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IARC Monographs on the Evaluation of... 1996
Review
Topics: Animals; Carcinogenicity Tests; Carcinogens; Humans; Tetranitromethane
PubMed: 9097115
DOI: No ID Found -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Carcinogens; Chemical Warfare Agents; Environmental Exposure; Explosive Agents; Humans; Neoplasms; Tetranitromethane
PubMed: 21863104
DOI: No ID Found -
Frontiers in Allergy 2023Protein modifications such as oligomerization and tyrosine nitration alter the immune response to allergens and may contribute to the increasing prevalence of allergic... (Review)
Review
Protein modifications such as oligomerization and tyrosine nitration alter the immune response to allergens and may contribute to the increasing prevalence of allergic diseases. In this mini-review, we summarize and discuss relevant findings for the major birch and grass pollen allergens Bet v 1 and Phl p 5 modified with tetranitromethane (laboratory studies), peroxynitrite (physiological processes), and ozone and nitrogen dioxide (environmental conditions). We focus on tyrosine nitration and the formation of protein dimers and higher oligomers via dityrosine cross-linking and the immunological effects studied.
PubMed: 38125293
DOI: 10.3389/falgy.2023.1303943 -
Biochemistry and Biophysics Reports Jul 2023Lactoferrin (LF) is a multifunctional antimicrobial, anti-inflammatory, and antioxidant protein that occurs naturally in mammals, most notably in exocrine gland tissues...
Lactoferrin (LF) is a multifunctional antimicrobial, anti-inflammatory, and antioxidant protein that occurs naturally in mammals, most notably in exocrine gland tissues and fluids, such as in the eye. Nitrosative stress can promote changes to tyrosine and other amino acid residues of the protein, which also reduces the activity of LF. l-ergothioneine (ET) is a potent anti-inflammatory antioxidant present in the eye and other tissues through nutrition or supplementation and that may play a role in the prevention or treatment of a variety of diseases. Here we investigated the ability of ET to reduce 3-nitrotyrosine (NTyr) formation using two separate substrates, with the goal of determining whether ET can protect the antibacterial function of LF and other proteins when exposed separately to peroxynitrite and tetranitromethane as nitrating reagents. Native human LF was used as a simple protein substrate, and lamb corneal lysate was chosen as one example of mammalian tissue with a more complex mixture of proteins and other biomolecules. Nitration was monitored by absorbance and fluorescence spectroscopy as well as sandwich (nitrated LF) and direct NTyr (corneal lysate) enzyme-linked immunosorbent assays (ELISAs). We found that pretreatment with ET reduced chemical modification of both native LF and corneal lysate samples and loss of antibacterial LF function due to exposure to the nitrating reagents. These initial results suggest that ET, raised to sufficiently elevated levels, could be tailored as a therapeutic agent to reduce effects of nitrosative stress on LF and in turn sustain the protein activity.
PubMed: 36942322
DOI: 10.1016/j.bbrep.2023.101447 -
Molecules (Basel, Switzerland) May 2022The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective...
The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target-ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains.
Topics: Amines; Antiviral Agents; Cyclooctanes; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Structure-Activity Relationship
PubMed: 35684482
DOI: 10.3390/molecules27113546 -
Urinary markers for measuring exposure to endogenous and exogenous alkylating agents and precursors.Environmental Health Perspectives Mar 1993Noninvasive methodologies for measuring carcinogen exposure in humans, based on the use of urinary markers, are being developed and validated for use in molecular... (Review)
Review
Noninvasive methodologies for measuring carcinogen exposure in humans, based on the use of urinary markers, are being developed and validated for use in molecular epidemiological studies. A range of 3-alkyladenines can be determined in urine samples by an immunoaffinity purification-GC/MS approach [3-methyladenine, 3-ethyladenine, 3-(2-hydroxyethyl)adenine, and 3-benzyladenine]. Using this method, recent results in human subjects suggest that urinary 3-alkyladenines are potentially useful markers of alkylating agent exposure, particularly where the backgrounds of such adducts are much lower than 3-methyladenine. Urinary excretion of S-benzylmercapturic acid has been studied in experimental animals as a marker of exposure to benzylating agents such as N-nitroso-methylbenzylamine. 3-Nitrotyrosine (NTyr) is formed in vivo in tissue or blood proteins after exposure to nitrosating and/or nitrating agents such as tetranitromethane. After turnover of proteins, NTyr is released and excreted in urine as metabolites 3-nitro-4-hydroxy-phenylacetic acid and 3-nitro-4-hydroxyphenylacetic acid, which are determined by GC with a thermal energy analyzer. The sensitivity and specificity, combined with ease of use, of these noninvasive biomonitoring approaches means that they may be readily incorporated into molecular epidemiological studies in which exposure to nitrosating and alkylating agents may be important risk factors.
Topics: Acetylcysteine; Adenine; Alkylating Agents; Animals; Biomarkers; DNA Damage; Environmental Monitoring; Humans; Tyrosine
PubMed: 8319651
DOI: 10.1289/ehp.939933 -
The Biochemical Journal Jan 19711. Tyrosine was treated with tetranitromethane. 2. Approx. 10% of the tyrosine was converted into 3-nitrotyrosine. 3. Three fluorescent compounds were also formed. They...
1. Tyrosine was treated with tetranitromethane. 2. Approx. 10% of the tyrosine was converted into 3-nitrotyrosine. 3. Three fluorescent compounds were also formed. They appear to be a dimer, trimer and tetramer in which tyrosine units are linked by biphenyl bonds. 4. The dimer and trimer have also been isolated from some proteins after treatment with tetranitromethane. 5. The yield of 3-nitrotyrosine from ovotransferrin after treatment with tetranitromethane was much smaller than the loss of tyrosine. 6. Several unidentified compounds were also formed by the reaction between tyrosine and tetranitromethane.
Topics: Electrophoresis; Fluorescence; Macromolecular Substances; Mass Spectrometry; Methane; Nitro Compounds; Polymers; Spectrum Analysis; Transferrin; Tyrosine; Ultraviolet Rays
PubMed: 5117027
DOI: 10.1042/bj1210203 -
Proceedings of the National Academy of... Mar 1978Electrophilic nitration of toluene and benzene was studied under various conditions with several nitrating systems. It was found that high orthopara regioselectivity is...
Electrophilic nitration of toluene and benzene was studied under various conditions with several nitrating systems. It was found that high orthopara regioselectivity is prevalent in all reactions and is independent of the reactivity of the nitrating agent. The methyl group of toluene is predominantly ortho-para directing under all reaction conditions. Steric factors are considered to be important but not the sole reason for the variation in the ortho/para ratio. The results reinforce our earlier views that, in electrophilic aromatic nitrations with reactive nitrating agents, substrate and positional selectivities are determined in two separate steps. The first step involves a pi-aromatic-NO(2) (+) ion complex or encounter pair, whereas the subsequent step is of arenium ion nature (separate for the ortho, meta, and para positions). The former determines substrate selectivity, whereas the latter determines regioselectivity. Thermal free radical nitration of benzene and toluene with tetranitromethane in sharp contrast gave nearly statistical product distributions.
PubMed: 16592503
DOI: 10.1073/pnas.75.3.1045 -
National Toxicology Program Technical... Mar 1990Tetranitromethane is a volatile contaminant formed during the manufacture of TNT and has been used as a rocket fuel and biochemical reagent. Toxicology and...
Tetranitromethane is a volatile contaminant formed during the manufacture of TNT and has been used as a rocket fuel and biochemical reagent. Toxicology and carcinogenesis studies were conducted in F344/N rats and B6C3F1 mice of each sex by whole body exposure to tetranitromethane vapor (greater than 99% pure), 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Additional groups of male mice were exposed to tetranitromethane for evaluation at 1 year. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Exposure concentrations ranged from 2 to 25 ppm for rats and from 2 to 50 ppm for mice. All rats exposed to 25 ppm and all mice exposed at the top concentration of 50 ppm died by day 2; reduced survival was seen in mice exposed to 25 ppm and in rats exposed to 10 ppm. Pulmonary edema in rats and inflammation of the lung in mice were seen in those animals in the 25- and 50-ppm exposure groups examined microscopically. Thirteen-Week Studies: Exposure concentrations ranged from 0.2 to 10 ppm for rats and mice. No exposure-related deaths occurred in rats. The final mean body weight of rats exposed to 10 ppm was 16% lower than that of controls for males and 6% lower for females. Exposure-related histologic effects included squamous metaplasia of the respiratory epithelium of the nasal mucosa and chronic inflammation of the lung. No deaths of mice could be clearly related to exposure to tetranitromethane. The final mean body weights of mice exposed to 5 or 10 ppm were 5% or 12% lower than that of controls for males and 9% or 12% lower for females. Exposure-related histologic effects in mice included inflammation and squamous metaplasia of the respiratory epithelium of the nasal mucosa and hyperplasia of the bronchiolar epithelium. Based on the incidences and severity of lesions in the respiratory at the higher concentrations used in the 13-week studies, exposure concentrations chosen for the 2-year studies were 0, 2, and 5 ppm for groups of 50 rats of each sex and 0, 0.5, and 2 ppm for groups of 50 mice of each sex. Additional groups of 6 or 10 male mice were exposed at concentrations of 0, 0.5, or 2 ppm for 1 year. Body Weights and Survival in the Two-Year Studies: Mean body weights of male and female rats exposed to 5 ppm were approximately 5%-15% lower than those of controls after week 70. Survival of rats at 104 weeks was as follows: male: control, 18/50; 2 ppm, 17/50; 5 ppm, 4/50; female: 25/50; 34/50; 15/50; survival of rats at the top concentration was reduced due to neoplasia. Mean body weights of exposed mice were variable and ranged as much as 10% below those of controls during the second year of the studies. Survival of exposed male mice at 104 weeks was significantly lower than that of controls due to neoplasia (control, 37/50; 0.5 ppm, 26/50; 2 ppm, 15/50). Survival of female mice was not significantly affected by exposure to tetranitromethane (31/50; 28/50; 24/50). Neoplastic and Nonneoplastic Effects in the Two-Year Studies: Effects of exposure to tetranitromethane were limited to the respiratory tract. Hyperplasia of the alveolar and bronchiolar epithelium was observed at increased incidences in exposed rats. The incidence of alveolar/bronchiolar adenomas and carcinomas were markedly increased in exposed male and female rats, with carcinomas (many of which metastasized to other sites) occurring in nearly all rats exposed to the top concentration of 5 ppm (adenomas or carcinomas-- male: control, 1/50; 2 ppm, 33/50; 5 ppm, 46/50; female: 0/50; 22/50; 50/50). Many of the rats exposed to 5 ppm also had squamous cell carcinomas of the lung (male: 0/50; 1/50; 19/50; female: 0/50; 1/50; 12/50). Hyperplasia of the respiratory epithelium and chronic inflammation of the nasal mucosa were observed at increased incidences in exposed male and female rats. Squamous metaplasia of the respiratory epithelium was increased in exposed male rats. No neoplasms of the nasal passage were seen. In exposed mice, hyperplasia of the alveolar and br were seen. In exposed mice, hyperplasia of the alveolar and bronchiolar epithelium was observed at increased incidences. Alveolar/bronchiolar neoplasms, primarily carcinomas (many of which metastasized to other sites), were increased in exposed male and female mice (male: control, 12/50; 0.5 ppm, 27/50; 2 ppm, 47/50; female: 4/49; 24/50; 49/50). Chronic inflammation of the nasal mucosa and hyperplasia and squamous metaplasia of the respiratory epithelium of the nasal cavity occurred at increased incidences in female mice exposed to 2 ppm. No primary neoplasms of the nasal passage were observed in mice. Oncogene Analysis: DNA from 14/19 rat and 4/4 mouse lung neoplasms caused morphologic transformation after transfection into cultured NIH/3T3 fibroblasts. The transforming gene from both rat and mouse lung neoplasms was determined by Southern blot analysis to be an activated K-ras oncogene. Further studies showed a GC-->AT transition in the second base of the 12th codon of the K-ras oncogene. Genetic Toxicology: Tetranitromethane was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation (S9); no mutagenic activity was observed in TA1537 with or without S9. Chromosomal aberrations were observed in CHO cells treated in vitro with tetranitromethane in the presence of S9. Sister chromatid exchanges were induced in CHO cells in the absence of S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of tetranitromethane for male and female F344/N rats and male and female B6C3F1 mice, based on increased incidences of alveolar/bronchiolar neoplasms in both species and squamous cell carcinomas of the lung in rats. Chronic inflammation of the nasal mucosa was related to exposure in rats and female mice, and hyperplasia and squamous metaplasia of the respiratory epithelium were increased in exposed male rats. Synonym: TNM
PubMed: 12637973
DOI: No ID Found -
Biochemistry and Biophysics Reports Jul 2022Tetranitromethane was used to selectively modify tyrosine residues of a humanized anti-cocaine mAb (h2E2), under development for the treatment of cocaine use disorders....
Tetranitromethane was used to selectively modify tyrosine residues of a humanized anti-cocaine mAb (h2E2), under development for the treatment of cocaine use disorders. The effect of mild tyrosine nitration on the affinity of cocaine and two high affinity cocaine metabolites, cocaethylene and benzoylecgonine, was assessed using differential scanning fluorimetry to measure ligand affinities via ligand-induced thermal stabilization of the mAb antigen binding region. Nitrated tyrosine residues were identified by mass spectral analysis of thermolysin peptides. One objective was to understand the binding affinity differences observed for these three ligands, which are not explained by the published crystal structure of the h2E2 mAb Fab fragment co-crystalized with benzoylecgonine, since the carboxylic acid of benzoylecgonine that is esterified to form cocaine and cocaethylene is not in contact with the mAb. Importantly, the binding affinity of the cocaine metabolite benzoylecgonine was not decreased by mild nitration, whereas the binding affinities of cocaine and cocaethylene were decreased about two-fold. These ligands differ only in the substituent attached to the carboxylate moiety of the compound, with benzoylecgonine having an unesterified carboxylate, and cocaine and cocaethylene having methyl and ethyl esters, respectively, at this position. The results are consistent with nitration of light chain tyrosine residue 34, resulting in a less favorable interaction with cocaine and cocaethylene carboxylate esters, while not affecting binding of benzoylecgonine. Thus, light chain Tyr34 residue may have molecular interactions with cocaine and cocaethylene not present for benzoylecgonine, leading to the observed affinity differences for these three ligands.
PubMed: 35600901
DOI: 10.1016/j.bbrep.2022.101278