title: The measurement of 2-thiothiazolidine-4-carboxylic acid as an index of the in vivo release of CS2 by dithiocarbamates.
abstract: Dithiocarbamates and their disulfides are used extensively as agricultural fungicides, as accelerators of the vulcanization process of rubber in industry, and as therapeutic agents in medicine. The widespread uses of these compounds in agriculture, industry, and medicine provide many avenues of exposure to the human population. Subchronic to chronic exposures to some dithiocarbamates have resulted in the development of neuropathy in humans and experimental animals. Decomposition to CS2 presents a potential mechanism through which the toxicity of dithiocarbamates may be mediated. The purpose of this study was to determine the potential of dithiocarbamates to release CS2 in vivo. The ability to release CS2 was assessed by measuring urinary 2-thiothiazolidine-4-carboxylic acid (TTCA), which is used in industry to measure the exposure of workers to CS2. In this study, rats were housed individually in metabolic cages and given daily equimolar ip or po doses (1.5 mmol/kg) of N,N-diethyldithio-carbamate (DEDC), disulfiram (DS), N-methyldithiocarbamate (NMDC), or CS2 for 5 days, and TTCA was measured in urine collected at 24 h intervals. For each compound administered, TTCA was produced in all of the treated animals and the amount of TTCA eliminated in urine from po administration was significantly greater than that from ip administration. The relative rates of TTCA elimination in urine were DS > DEDC approximately equal to CS2 > NMDC for both routes of administration. Following administration of N,N-diethyl[13C = S] dithiocarbamate, carbon-13 enrichment at the thiocarbonyl carbon of TTCA was demonstrated using 13C NMR. Analysis of urinary TTCA proved to be useful both for establishing the in vivo release of CS2 by dithiocarbamate containing compounds and for evaluating the bioavailability of CS2. The results appear especially relevant to disulfiram, which is given orally for sustained periods in the treatment of alcoholism and has resulted in the development of neuropathy in susceptible individuals.
authors.affiliation: Department of Pharmacology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Johnson
authors.forename: D G
authors.initials: DG
authors.lastname: Graham
authors.forename: V
authors.initials: V
authors.lastname: Amarnath
authors.forename: K
authors.initials: K
authors.lastname: Amarnath
authors.forename: W M
authors.initials: WM
authors.lastname: Valentine
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002246:Carbon Disulfide / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000032:analysis* / Q000652:urine; D053778:Thiazolidines; D013859:Thiocarbamates / Q000737:chemistry* / Q000652:urine
chemical_list: D013844:Thiazoles; D053778:Thiazolidines; D013859:Thiocarbamates; C031677:2-thioxo-4-thiazolidinecarboxylic acid; D002246:Carbon Disulfide