Oxidation of 2-Mercaptobenzothiazole in Latex Gloves and Its Possible Haptenation Pathway

Abstract

The rubber accelerator, 2-mercaptobenzothiazole (MBT), has been reported to cause allergic contact dermatitis from gloves and other rubber products, but its chemical fate when exposed to occupational oxidants and the mechanism of its pathogenesis are not known. It was hypothesized that the thiol group is critical to MBT's (its oxidation products or metabolites) covalent binding and/or haptenation to nucleophilic protein residues. Oxidative transformation of MBT to the disulfide 2,2'-dithiobis(benzothiazole) (MBTS) was observed within the glove matrix when hypochlorous acid, iodine, and hydrogen peroxide were used as oxidants. Cysteine reduced MBTS to MBT with subsequent formation of the mixed disulfide 2-amino-3-(benzothiazol-2-yl disulfanyl)propionic acid which was identified and characterized. Spectrophotometry and mass spectrometry experiments demonstrated the simultaneous reduction of MBTS and disulfide formation with Cys34 on bovine serum albumin, suggesting a potential route of protein haptenation through covalent bonding between protein cysteinyl residues and the MBT/MBTS thiol moiety. Metabolism of MBT using isoniazid and dexamethasone-induced rat liver microsomes, to give a protein reactive epoxide intermediate and provide an alternative protein haptenation mechanism, was not observed. The data suggest that the critical functional group on MBT is the thiol, and haptenation is via the formation of mixed disulfides between the thiol group on MBT and a protein sulfhydryl group.

Haptenation: Chemical Reactivity and Protein Binding

“…ACD cases which have also been reported for chemicals like diallyl disulfide [35] and lipoic acid [36] which are thiols further indicate that disulfide formation may be a common mechanism for chemical thiol haptenation. The conclusion that MBT/MBTS haptenates proteins via disulfide formation was supported by enzyme inhibition and protein-binding studies where binding of MBTS to enzymes (reductases) and other protein cysteine residues was through disulfide formation [37]. Bioactivation of MBT, which could potentially lead to an electrophilic hapten was not observed [37], suggesting that MBT is not a metabolically activated prohapten.…”

“…The conclusion that MBT/MBTS haptenates proteins via disulfide formation was supported by enzyme inhibition and protein-binding studies where binding of MBTS to enzymes (reductases) and other protein cysteine residues was through disulfide formation [37]. Bioactivation of MBT, which could potentially lead to an electrophilic hapten was not observed [37], suggesting that MBT is not a metabolically activated prohapten. To date, there are no reports of MBT bioactivation by cutaneous cytochrome P450s (CYPs) enzymes.…”

Substituent Effects on the Reactivity of Benzoquinone Derivatives with Thiols

“…We have previously reported the haptenation of mercaptobenzothiazole to proteins via disulfide formation as an example of non-electrophile-nucleophile interaction. 16 Binding of the skin sensitizer 7-oxodehydroabietic acid to proteins has been reported to be via a free radical mechanism 17 showing it as a viable protein modification pathway. Diverse BQ-protein haptenation pathways/mechanism may result in different adducts with varying immunogenicity.…”

Stoffmonographie für 2-Mercaptobenzothiazol (2-MBT) und HBM-Werte für 2-MBT im Urin von Erwachsenen und Kindern

“…Sie ist auf den Kontaktbereich begrenzt, Effekte treten nach der Exposition zeitverzögert auf, und es kommt zu keiner Erhöhung von IgE. Es wird diskutiert, dass eine Haptenbildung nach Oxidation zu Mercaptobenzothiazoldisulfid und anschließender Reduktion über einen Disulfid-Protein-Komplex erfolgt [37,38]. Die Substanz wurde vom damaligen Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin (BgVV) in die Kategorie A: bedeutende Kontaktallergene aufgenommen [39,40].…”