Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line

Balszuweit, Frank; Menacher, Georg; Schmidt, Annette; Kehe, Kai; Popp, Tanja; Worek, Franz; Thiermann, Horst; Steinritz, Dirk

doi:10.1016/j.toxlet.2015.09.002

Cited by 26 publications

(10 citation statements)

References 25 publications

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“…In numerous studies, NAC was shown to mitigate symptoms of SM poisoning and is therefore considered as an antidote . However, the relevant mechanism of this effect is not elucidated completely.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, it was also applied successfully to human SM victims and suggests its prophylactic administration to military fielded forces if SM exposure was concerned . A direct chemical reaction of NAC with SM in the extracellular space is discussed as a possible reason for the beneficial effect . The free thiol‐group of NAC might serve as a nucleophilic reactant for SM (Figure ).…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12] In addition, anti-inflammatory effects were observed triggered by inhibition of NF-κB pathway. 13,14 The benefit of NAC therapy for the treatment of SM intoxication has been documented in studies using cell culture [14][15][16][17][18] and animal models. 19,20 Furthermore, it was also applied successfully to human SM victims 7,21-23 and suggests its prophylactic administration to military fielded forces if SM exposure was concerned.…”

Section: Introductionmentioning

confidence: 99%

“…24 A direct chemical reaction of NAC with SM in the extracellular space is discussed as a possible reason for the beneficial effect. 18 The free thiol-group of NAC might serve as a nucleophilic reactant for SM ( Figure 1). SM itself is a strong electrophile alkylating nucleophilic (bio-)molecules like DNA or proteins by attaching the characteristic hydroxyethylthioethyl (HETE) moiety after subsequent hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

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N‐Acetylcysteine as a chemical scavenger for sulfur mustard: New insights by mass spectrometry

Siegert

Kranawetvogl²,

Thiermann³

et al. 2017

Drug Testing and Analysis

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The vesicant sulfur mustard (SM) is a banned chemical warfare agent. Although, SM has been used in combat since WWI, there is no causal therapy currently available. Accordingly, development and investigation of antidotes and scavengers targeting SM are of high clinical relevance. N-acetylcysteine (NAC) was shown to mitigate symptoms of SM intoxications in vitro and in vivo. However, it is still unclear whether the beneficial effects of NAC are only due to physiological processes or also due to chemical scavenging of SM. Therefore, in this study, we examined the scavenging potential of NAC toward SM. Co-incubations of SM and different NAC concentrations in human serum were performed to monitor diverse adducts (covalent reaction products) of human serum albumin (HSA), NAC, and SM. After proteolytic cleavage of HSA with proteinase K the alkylated tripeptide hydroxyethylthioethyl-CysProPhe (HETE-CPF) and the disulfide bridged tripeptide NAC-CPF were detected. Samples were analyzed by microbore liquid chromatography-electrospray ionization-high-resolution tandem-mass spectrometry (μLC-ESI MS/HR MS). Furthermore, degradation kinetics of SM in phosphate buffered saline were measured in the presence and absence of NAC. Although NAC-CPF was identified and characterized for the first time by mass spectrometry and reaction products of NAC and SM were detected and identified by MS/HR MS, analyses clearly documented minor reactivity not significantly contributing to reduction of SM concentrations. Therefore, we conclude that chemical scavenging of SM by NAC does not play the key role in NAC therapy of SM poisoning.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N‐Acetylcysteine as a chemical scavenger for sulfur mustard: New insights by mass spectrometry

Siegert

Kranawetvogl²,

Thiermann³

et al. 2017

Drug Testing and Analysis

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“…GSH and NAC displayed protective effects against SM by reducing apoptosis, necrosis and interleukin levels (Balszuweit et al, 2016). NAC was also shown to prevent SM-induced activation of transient receptor potential ankyrin 1 (TRPA1) cation channel (Stenger et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Sulfur mustard resistant keratinocytes obtained elevated glutathione levels and other changes in the antioxidative defense mechanism

et al. 2018

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Background: Sulfur mustard (SM) is a potent blistering chemical warfare agent, which was first used in 1917. Despite the Chemical Weapons Convention, a use was recently reported in Syria in 2015. This emphasizes the importance to develop countermeasures against chemical warfare agents. Despite intensive research, there is still no antidote or prophylaxis available against SM. Methods: The newly developed SM-resistant keratinocyte cell line HaCaT/SM was used to identify new target structures for drug development, particularly the adaptations in protective measures against oxidative stress. For this purpose, glutathione (GSH) and NAD(P)H levels, the effect of glutathione S-transferase (GST) inhibition as well as activation and expression of Nrf2, GST, glutamate cysteine ligase (GCL) and glutathione-disulfide reductase (GSR) as well as multi-drug resistance (MDR) proteins 1, 3 and 5 were investigated. Results: The HaCaT/SM cells showed not only a better survival after treatment with SM or cytostatic drugs, but also hydrogen peroxide (H2O2). They exhibit more GSH even after SM treatment. Nrf2 levels were significantly lower. Inhibition of GST led to significantly decreased, activation to slightly higher IC50 values after SM treatment and a lower expression of GST was observed. The cells also expressed less GCLC and GSR. Expression of MDR1, MDR3 and MDR5 was higher under control conditions, but less stimulated by SM treatment. An increased NADP+/NADPH ratio as well as higher NAD+ levels were shown. Conclusion: In summary, an improved response of the resistant cell line to oxidative stress was observed. The underlying mechanisms are elevated GSH levels as well as lower expression of Nrf2 and its targets GCLC and GST as well as GSR and MDR1, MDR3 and MDR5. GST is an especially interesting target because its inhibition already induced a significant SM sensitivity. SM resistance also caused redox equivalent level differences. Taken together, these findings provide further insight into the mechanism of SM resistance and may open a window for novel therapeutic targets in SM therapy.

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Sulfur Mustard

Steinritz¹,

Thiermann²

2017

Critical Care Toxicology

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Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line

Cited by 26 publications

References 25 publications

N‐Acetylcysteine as a chemical scavenger for sulfur mustard: New insights by mass spectrometry

N‐Acetylcysteine as a chemical scavenger for sulfur mustard: New insights by mass spectrometry

Sulfur mustard resistant keratinocytes obtained elevated glutathione levels and other changes in the antioxidative defense mechanism

Sulfur Mustard

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