The role of thiols and disulfide formation in mercaptobenzothiazole allergenicity.
Chipinda-I; Hettick-JM; Simoyi-RH; Zhang-X; Siegel-PD
Toxicologist 2007 Mar; 96(1):240
The rubber accelerator, 2-mercaptobenzothiazole (MBT), can cause allergic contact dermatitis (ACD) from gloves and other rubber products, but the chemical mechanism leading to MBT's allergenicity is unknown. It was hypothesized that the thiol group is critical to MBT's covalent binding/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 or 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. Simultaneous reduction of MBTS and disulfide formation with Cys34 on bovine serum albumin was observed, suggesting a potential route of protein haptenation through covalent bonding between cysteinyl residues on proteins and the MBT/MBTS thiol moiety. MBT metabolites were not found following incubation with isoniazid and dexamethasone-induced rat liver microsomes and a NADPH regeneration system. Guinea pigs were sensitized to MBT using a modified guinea pig maximization assay (GPMT) and cross-reactivity towards MBTS and the free thiol lacking or blocked compounds benzothiazole (BT), 2-hydroxybenzothiazole (HBT) and 2-(methylthio)benzothiazole (MTBT) assessed. MBT and MBTS, but not BT, HBT or MTBT elicited ACD in MBT-sensitized animals. Both chemical and experimental animal studies demonstrate that the thiol group is required for MBT allergenicity and also suggest that MBT first undergoes non-enzyme mediated oxidation to MBTS with subsequent haptenation via the formation of mixed disulfides with sulfhydryl groups on proteins.
Skin-diseases; Skin-disorders; Skin-exposure; Skin-lesions; Dermatitis; Dermatosis; Allergic-dermatitis; Allergens; Allergic-reactions; Laboratory-animals; Animal-studies; Animals
The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina