Abstract
Skin allergy is a chronic condition that affects about 20% of the population of the western world. This disease is caused by small reactive compounds, haptens, able to penetrate into the epidermis and modify endogenous proteins, thereby triggering an immunogenic reaction. Phenyl isothiocyanate (PITC) and ethyl isothiocyanate (EITC) have been suggested to be responsible for allergic skin reactions to chloroprene rubber, the main constituent of wetsuits, orthopedic braces, and many types of sports gear. In the present work we have studied the reactivity of the isothiocyanates PITC, EITC, and tetramethylrhodamine-6-isothiocyanate (6-TRITC) toward peptides under aqueous conditions at physiological pH to gain information about the types of immunogenic complexes these compounds may form in the skin. We found that all three compounds reacted quickly with cysteine moieties. For PITC and 6-TRITC the cysteine adducts decomposed over time, while stable adducts with lysine were formed. These experimental findings were verified by DFT calculations. Our results may suggest that the latter are responsible for allergic reactions to isothiocyanates. The initial adduct formation with cysteine residues may still be of great importance as it prevents hydrolysis and facilitates the transport of isothiocyanates into epidermis where they can form stable immunogenic complexes with lysine-containing proteins.
Highlights
Skin allergy is a chronic condition that affects as many as 20% of the population in the western world.[1]
In the present work we have studied the reactivity of the isothiocyanates Phenyl isothiocyanate (PITC), ethyl isothiocyanate (EITC), and 6-TRITC toward different model peptides to gain information about the possible identity of the immunogenic hapten-protein complexes that these compounds may form when entering the skin
This can be compared with PITC which has been shown to be a strong contact sensitizer with an EC3 value of 30 mM (0.40%)[5] and EITC which has been classified as an extreme sensitizer with an EC3 value of 4.6 mM (0.040%)[6]
Summary
Skin (contact) allergy is a chronic condition that affects as many as 20% of the population in the western world.[1]. When assessed in the murine local lymph node assay (LLNA), PITC was identified as a strong skin sensitizer[5] and EITC was identified as an extreme skin sensitizer[6] Another example of an isothiocyanate is tetramethylrhodamine-6-isothiocyanate (6-TRITC) (Fig. 1), a synthetic compound not present in daily life but used as a fluorescent tracer. In the present work we have studied the reactivity of the isothiocyanates PITC, EITC, and 6-TRITC toward different model peptides to gain information about the possible identity of the immunogenic hapten-protein complexes that these compounds may form when entering the skin. Based on these results, we discuss the role and importance of haptenation of cysteine and lysine in the induction of contact sensitization of the skin
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