Covalent binding of the 13C-labeled skin sensitizers 5-chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI) to a model peptide and glutathione

Alvarez-Sánchez, Rubén; Basketter, David A.; Pease, Camilla; Lepoittevin, Jean Pierre

doi:10.1016/j.bmcl.2003.11.002

Cited by 47 publications

(39 citation statements)

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“…Signals in the NMR spectra did not allow us to find out if the attack of the amino group of GSH was of the intermolecular kind or if adducts 16 and 17 afforded 18 and 19 by intramolecular attack of the amino group and cyclization followed by opening of the cycle. This kind of intramolecular cyclization has already been observed, for example, in the reaction of 2-methylisothiazol-3-one with GSH (29). However, in the case of the isocyanates, the signals corresponding to thiocarbamate adducts 16 and 17 at 167.3 and 166.7 ppm did not disappear to the profit of signals attributed to urea derivatives 18 and 19 at 157.4 and 156.9 ppm.…”

Section: Reaction Of Phenyl-[ 13 C]-isocyanate (1) and P-tolyl-[ 13 Cmentioning

confidence: 63%

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl ¹³C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Fleischel

Giménez‐Arnau

Lepoittevin

2009

Chem. Res. Toxicol.

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Exposure to aryl isocyanates, intermediates in the manufacture of polyurethanes, provokes lung sensitization and asthma but also occupational allergic contact dermatitis, sensitization occurring from a single accidental exposure. The initial step in the sensitization process is believed to be the covalent binding of the -N triple bond C triple bond O group with nucleophilic residues on proteins. While a wide knowledge exists on the reactivity of skin sensitizers toward amino acids, little is known about respiratory sensitizers such as aryl isocyanates. (13)C-Labeled monofunctional aryl isocyanates were synthesized, and their reactivities toward nucleophilic amino acids, GSH, and a model peptide were studied by (13)C and [(1)H-(13)C] NMR spectroscopy. An acetonitrile/buffer solution was used as a solvent to avoid the hampering of the follow up of the reactivity by the isocyanate hydrolysis competing reaction. The compounds reacted with thiol groups, through the formation of thiocarbamate bonds and with amino groups to form urea derivatives. The reactivity was confirmed with GSH, containing both free amino and thiol groups, and with a model peptide, particularly in the case of the reaction with lysine. The use of (13)C NMR to follow the aryl isocyanates reversible conjugation with thiol groups is also reported. Particularly, it is shown that thiocarbamate adducts can be converted into adducts of the urea kind by reaction with amino groups. These results confirmed the hypothesis by which thiol-containing peptides/proteins may act as carriers of isocyanates for possible reaction at a later time and/or place with other nucleophiles and confirmed the role of lysine as a good competing nucleophilic amino acid. The reactivity of aryl isocyanates with thiol and amino groups needs thus to be considered in their assigned sensitization processes.

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Section: Reaction Of Phenyl-[ 13 C]-isocyanate (1) and P-tolyl-[ 13 Cmentioning

confidence: 63%

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl ¹³C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Fleischel

Giménez‐Arnau

Lepoittevin

2009

Chem. Res. Toxicol.

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“…The nature of these modifications is, however, understood most fully only in experimental systems for contact allergy [6,72,73]. The data so far is not yet sufficient to permit the predictive use of evidence of hapten peptide binding except for the lowest level of the identification of potential hazards.…”

Section: Opinionmentioning

confidence: 93%

“…One possible mechanism by which haptens could interface with protein tolerance is through their known ability to covalently bind to peptides and proteins and so alter their immunogenic profile [6,72,73]. The nature of these modifications is, however, understood most fully only in experimental systems for contact allergy [6,72,73].…”

Section: Opinionmentioning

confidence: 98%

Does hapten exposure predispose to atopic disease? The hapten-atopy hypothesis

McFadden

White

Basketter

et al. 2009

Trends in Immunology

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“…Similarly, evidence of covalent binding to model peptide was observed for all tested sensitizers except MI (non‐chlorinated structural relative of MCI). The affinity of MI was previously reported only for Cys of GSH (44), but the lack of evidence for covalent binding may be due to a rapid reaction with thiols yielding unstable products. Conversely, compounds characterized as non‐sensitizers in vivo (DCNB and benzaldehyde) have demonstrated evidence of covalent binding to the model peptide.…”

Section: New Insightsmentioning

confidence: 99%

“…Peptides with sequences analogous to a part of human proteins are also used to assess chemical reactivity. DS3 peptide, which has a sequence analogous to the N‐terminal part of the human globin (sequence VLSPADKTNWGHEYRMFCQIG), was used to investigate binding of 4‐chlorobenzenediazonium hexafluorophosphate (27), acetaldehyde (24) and 5‐chloro‐2‐methylisothiazol‐3‐one (44). Glycine apart, this peptide contains 1 residue of each of the commonly occurring amino acids.…”

Section: Chemistrymentioning

confidence: 99%

Hapten–protein binding: from theory to practical application in the in vitro prediction of skin sensitization

et al. 2005

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In view of the forthcoming European Union ban on in vivo testing of cosmetic and toiletry ingredients, following the publication of the 7th amendment to the Cosmetics Directive, the search for practical, alternative, non-animal approaches is gathering pace. For the end-point of skin sensitization, the ultimate goal, i.e. the development and validation of alternative in vitro/in silico assays by 2013, may be achieved through a better understanding of the skin sensitization process on the cellular and molecular levels. One of the key molecular events in skin sensitization is protein haptenation, i.e. the chemical modification of self-skin protein(s) thus forming macromolecular immunogens. This concept is widely accepted and in theory can be used to explain the sensitizing capacity of many known skin sensitizers. Thus, the principle of protein or peptide haptenation could be used in in vitro assays to predict the sensitization potential of a new chemical entity. In this review, we consider some of the theoretical aspects of protein haptenation, how mechanisms of protein haptenation can be investigated experimentally and how we can use such knowledge in the development of novel, alternative approaches for predicting skin sensitization potential in the future.

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Covalent binding of the 13C-labeled skin sensitizers 5-chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI) to a model peptide and glutathione

Cited by 47 publications

References 4 publications

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl ¹³C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl ¹³C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Does hapten exposure predispose to atopic disease? The hapten-atopy hypothesis

Hapten–protein binding: from theory to practical application in the in vitro prediction of skin sensitization

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Covalent binding of the 13C-labeled skin sensitizers 5-chloro-2-methylisothiazol-3-one (MCI) and 2-methylisothiazol-3-one (MI) to a model peptide and glutathione

Cited by 47 publications

References 4 publications

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl 13C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl 13C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Does hapten exposure predispose to atopic disease? The hapten-atopy hypothesis

Hapten–protein binding: from theory to practical application in the in vitro prediction of skin sensitization

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Product

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Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl ¹³C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts

Nuclear Magnetic Resonance Studies on Covalent Modification of Amino Acids Thiol and Amino Residues by Monofunctional Aryl ¹³C-Isocyanates, Models of Skin and Respiratory Sensitizers: Transformation of Thiocarbamates into Urea Adducts