RESUMO
Inhaled toxicants are used for diverse purposes, ranging from industrial applications such as agriculture, sanitation, and fumigation to crowd control and chemical warfare, and acute exposure can induce lasting respiratory complications. The intentional release of chemical warfare agents (CWAs) during World War I caused life-long damage for survivors, and CWA use is outlawed by international treaties. However, in the past two decades, chemical warfare use has surged in the Middle East and Eastern Europe, with a shift toward lung toxicants. The potential use of industrial and agricultural chemicals in rogue activities is a major concern as they are often stored and transported near populated areas, where intentional or accidental release can cause severe injuries and fatalities. Despite laws and regulatory agencies that regulate use, storage, transport, emissions, and disposal, inhalational exposures continue to cause lasting lung injury. Industrial irritants (e.g., ammonia) aggravate the upper respiratory tract, causing pneumonitis, bronchoconstriction, and dyspnea. Irritant gases (e.g., acrolein, chloropicrin) affect epithelial barrier integrity and cause tissue damage through reactive intermediates or by direct adduction of cysteine-rich proteins. Symptoms of CWAs (e.g., chlorine gas, phosgene, sulfur mustard) progress from airway obstruction and pulmonary edema to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which results in respiratory depression days later. Emergency treatment is limited to supportive care using bronchodilators to control airway constriction and rescue with mechanical ventilation to improve gas exchange. Complications from acute exposure can promote obstructive lung disease and/or pulmonary fibrosis, which require long-term clinical care. SIGNIFICANCE STATEMENT: Inhaled chemical threats are of growing concern in both civilian and military settings, and there is an increased need to reduce acute lung injury and delayed clinical complications from exposures. This minireview highlights our current understanding of acute toxicity and pathophysiology of a select number of chemicals of concern. It discusses potential early-stage therapeutic development as well as challenges in developing countermeasures applicable for administration in mass casualty situations.
Assuntos
Lesão Pulmonar Aguda , Substâncias para a Guerra Química , Fosgênio , Humanos , Pulmão , Cloro/farmacologia , Cloro/toxicidade , Substâncias para a Guerra Química/toxicidade , Fosgênio/metabolismo , Fosgênio/farmacologia , Lesão Pulmonar Aguda/metabolismo , IrritantesRESUMO
Mesenchymal stem cells (MSCs) have promising potential in the treatment of various diseases, such as the therapeutic effect of bone marrow-derived MSCs for phosgene-induced acute lung injury (P-ALI). However, MSC-related therapeutics are limited due to poor cell survival, requiring appropriate MSC delivery systems to maximise therapeutic capacity. Biomaterial RGD-hydrogel is a potential cell delivery vehicle as it can mimic the natural extracellular matrix and provide cell adhesion support. The application of RGD-hydrogel in the MSC treatment of respiratory diseases is scarce. This study reports that RGD-hydrogel has good biocompatibility and can increase the secretion of Angiopoietin-1, hepatocyte growth factor, epidermal growth factor, vascular endothelial cell growth factor, and interleukin-10 in vitro MSCs. The hydrogel-encapsulated MSCs could further alleviate P-ALI and show better cell survival in vivo. Overall, RGD-hydrogel could improve the MSC treatment of P-ALI by modulating cell survival and reparative activities. It is exciting to see more and more ways to unlock the therapeutic potential of MSCs.
Assuntos
Lesão Pulmonar Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Fosgênio , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/terapia , Animais , Medula Óssea/metabolismo , Hidrogéis/efeitos adversos , Hidrogéis/metabolismo , Células-Tronco Mesenquimais/metabolismo , Oligopeptídeos/efeitos adversos , Oligopeptídeos/metabolismo , Fosgênio/metabolismo , Fosgênio/toxicidade , RatosRESUMO
In order to identify intermediates of CCl4 metabolism, whole, suitably fortified rat liver homogenates were incubated with 14CCl4 in the presence and absence of "pools" of unlabeled suspected intermediates. In the presence of NADH or NADPH, incorporation of radioactivity was rapid and substantial in CO2, lipid, protein, and the acid-soluble fraction. It was not influenced by the presence of large pools of unlabeled chloroform or formate, thus excluding these substances as obligatory intermediates. However, when incubated with L-cysteine, radioactivity incorporation in the acid-soluble fraction was almost doubled, and about one-third of the radioactivity of this fraction was identified as 2-oxothiazolidine 4-carboxylic acid. This substance is formed chemically by condensation of cysteine with carbonyl chloride and has been identified previously by others as a product of chloroform metabolism by liver microsomes in the presence of L-cysteine. Based on current knowledge of CCl4 metabolism, the following aerobic pathway is envisioned: microsomal cleavage to Cl- and .CCl3 and oxidation of the latter to the unstable intermediate, Cl3COH, which loses HCl to yield COCl2. COCl2 is likely to be the major source of CO2 from CCl4 but is probably not the intermediate that binds to lipid and protein. The addition of glutathione had no effect on CCl4 metabolism in rat liver homogenate, suggesting that glutathione S-transferases, which catalyze other dehalogenation reactions, do not play a role in CCl4 metabolism.
Assuntos
Tetracloreto de Carbono/metabolismo , Ácidos Carboxílicos/metabolismo , Fígado/metabolismo , Aerobiose , Animais , Formiatos/metabolismo , Glutationa/farmacologia , Técnicas In Vitro , Fígado/efeitos dos fármacos , Masculino , Modelos Químicos , Fosgênio/metabolismo , RatosRESUMO
The dose and time dependence of formation of a specific adduct between mitochondrial phospholipid and phosgene have been determined in the liver of Sprague-Dawley (SD) rats as well as in the liver and kidney of B6C3F1 mice after dosing with chloroform. Rats were induced with phenobarbital or non-induced. Determination of tissue glutathione (GSH) and of serum markers of hepatotoxicity and nephrotoxicity was also carried out. With dose-dependence experiments, a strong correlation between the formation of the specific phospholipid adduct, GSH depletion and organ toxicity could be evidenced in all the organs studied. With non-induced SD rats, no such effects could be induced up to a dose of 740 mg/kg. Time-course studies with B6C3F1 mice indicated that the specific adduct formation took place at very early times after chloroform dosing and was concurrent with GSH depletion. The adduct formed during even transient GSH depletion (residual level: 30% of control) and persisted after restoration of GSH levels. Following a chloroform dose at the hepatotoxicity threshold (150 mg/kg), the elimination of the adduct in the liver occurred within 24 h and correlated with the recovery of ALT, which was slightly increased (12 times) after treatment. Following a moderately nephrotoxic dose (60 mg/kg), the renal adduct persisted longer than 48 h, when a 100% increase in blood urea nitrogen and a 40% increase in serum creatinine indicated the onset of organ damage. The formation of the adduct in the liver mitochondria of B6C3F1 mice was associated with the decrease of phosphatidyl-ethanolamine (PE), in line with previous results in rat liver indicating that the adduct results from the reaction of phosgene with PE. The adduct levels implicated the reaction of phosgene with about 50% PE molecules in the liver mitochondrial membrane of phenobarbital-induced SD rats and of about 10% PE molecules of the inner mitochondrial membrane of the liver of B6C3F1 mice. The association of this adduct with the toxic effects of chloroform makes it a very good candidate as the primary critical alteration in the sequence of events leading to cell death caused by chloroform.
Assuntos
Substâncias para a Guerra Química/metabolismo , Clorofórmio/toxicidade , Mitocôndrias/metabolismo , Fosgênio/metabolismo , Fosfolipídeos/metabolismo , Animais , Cromatografia em Camada Fina , Rim/efeitos dos fármacos , Rim/metabolismo , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismoRESUMO
[carbonyl-11C]Estramustine and [carbonyl-11C]estramustine phosphate were synthesized from [11C]phosgene using a one pot procedure. [carbonyl-11C]Estramustine was obtained in 31-43% decay corrected yield based on radioactivity trapped in the reaction vessel. The product was obtained 25 min after the end of radionuclide production with a specific radioactivity of 0.38-1.11 Ci/mumol. A method was developed yielding [carbonyl-11C]estramustine phosphate in 29-45% decay corrected yield based on trapped radioactivity, without purification of the [carbonyl-11C]estramustine intermediate. The product was obtained within 40 min of the end of radionuclide production with a specific radioactivity of 0.59-0.86 Ci/mumol. Results from in vitro experiments suggest that because of their high nonspecific binding, the compounds are unsuitable for positron emission tomography as imaging agents for the estramustine binding protein in cancer.
Assuntos
Estramustina/síntese química , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Hormonais/síntese química , Antineoplásicos Hormonais/farmacocinética , Estramustina/farmacocinética , Humanos , Modelos Químicos , Fosgênio/metabolismo , Fosforilação , Protetores contra Radiação/síntese química , Protetores contra Radiação/farmacocinética , Ratos , Suínos , Tomografia Computadorizada de Emissão , Células Tumorais CultivadasRESUMO
The effects of cysteine, diethyl maleate and phenobarbital treatments and 2H-substitution on the hepatotoxicity of chloroform were investigated. Time course studies of covalent binding and hepatoxicity in phenobarbital-treated rats showed that covalent binding of 14C-label from [14C]chloroform was maximal at 6 h after chloroform administration while hepatotoxicity reached a peak at 18 h. Cysteine treatment reduced both covalent binding and hepatotoxicity, while diethyl maleate and phenobarbital treatments increased both the hepatotoxicity of chloroform and the covalent binding of chloroform metabolites to hepatic proteins. A deuterium isotope effect was present on chloroform-induced hepatotoxicity in diethyl maleate-treated rats suggesting that the previously reported inhibition of haloform metabolism by diethyl maleate occurs at a step in the reaction mechanism after phosgene production. These data support the concept that phosgene is the toxic intermediate in chloroform metabolism.
Assuntos
Clorofórmio/toxicidade , Cisteína/farmacologia , Fígado/efeitos dos fármacos , Maleatos/farmacologia , Fenobarbital/farmacologia , Alanina Transaminase/sangue , Animais , Biotransformação/efeitos dos fármacos , Fígado/metabolismo , Masculino , Fosgênio/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Chloroform and Halothane are well known hepatotoxic anesthetics for which toxicity is attributed to their reactive metabolites. The molecular level details of reactions leading to the formation of reactive metabolites from chloroform and halothane have not been explored. Potential energy surface (PES) for the formation of phosgene (a toxic intermediate) from Chloroform has been studied using quantum chemical methods. The HOOH mediated reaction of chloroform to give phosgene has been found to be exothermic by 81.24 kcal/mol with a barrier of ~ 3 kcal/mol through the water catalyzed transition sate. The quantum chemical studies on the reactivity profile of phosgene indicated that urea derivatives need to be considered on the mechanism leading to toxicity. Similarly, metabolic pathways of Halothane oxidation have been studied. The C-H bond dissociation energies (BDE) and radical stabilization energies (RSE) for Chloroform and Halothane (< 95 kcal/mol and > 10 kcal/mol) were found to be significantly different for these toxic anesthetics in comparison to their safer analogues (> 100 kcal/mol and < 5 kcal/mol) respectively; thus these parameters can be employed to distinguish toxic and non-toxic general anesthetics. Enthalpy for the Cpd I, a widely used model for CYP450 enzymes, mediated reactions also agreed well with these results.
Assuntos
Anestésicos Gerais/metabolismo , Anestésicos Gerais/química , Anestésicos Gerais/toxicidade , Clorofórmio/metabolismo , Halotano/metabolismo , Fosgênio/metabolismo , TermodinâmicaAssuntos
Clorofórmio/metabolismo , Deutério/farmacologia , Fosgênio/metabolismo , Animais , Biotransformação , Técnicas In Vitro , Masculino , RatosAssuntos
1-Propanol/toxicidade , Intoxicação por Tetracloreto de Carbono/metabolismo , Tetracloreto de Carbono/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fosgênio/metabolismo , Animais , Dióxido de Carbono/metabolismo , Clorofórmio/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Fenobarbital/farmacologia , RatosRESUMO
Antiedematous activity of new thiazolo[5,4-b]indole derivatives containing a fragment of isothiourea and characterized by higher antihypoxic activity compared to known antihypoxants was studied on a model of toxic edema of the lungs in mice. Compounds exhibiting high activity on two models of hypoxia (hypobaric and hemic) better protected from lung edema than compounds active only in hypobaric hypoxia.
Assuntos
Indóis/farmacologia , Edema Pulmonar/tratamento farmacológico , Tiazóis/farmacologia , Animais , Hipóxia , Cinética , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Modelos Químicos , Fosgênio/metabolismo , Ratos , Tioureia/farmacologiaRESUMO
A thorough analysis of the pertinent literature leads to the conclusion that there is no justification for the use of methenamine (hexamethylene tetramin, Urotropin) for the therapy of phosgene poisoning.
Assuntos
Metenamina/uso terapêutico , Fosgênio/intoxicação , Animais , Cães , Humanos , Metenamina/metabolismo , Fosgênio/metabolismo , Ratos , Dispositivos de Proteção RespiratóriaRESUMO
The mechanism of metabolism of carbon tetrachloride (CCl4) to phosgene (COCl2) in rat liver microsomes was investigated. When the oxygen dependency of the reaction was studied, it was found that the rate of the reaction increased as the oxygen concentration in the reaction atmosphere was decreased from 100% to 5%. Decreasing the oxygen concentration below 5% caused a decrease in the rate of the reaction. The reaction was not inhibited by superoxide dismutase or catalase nor was it supported by cumene hydroperoxide. A reconstituted form of cytochrome P-450 from phenobarbital-pretreated rats metabolized CCl4 to COCl2. These results are consistent with a mechanism we call reductive oxygenation. The first step of the reaction is the cytochrome P-450-dependent reductive dechlorination of CCl4 to trichloromethyl radical (CCl3.). This intermediate is trapped by oxygen to form trichloromethylperoxyl radical (CCl3OO.), which decomposes to COCl2 and possibly an electrophilic form of chlorine.
Assuntos
Tetracloreto de Carbono/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Fosgênio/metabolismo , Animais , Masculino , Microssomos Hepáticos/metabolismo , Oxirredução , Oxigênio/metabolismo , RatosRESUMO
The development of procedures for retrospective detection and quantitation of exposure to phosgene, based on adducts to hemoglobin and albumin, is described. Upon incubation of human blood with [(14)C]phosgene (0-750 microM), a significant part of radioactivity (0-13%) became associated with globin and albumin. Upon Pronase digestion of globin, one of the adducts was identified as the pentapeptide O=C-(V-L)-S-P-A, representing amino acid residues 1-5 of alpha-globin, with a hydantoin function between N-terminal valine and leucine. Micro-LC/tandem MS analyses of tryptic as well as V8 protease digests identified one of the adducts to albumin as a urea resulting from intramolecular bridging of lysine residues 195 and 199. The adducted tryptic fragment could be sensitively analyzed by means of micro-LC/tandem MS with multiple-reaction monitoring (MRM), enabling the detection in human blood of an in vitro exposure level of >/=1 microM phosgene.
Assuntos
Albuminas/metabolismo , Hemoglobinas/metabolismo , Fosgênio/metabolismo , Cromatografia Líquida de Alta Pressão , Exposição Ambiental , Monitoramento Ambiental/métodos , Humanos , Espectrometria de Massas , Fosgênio/farmacologia , Ligação Proteica/efeitos dos fármacosRESUMO
Human exposure to trihalomethanes such as chloroform has been associated with both cancer and reproductive toxicity. While there is little evidence for chloroform mutagenicity or DNA adduct formation, in vivo studies in rats have demonstrated adduction to histones and other nuclear proteins. Histones play a key role in controlling DNA expression particularly through the acetylation of lysine residues in their N-termini. Therefore, we studied the reaction of phosgene, the major active metabolite of chloroform, with the N-terminus of human histone H2B (Hpep, Pro-Glu-Pro-Ala-Lys-Ser-Ala-Pro-Ala-Pro-Lys-Lys-Gly-Ser-Lys-Lys-Ala-Val-Thr-Lys-Ala-Gln-Lys) in a model chemical system. The aim of this study was to assess whether phosgene is able to form irreversible adducts with this peptide and to investigate which residues are most susceptible. Hpep was reacted with a range of phosgene concentrations (0.03-36 mM) at 37 degrees C, pH 7.4. The products of these reactions, analyzed by matrix-assisted laser desorption ionization MS, showed that up to three CO moieties could be adducted to the peptide. The singly and doubly adducted peptides were purified by HPLC and then hydrolyzed with trypsin to produce a series of fragments that were analyzed by HPLC-MS. The tryptic products showed that adduction occurred principally at lysine residues, and that all seven lysine residues of the peptide were subject to adduction. Collision-induced dissociation analysis using ion trap MS-MS of the tryptic fragment [Pro-Glu-Pro-Ala-Lys-Ser-Ala-Pro-Ala-Pro-Lys + CO] and of the full-length singly adducted peptide supported the role of lysine residues in adduction; the data also indicated that the N-terminal proline and the serine residues are susceptible. Addition of glutathione to the reaction mixture only partially attenuated adduct formation and allowed production of another adducted species, i.e., Hpep-CO-glutathione. The occurrence of such reactions to the N-termini of histones, if confirmed by in vivo studies, could help to explain the mechanism of chloroform carcinogenicity.
Assuntos
Clorofórmio/metabolismo , Histonas/metabolismo , Lisina/química , Fosgênio/metabolismo , Sequência de Aminoácidos , Histonas/química , Humanos , Dados de Sequência Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Fragmentos de Peptídeos/análise , Fosgênio/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Tripsina/metabolismoRESUMO
Pseudomonas sp. strain KC transforms carbon tetrachloride into carbon dioxide and nonvolatile products, without chloroform as an intermediate. To define the pathway for hydrolysis, nonvolatile products were analyzed. Condensation products containing the carbon atom of carbon tetrachloride as carbonyl and thioxo moieties were identified, indicating the intermediacy of phosgene and thiophosgene in the pathway.
Assuntos
Tetracloreto de Carbono/metabolismo , Pseudomonas/metabolismo , Biotransformação , Dióxido de Carbono/metabolismo , Tetracloreto de Carbono/química , Cromatografia Gasosa-Espectrometria de Massas , Hidrólise , Espectrometria de Massas , Modelos Químicos , Oxirredução , Oxigênio/metabolismo , Fosgênio/análogos & derivados , Fosgênio/química , Fosgênio/metabolismo , Enxofre/metabolismoRESUMO
In this investigation, we have attempted to determine whether chloroform (CHCl3)-induced nephrotoxicity might be due to its metabolism to phosgene (COCl2) in the kidney. We have found that kidney homogenates from DBA/2J male mice in the presence of glutathione metabolize CHCl3 to 2-oxothiazolidine-4-carboxylic acid (OTZ). This product appears to be formed by the initial trapping of COCl2 by two molecules of GSH to form diglutathionyl dithiocarbonate (GSCOSG). Kidney gamma-glutamyl transpeptidase can rapidly metabolize GSCOSG to N-(2-oxothiazolidine-4-carbonyl)-glycine which is then hydrolyzed, possibly by cysteinyl glycinase to OTZ. The finding that deuterium-labeled chloroform (CDCl3) was less nephrotoxic and depleted less renal GSH than did CHCl3 suggests that the metabolism of CHCl3 to COCl2 may also occur in the kidney in vivo and lead to nephrotoxicity.