ADDUCT FORMATION IN THE TOXICITY OF DITHIOCARBAMATES

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Human exposure to dithiocarbamates derives from their many uses in agriculture, industry. and medicine. Although the degradative and metabolic pathways of dithiocarbamates are fairly well understood, there is currently little knowledge regarding the molecular targets and mechanisms underlying the observed biological effects of dithiocarbamates. The long range objectives of this project are to delineate the interactions of dithiocarbamates and their metabolites within biological systems, and to determine both the relevance of these interactions as mechanisms of toxicity and the utility of these interactions as biomarkers of exposure and effect. Previous investigations have demonstrated the ability of N,N-diethyldithiocarbamate to produce a CS2-mediated central-peripheral distal axonopathy whereas its disulfide, disulfiram, produces a selective Schwann cell neurotoxicity. The investigations in this application are guided by the following working hypotheses: 1)bis(thiocarbamoyl) disulfides exert Schwann cell toxicity from bioactivation to a thiocarbamate sulfoxide metabolite capable of inhibiting myelin synthesis via covalent modification of cysteine residues; 2)disulfiram inhibits low Km aldehyde dehydrogenase by carbamylation of an active site cysteine residue; 3)thiocarbamate esters as well as other compounds that can be metabolized to thiocarbamate sulfoxides are neurotoxic through a mechanism identical to bis(thiocarbamoyl) disulfides. These hypotheses will be tested through determining the relative neurotoxic potencies of bis(thiocarbamoyl)disulfide and thiocarbamate esters in vitro and in vivo using altered expressions of Po and p75; determining the identity and location of proteins covalently modified by dithiocarbamates within the nervous system and liver; determining the influence of age, route of exposure and acid stability on dithiocarbamate induced neurotoxicity; and determining the effects of disulfiram upon myelin synthesis within Schwann cells. Delineating the mechanisms of toxicity, defining the biological effects, and identifying susceptible populations for dithiocarbamates will aid in developing mechanistically based exposure recommendations and formulating structure activity relationships for predicting other agents that may act through a similar mechanism.