Methimazole, an Effective Neutralizing Agent of the Sulfur Mustard Derivative 2-Chloroethyl Ethyl Sulfide
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ABSTRACT:
SUBMITTER: Armoo A
PROVIDER: S-EPMC10591301 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:Sulfur mustard (bis-(2-chloroethyl)sulfide) is a well-known chemical warfare agent that induces debilitating cutaneous toxicity in exposed individuals. It is also known to be carcinogenic and mutagenic because of its ability to damage DNA via electrophilic attack. We previously showed that a nucleophilic scavenger, 2,6-dithiopurine (DTP), reacts chemically with several electrophilic carcinogens, blocking DNA damage in vitro and in vivo and abolishing tumor formation in a two-stage mouse skin carcinogenesis model. To assess the potential of DTP as an antagonist of sulfur mustard, we have utilized monofunctional chemical analogues of sulfur mustard, 2-chloroethyl ethyl sulfide (CEES) and 2-chloroethyl methyl sulfide (CEMS), to induce toxicity and mutagenesis in a cell line, NCTC2544, derived from a human skin tumor. We show that DTP blocks cytotoxicity in CEMS- and CEES-treated cells when present at approximately equimolar concentration. A related thiopurine, 9-methyl-6-mercaptopurine, is similarly effective. Correlated with this, we find that DTP is transported into these cells and that adducts between DTP and CEES are found intracellularly. Using a shuttle vector-based mutagenesis system, which allows enumeration of mutations induced in the skin cells by a blue/white colony screen, we find that DTP completely abolishes the mutagenesis induced by CEMS and CEES in human cells.
| S-EPMC2838951 | biostudies-literature
Project description:The inhalation of sulfur mustard (SM) causes substantial deposition in the nasal region. However, specific injury has not been characterized. 2-chloroethyl ethyl sulfide (CEES) is an SM analogue used to model injury and screen potential therapeutics. After the inhalation of CEES, damage to the olfactory epithelium (OE) was extensive. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were present by 4 hours, and maximal at 18-72 hours. Cleaved caspase 3 immunohistochemistry (IHC) was maximal at 18 hours after the inhalation of 5% CEES. Olfactory marker protein (OMP)-positive olfactory neurons were markedly decreased at 18 hours. IHC-positive cells for 3-nitrotyrosine (3-NT) within epithelium were elevated by 8 hours, waning by 18 hours, and absent by 72 hours. AEOL 10150, a catalytic manganoporphyrin antioxidant, administered both subcutaneously (5 mg/kg) and intranasally (50 μM, "combined treatment"), decreased OE injury. CEES-induced increases in markers of cell death were decreased by combined treatment involving AEOL 10150. CEES-induced changes in OMP and 3-NT immunostaining were markedly improved by combined treatment involving AEOL 10150. The selective inducible nitric oxide synthase inhibitor 1400W (5 mg/kg, subcutaneous), administered 1 hour after inhalation and thereafter every 4 hours (five doses), also reduced OE damage with improved OMP and 3-NT staining. Taken together, these data indicate that reactive oxygen and nitrogen species are important mediators in CEES-induced nasal injury.
| S-EPMC3175559 | biostudies-literature
Project description:2-Choloroethyl Ethyl Sulfide (CEES) exposure causes inflammatory lung diseases, including acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. This may be associated with oxidative stress, which has been implicated in the desensitization of beta-adrenergic receptors (beta-ARs). The objective of this study was to investigate whether lung injury induced by intratracheal CEES exposure (2 mg/kg body weight) causes desensitization of beta-ARs. The animals were sacrificed after 7 days and lungs were removed. Lung injury was established by measuring the leakage of iodinated-bovine serum albumin ([(125)I]-BSA) into lung tissue. Receptor-binding characteristics were determined by measuring the binding of [(3)H] dihydroalprenolol ([(3)H] DHA) (0.5-24 nM) to membrane fraction in the presence and absence of DLDL-propranolol (10 micro M). Both high- and low-affinity beta-ARs were identified in the lung. Binding capacity was significantly higher in low-affinity site in both control and experimental groups. Although CEES exposure did not change K(D) and B(max) at the high-affinity site, it significantly decreased both K(D) and B(max) at low affinity sites. A 20% decrease in beta(2)-AR mRNA level and a 60% decrease in membrane protein levels were observed in the experimental group. Furthermore, there was significantly less stimulation of adenylate cyclase activity by both cholera toxin and isoproterenol in the experimental group in comparison to the control group. Treatment of lungs with 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase (PDE) could not abolish the difference between the control group and the experimental group on the stimulation of the adenylate cyclase activity. Thus, our study indicates that CEES-induced lung injury is associated with desensitization of beta(2)-AR.
| S-EPMC2863039 | biostudies-literature
Project description:By combining the anionic salt meso-tetra(4-carboxyphenyl)porphyrin (TCPP4-) and the Keggin polyoxometalate cation cluster [Al13O4(OH)24(H2O)12]7+ via a simple ion-exchange method, a hybrid (C48H26N4O8)[Al13O4(OH)24(H2O)12]2(OH)10·18H2O (Al13-TCPP) was prepared and thoroughly characterized as a prototype of polyoxometalate-porphyrin hybrids for the photocatalytic degradation of the mustard gas simulant 2-chloroethyl ethyl sulfide (CEES). The experimental results showed that the catalytic degradation rate of CEES in the presence of Al13-TCPP reached 96.16 and 99.01% in 180 and 90 min in methanol and methanol-water solvent mixture (v/v = 1 : 1), respectively. The reaction followed first-order reaction kinetics, and the half-life and kinetic constant in methanol and solvent mixture were 39.8 min, -0.017 min-1 and 14.7 min, -0.047 min-1. Mechanism analysis indicated that under visible light irradiation in air, CEES was degraded through a combination of oxidation and alcoholysis/hydrolysis in methanol and the methanol-water solvent mixture. The superoxide radical (O2˙-) and singlet molecular oxygen (1O2) generated by Al13-TCPP selectively oxidized CEES into a non-toxic sulfoxide. The singlet oxygen capture experiments showed that Al13-TCPP (Φ = 0.236) had a higher quantum yield of singlet oxygen generation than H4TCPP (Φ = 0.135) under visible light irradiation in air. The material Al13-TCPP has good reusability, and the degradation rate of CEES can still reach 98.37% after being recycled five times.
| S-EPMC9277536 | biostudies-literature
Project description:A microhydration study of sulfur mustard (SM) was carried out using M06-2X, B3LYP, B3LYP-D3, and MP2 levels of theory with the 6-311++G(2d,2p) basis set. The changes in energetics, structural parameters and vibrational wavenumbers following the addition of up to three discrete water molecules to SM were analyzed. We observed slight changes in the geometry of SM upon microhydration. The stability of hydrated clusters is due to weak C-H···O-H hydrogen bonds. The free energy change for the formation of the clusters is positive at room temperature and becomes exergonic when the temperature decreases. The infrared stretchings of C-Cl of SM and O-H of water are redshifted upon the addition of water molecules. The findings from this work add to the literature of hydrated SM and can be useful in its detection and subsequent destruction.
| S-EPMC7003240 | biostudies-literature
Project description:Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2), and sulfur mustard are potent vesicants that modify and disrupt cellular macromolecules including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia mutated- and Rad3-related (ATR) as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between the HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1-20 μM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (Ser1981), Chk2 (Thr68), H2AX (Ser139), and p53 (Ser15). Activation of DNA damage signaling was most pronounced in S-phase cells followed by G2/M-phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PK inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PK signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.
| S-EPMC6626495 | biostudies-literature
Project description:Sulfur mustard (SM) is a chemical warfare agent and a terrorism choice that targets various organs and tissues, especially lung tissues. Its toxic effects are tightly associated with oxidative stress. The signaling molecule hydrogen sulfide (H2S) protects the lungs against oxidative stress and activates the NF-E2 p45-related factor 2 (Nrf2) pathway. Here, we sought to establish whether endogenous H2S plays a role in SM induced lesion in mouse lungs and lung cells and whether endogenous H2S plays the role through Nrf2 pathway to protect against SM-induced oxidative damage. Furthermore, we also explored whether activation of Nrf2 by H2S involves sulfhydration of Kelch-like ECH-associated protein-1 (Keap1). Using a mouse model of SM-induced lung injury, we demonstrated that SM-induced attenuation of the sulfide concentration was prevented by NaHS. Concomitantly, NaHS attenuates SM-induced oxidative stress. We also found that H2S enhanced Nrf2 nuclear translocation, and stimulated expression of Nrf2-targeted downstream protein and mRNA levels. Incubation of the lung cells with NaHS decreased SM-induced ROS production. Furthermore, we also found that H2S S-sulfhydrated Keap1, which induced Nrf2 dissociation from Keap1, and enhanced Nrf2 nuclear translocation. Our data indicate that H2S is a critical, however, being long neglected signal molecule in SM-induced lung injury.
| S-EPMC5572733 | biostudies-literature
Project description:Most of the copper sulfide synthetic approaches developed until now are still facing issues in their procedure, such as long synthesis duration, high energetic consumption, and high implementation costs. This publication reports a facile and sustainable approach for synthesizing copper sulfides on a large scale. In particular, an industrial by-product of sulfur waste was used as a sulfurizing agent for copper sulfide synthesis in a water medium. The reaction was performed in the hydrothermal environment by following a novel proposed mechanism of copper sulfide formation. The investigation of morphological and optical properties revealed that the target products obtained by using waste possess the resembling properties as the ones synthesized from the most conventional sulfurizing agent. Since the determined band gap of synthesis products varied from 1.72 to 1.81 eV, the photocatalytic properties, triggered under visible light irradiation, were also investigated by degrading the methylene blue as a model pollutant. Importantly, the degradation efficiency of the copper sulfide synthesized from sulfur waste was equivalent to a sample obtained from a reference sulfurizing agent since the value for both samples was 96% in 180 min. This very simple synthetic approach opens up a new way for large-scale sustainable production of visible-light-driven photocatalysts for water purification from organic pollutants.
| S-EPMC9369765 | biostudies-literature
Project description:Tris(2-chloroethyl)phosphates (TCEP) is a widely used flame retardant in the US. It has recently been identified as one of the most frequently detected contaminants in US streams. This contaminant is of toxicological concern in sensitive coastal ecosystems such as estuaries and salt marshes. It is likely that reactions with reduced sulfur species such as polysulfides (S(n)(2-)), bisulfide (HS(-)), and thiophenolate (PhS(-)) present in anoxic subregions of coastal water bodies could have a significant impact on rates of removal of such a contaminant. The kinetics of reaction of reduced sulfur species with tris(2-chloroethyl)phosphate have been determined in well-defined aqueous solutions under anoxic conditions. Reactions were monitored at varying concentrations of reduced sulfur species to obtain the second-order rate constants from the observed pseudo-first-order rate constants. The determined second-order rate constant for the reaction of TCEP with polysulfide at 25°C is 5.0 (±1.4)×10(-4) M(-1) s(-1), with thiophenolate at 50°C is 34 (±2)×10(-4) M(-1) s(-1) and with bisulfide at 50°C is 0.9×10(-4) M(-1) s(-1), respectively. In addition, the degradation products of hydrolysis and the reactions with polysulfides, thiophenolate, and bisulfide with TCEP were studied with GC-FID and LC-MS-MS and were quantified.
| S-EPMC4112502 | biostudies-literature
Project description:Sulfur mustard (SM) is a potent vesicant that targets epithelial cells and tissues. Most vesicant research has been performed using bona fide SM; however, some studies have used simulants, most notably half mustard (2-chloroethyl ethylsulfide; CEES) and nitrogen mustard (mechlorethamine; NM). Although CEES and NM have similarities to SM and can cause vesication, there are distinct differences in the chemical structures and physical properties of these compounds that may impact their toxic effects. Microarray analysis of cultured primary human epidermal keratinocytes (HEK) exposed to each of these vesicants was performed to directly compare the transcriptional responses induced by these vesicants. HEK were exposed in triplicate to concentrations ranging from 0-1000 µM for SM and NM and 0-4000 µM for CEES. Cells were harvested at 1, 2, 4, 8, 16, and 24 h and the RNA isolated for microarray analysis. Transcriptional responses were phenotypically anchored to cell morphology. The dataset was filtered by exposure and timepoint, and an analysis of variance was performed using dose as the factor. The top 500 genes ranked by p-value were analyzed using gene ontology algorithms to identify biological pathways significantly affected by each vesicant. At 2 h post-exposure, p53 signaling, Erk/MAPK signaling, and BMP signaling were significantly affected by all three vesicants. At 4 h post-exposure, p53 signaling , B cell activating factor, and glucocorticoid receptor signaling were significantly affected by all three vesicants. At 8 h post-exposure, there were no significant pathways commonly affected by all three vesicants. These results suggest that, although there are similarities in the transcriptional responses to each of these vesicants, the transcriptional responses appear to differ over time. Thus, extrapolation of results obtained with one vesicant to other vesicants may be complex and may have important implications for the development of vesicant therapeutics.
2018-06-15 | GSE29604 | GEO