Characterization of protein adducts produced by N-methyldithiocarbamate and N-methyldithiocarbamate esters

Article abstract of DOI:10.1021/tx00044a011

The toxicity of N-methyldithiocarbamate may be mediated through decomposition to more biologically active compounds. Two principal products, CS₂ and methyl isothiocyanate, have the potential to interact covalently with macromolecules in biological systems. In this investigation the ability of N-methyldithiocarbamate to generate methyl isothiocyanate and CS₂ under physiological conditions resulting in acylation and covalent cross-linking of proteins was examined using ¹³C NMR and GC/MS. Two N-methyldithiocarbamate esters, S-methyl N-methyldithiocarbamate and (N-acetyl-S- methylthiocarbamoyl)cysteine, were also investigated to evaluate the acylating ability of sulfhydryl conjugates of N-methyldithiocarbamate. The predominant and most stable adduct produced by the free dithiocarbamate and its S-substituted esters was methylthiourea on ε-lysyl and N-terminal α- amino groups. Derivatization on N-terminal amino groups progressed more rapidly for the dithiocarbamate than for its mercapturate. Methylurea protein adducts were also produced by the dithiocarbamate and its esters, suggesting production of methyl isocyanate in the decomposition of N- methyldithiocarbamate. Covalent cross-linking of β-lactoglobulin by N- methyldithiocarbamate resulting from its decomposition to CS₂ was observed using denaturing polyacrylamide gel electrophoresis. These results demonstrate the ability of a monoalkyldithiocarbamate to acylate protein amino groups and effect covalent cross-linking. These processes represent molecular mechanisms that may contribute to the toxicity of this class of compounds.