Enzyme inhibition as a possible mechanism of the mutagenicity of dithiocarbamic acid derivatives in Salmonella typhimurium.

In recent years data have accumulated regarding genotoxic properties of dithiocarbamic acid derivatives. The results from the present work indicate that the mutagenicity of these compounds depends on an indirect effect via oxygen radicals. Mutagenicity of tetramethylthiuram disulfide ( TMTD ), that was used as a model substance, was established with both frameshift and base substitution sensitive strains of Salmonella typhimurium. Addition of copper ions resulted in a decreased survival at low dithiocarbamate doses. The dose response curves seem to correlate with the formation of two types of metal dithiocarbamate complexes. At low doses charged complexes are formed, while the formation of uncharged complexes is favoured at higher dosages. The data suggest that this formation of uncharged metal complexes implies a decreased toxicity but at the same time an increased mutagenicity. The mutagenicity of both TMTD and its ethyl analogue TETD was enhanced by oxygen. Furthermore, TMTD potentiates the mutagenic action of menadione, a substance that produces O(2) and H2O2 by redox cycling with molecular oxygen. Interaction of uncharged metal dithiocarbamate complexes with both production and detoxification of reactive forms of oxygen is suggested to be responsible for the direct mutagenic effects via oxidative damage to DNA. A further enhancement of the oxygen radical content of the cells by adding microsomes that produce oxygen radicals via autoxidation of cytochrome P-450 is proposed as the mechanism for the 'metabolic activation of TMTD '.