Document Detail

Characterizing the influence of structure and route of exposure on the disposition of dithiocarbamates using toluene-3,4-dithiol analysis of blood and urinary carbon disulfide metabolites.
MedLine Citation:
PMID:  12972631     Owner:  NLM     Status:  MEDLINE    
Differences in the toxicities observed for dithiocarbamates have been proposed to result from the influence of nitrogen substitution, oxidation state, and route of exposure. To better characterize the fate of dithiocarbmates in vivoas a function of structure and route of exposure, rats were administered equimolar doses of carbon disulfide (CS2), N-methyldithiocarbamate, pyrrolidine dithiocarbamate, N,N-diethyldithiocarbamate, or disulfiram daily for five days, either po or ip, and sequential blood samples obtained. Protein dithiocarbamates formed by the in vivo release of CS2, parent dithiocarbamate, and protein-bound mixed disulfides were assessed in plasma and hemolysate by measuring toluene trithiocarbonate generated upon treatment with toluene-3, 4-dithiol (TdT). To aid in determining the bioavailability of CS2 from the administered dithiocarbamates, the urinary CS2 metabolites, 2-thiothiazolidine-4-carboxylic acid (TTCA) and 2-thiothiazolidin-4-ylcarbonylglycine (TTCG), were also determined. The levels of TdT-reactive moieties detected depended upon both the compound administered and the route of exposure. Parent dithiocarbamates, with the exception of disulfiram, were eliminated from blood within 24 h; but protein associated TdT-reactive moieties persisted and accumulated with repeated exposure, regardless of the route of exposure. N-Methyldithiocarbamate demonstrated the greatest potential to produce intracellular globin modifications, presumably through its unique ability to generate a methylisothiocyanate metabolite. Urinary excretion of TTCA and TTCG was more sensitive than TdT analysis for detecting dithiocarbamate exposure, but TdT analysis appeared to be a better indicator of in vivo release of CS2 by dithiocarbamates than were urinary CS2 metabolites. These data suggest that CS2 is a more important metabolite, following oral exposure, than are other routes of exposure, e.g., inhalation or dermal. In addition, data also suggest that acid stability, nitrogen substitution, and route of exposure are important factors governing the toxicity observed for a particular dithiocarbamate.
D J Johnson; V Amarnath; K Amarnath; H Valentine; W M Valentine
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2003-09-12
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  76     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-10-21     Completed Date:  2004-06-14     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  65-74     Citation Subset:  IM    
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561, USA.
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MeSH Terms
Administration, Oral
Carbon Disulfide / metabolism*
Chromatography, High Pressure Liquid
Injections, Intraperitoneal
Proteins / metabolism
Rats, Sprague-Dawley
Structure-Activity Relationship
Thiocarbamates / blood,  chemistry*,  urine
Tissue Distribution
Toluene* / analogs & derivatives*,  blood,  metabolism,  urine
Grant Support
Reg. No./Substance:
0/Proteins; 0/Thiocarbamates; 108-88-3/Toluene; 496-74-2/dithiol; 75-15-0/Carbon Disulfide

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