Characterization of carbon disulfide binding in blood and to other biological substances

Lam, C.C.; DiStefano, Victor

doi:10.1016/0041-008x(86)90054-2

Cited by 21 publications

(9 citation statements)

References 14 publications

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“…In vivo experiments in rats exposed to UCS2 or C35S2 demonstrated tissue radioactivity in free, acid-labile, and acid-resistant forms, representing unbound CS2, dithiocarbamate and trithiocarbonate adducts, and unidentified stable reaction products, respectively (16,17). In vitro studies produced similar results (18). N-Monoalkyldithiocarbamates are only moderately stable under aqueous conditions (19-21), and early workers suggested their in vivo conversion to isothiocyanates via elimination of hydrosulfide ion (11,12).…”

Section: Introductionmentioning

confidence: 65%

Characterization of isothiocyanates, thioureas, and other lysine adduction products in carbon disulfide-treated peptides and protein

DeCaprio¹,

Spink²,

Chen³

et al. 1992

Chem. Res. Toxicol.

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Carbon disulfide (CS2) is an industrial solvent used in rayon production and as an organic synthetic precursor. It is also a member of the class of neuropathy-inducing xenobiotics known as the "neurofilament (NF) neurotoxicants". Current hypotheses propose direct reaction of CS2 with NF lysine epsilon-amine moieties as a step in the mechanism of this neuropathy. In this study, covalent CS2 binding in a lysine-containing dipeptide and in bovine serum albumin (BSA) in vitro was characterized. Dipeptide and BSA, incubated with 14CS2, exhibited stable incorporation of radioactivity after removal of unbound CS2 and reincubation in physiological buffer for up to 10 days. In contrast, free thiol levels decreased from a maximum immediately following CS2 exposure to near-base-line levels after 10 days, consistent with time-dependent conversion of initially formed N-substituted dithiocarbamate adducts into secondary products. HPLC/thermospray-MS and HPLC/UV photodiode-array analysis of CS2-dipeptide adducts confirmed dithiocarbamate formation and demonstrated their conversion into N-alkylisothiocyanates and, ultimately, N,N'-disubstituted thioureas and ureas. The results of UV spectrophotometry of CS2-treated BSA were also consistent with loss of dithiocarbamate and appearance of thioureas. Similar time-dependent formation of these products, in addition to N,N'-disubstituted thiuram disulfides, was demonstrated in CS2-treated BSA by means of 13C-NMR spectroscopy. SDS-PAGE analysis of adducted protein revealed a discrete, higher mobility band, likely representing a specific intramolecular cross-link. In contrast, no evidence for intermolecular protein cross-linking was obtained. Identical results were obtained with cysteinyl-blocked BSA, indicating the lack of formation of N,S-dialkyldithiocarbamate (dithiourethane) cross-links in these preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Introductionmentioning

confidence: 65%

Characterization of isothiocyanates, thioureas, and other lysine adduction products in carbon disulfide-treated peptides and protein

DeCaprio¹,

Spink²,

Chen³

et al. 1992

Chem. Res. Toxicol.

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“…1. The formation of dithiocarbamate ester could account for the previous observation that part of the radioactivity from 14CS2-treated plasma is not released on heating with acid (19).…”

Section: Methodsmentioning

confidence: 83%

The molecular mechanism of the carbon disulfide mediated crosslinking of proteins

Amarnath¹,

Anthony²,

Valentine³

et al. 1991

Chem. Res. Toxicol.

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“…iP-NLeuTH was detected in both samples, indicating that at least one subtype of the α- and β-globin chains of rat globin had been cross-linked by CS 2 through the formation of Val−Lys thiourea (data not shown). Human hemoglobin, also possessing N-terminal Val on both α- and β-chains, treated with either CS 2 or DEDC in vitro also produced iP-NLeuTH in quantities significantly greater than control quantities 3 Tandem mass spectrum of the [M + ] parent ( m / z 490.3) of iP-NLeuTH derivatized with PETAPITC.…”

Section: Resultsmentioning

confidence: 99%

“…N , N -Diethyldithiocarbamate (DEDC), which is a metabolic product of the drug disulfiram, and the active component of certain dithiocarbamate-containing pesticides, may also be a source of CS 2 exposure to humans. Currently, several methods are available for estimating recent CS 2 exposure, such as levels of blood CS 2 , CS 2 -derivatized blood proteins ( , ), and, the most widely used method, urinary CS 2 metabolites (). All of these methods have recognized limitations.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Valine−Lysine Thiourea Cross-Link on Rat Globin Produced by Carbon Disulfide or N,N-Diethyldithiocarbamate in Vivo

Erve

Amarnath

Sills

et al. 1998

Chem. Res. Toxicol.

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Previous in vivo studies have supported protein cross-linking by CS2 as both a mechanism of neurotoxicity and a potential biomarker of effect through the detection of a structure responsible for CS2-mediated protein cross-linking, namely, lysine-lysine thiourea. In this study, the structure of a previously uncharacterized stable protein cross-link produced by CS2 in vivo involving lysine and the N-terminal valine of globin has been determined. Rats were exposed to 50, 500, and 800 ppm CS2 for 2, 4, 8, and 13 weeks by inhalation or to 3 mmol/kg N,N-diethyldithiocarbamate administered orally on alternating days for 8 and 16 weeks. Acid hydrolysis, using 6 N HCl, of globin from control and exposed rats caused cyclization of the valine-lysine thiourea cross-link in treated rats to isopropyl norleucyl thiohydantoin. The hydrolysate was separated by size-exclusion chromatography, and the fraction that coeluted with the synthetic deuterated isopropyl norleucyl thiohydantoin internal standard was derivatized with 3-[4'-(ethylene-N,N, N-trimethylamino)phenyl]-2-isothiocyanate and analyzed by liquid chromatography/tandem mass spectrometry using selected reaction monitoring detection. Derivatized isopropyl norleucyl thiohydantoin obtained from CS2-treated rats displayed a cumulative dose response and was detectable at the lowest exposure (50 ppm, 2 weeks) at levels of approximately 50 pmol/g of globin. N, N-Diethyldithiocarbamate-treated rats, but not controls, also contained a CS2-generated valine-lysine thiourea cross-link on globin. In vitro incubation of human hemoglobin with either CS2 or N, N-diethyldithiocarbamate also resulted in the formation of CS2-generated valine-lysine thiourea. These observations demonstrate the potential of thiourea cross-linking involving a free amino terminus and epsilon-amino groups of lysine to accumulate in a long-lived globular protein and suggest that cross-linking of globin may provide a specific dosimeter of internal exposure for CS2 capable of assessing exposure over subchronic periods.

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Characterization of carbon disulfide binding in blood and to other biological substances

Cited by 21 publications

References 14 publications

Characterization of isothiocyanates, thioureas, and other lysine adduction products in carbon disulfide-treated peptides and protein

Characterization of isothiocyanates, thioureas, and other lysine adduction products in carbon disulfide-treated peptides and protein

The molecular mechanism of the carbon disulfide mediated crosslinking of proteins

Characterization of a Valine−Lysine Thiourea Cross-Link on Rat Globin Produced by Carbon Disulfide or N,N-Diethyldithiocarbamate in Vivo

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