamines and polycyclic hydrocarbons such as benzopyrene are converted to carcinogenic epoxides. The liver converts carbon tetrachloride to a free radical which causes liver necrosis (Slater, 1966). 

We now illustrate the opposite case where the intermediate is in fact a highly undesirable substance, as it presents a health, or even explosion, hazard. The hydrogenation of aromatic nitro compounds, such as the one shown in Fig. 2.6, is industrially important for the production of dyes, whiteners, agrochemicals and pharmaceuticals. The reaction occurs in the presence of a platinum catalyst and proceeds via intermediates, among which the hydroxylamine (-NHOH) species is particularly hazardous, as it is both carcinogenic and explosive. Unfortunately, standard platinum catalysts give rise to high levels of this undesired intermediate. 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

It is also useful to compare the bioactivation of aminobiphenyl and sulfamethoxazole. Aminobiphenyl is a carcinogen found in cigarette smoke. Its bioactivation is similar to that of N-acctylaminolluorcnc in which the first step is oxidation to form a hydroxylamine. The... 

There has been considerable interest in the chemistry of hydroxylamines, since it is believed52 that the carcinogenicity of some arylamines results from the formation of the TV-hydroxy species, which in turn generate nitrenium ions that react in a conventional electrophilic sense with nucleic acids. 

Carcinogenicity of hydroxylamine and its salts has not been demonstrated. Several studies have shown a decreased incidence of spontaneous mammary tumors in mice exposed to the sulfate and hydrochloride. There was some indication of an increase in the incidence of spontaneous mammary tumors when the sulfate was administered to older animals whose mammary glands were already well developed. 

Cytochrome fcs/NADH cytochrome b reductase (human) Reductive detoxification of substituted hydroxylamine carcinogens (K = 200-400 p.M) 27-29, 50... 

Nitration opens up another pathway to metabolic activation. Nitro-PAHs are wide-spread environmental pollutants that are mutagenic and carcinogenic. Metabolism of nitro-PAHs could occur via nitro-activation (reduction to hydroxylamine, eventually leading to nitrenes that can bind to nucleotides) and/or by ring oxidation and formation of DEs. ... 

An important example is the reduction of nitroquinoline N-oxide. This proceeds via the hydroxylamine, which is an extremely carcinogenic metabolite, probably the ultimate carcinogen (Fig. 4.40). 

A similar example is 2,6 dinitrotoluene where reduction in rats of a nitro group to a hydroxylamine occurs, which yields a liver carcinogen (see chap. 5). 

There is some evidence that the form of the chemical carcinogen that ultimately reacts with cellular macromolecules must contain a reactive electrophilic center, that is. an electron-deficient atom that can attack the numerous electron-rich centers in polynucleotides and proteins. As examples, significant electrophilic centers include free radicals, carbonium ions, epoxides, the nitrogen in esters of hydroxylamines and hydroxamic acids, and some metal cations. It is believed that carcinogens, which in themselves are not electrophiles, are metabolized to electrophilic derivatives that then become the ultimate" carcinogens. 

Metabolism, Mutagenicity and Carcinogenicity (Refs 14, 33, 34, 39, 46 48). A number of metabolities of TNT were reported in the literature prior to 1974. These were apparently formed by the reduction of nitro groups or by oxidation of the methyl group, and possibly by condensation of hydroxylamine groups produced by reduction (Table 1). Moreover, an unidentified glucuronide was claimed as a major metabolite and was presumed to involve the... 

N-Oxidation. (V-oxidation can occur in a number of ways, including hydroxylamine formation, oxime formation, and N-oxide formation, although the latter is primarily dependent on the FMO enzyme. Hydroxylamine formation occurs with a number of amines such as aniline and many of its substituted derivatives. In the case of 2-acetylaminofluorene the product is a potent carcinogen, and thus the reaction is an activation reaction (Figure 7.6). 

N,0-Acyltransferase. The /V-acyl transferase enzyme is believed to be involved in the carcinogenicity of arylamines. These compounds are first V-oxidized, and then, in species capable of their A-acetylation, acetylated to arylhydroxamic acids. The effect of N, O-transacetylation is shown in Figure 7.22. The A/-acyl group of the hydroxamic acid is first removed and is then transferred, either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylaminc. These compounds are highly reactive in the formation of adducts with both proteins and nucleic acids, and N, O -acy I Iransfcrasc, added to the medium in the Ames test, increases the mutagenicity of compounds such as A-hydroxy-2-acetylaminofluorine. 

The most studied kinds of explosives are nitroaromatic explosives and their metabolites. Therefore, the emphasis of this review is on properties of nitroaromatic explosives, rather than propellants, pyrotechnics, or munitions, and their interactions with soils. Nitroaromatic explosives are toxic, and their environmental transformation products, including arylamines, arylhydroxyl-amines, and condensed products such azoxy- and azo-compounds, are equally or more toxic than the parent nitroaromatic [3]. Aromatic amines and hydroxylamines are implicated as carcinogenic intermediates as a result of nitrenium ions formed by enzymatic oxidation [4], Aromatic nitro compounds... 

Hydroxylation may also take place at nitrogens, resulting in hydroxylamines (e.g., acetaminophen). Benzene, polycyclic aromatic compounds, (e.g., benzopyrene), and unsaturated cyclic carbohydrates can be converted by monooxygenases to epoxides, highly reactive electrophiles that are hepa-totoxic and possibly carcinogenic. 

OSHA PEL TWA 0.5 mg(Ba)/m3 ACGIH TLV TWA 0.5 mg(Ba)/m3 Not Classifiable as a Human Carcinogen DFG MAK 0.5 mg(Ba)/m3 DOT CLASSIFICATION 6.1 Label KEEP AWAY FROM FOOD SAFETY PROFILE A poison via subcutaneous route. See also BARIUM COMPOUNDS (soluble). Combustible by spontaneous chemical reaction produces heat on contact with water or steam. Reacts with H2O, Ba(OH)2. Incompatible with H2S, hydroxylamine, N2O4, triuranium octaoxide, SO3. 

Amines are readily oxidized by CYP enzymes. Aliphatic amines are converted to hydroxylamines as shown in Scheme 11.19 compared to the parent amines, hydroxylamines are less basic. Aromatic amines are converted to products that are more toxic than their parent amines are, frequently producing hypersensitivity or carcinogenicity. 

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