Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.

The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.

Bioorthogonal Delivery of Carbon Disulfide in Living Cells.

Carbon disulfide (CS2) is an environmental contaminant, which is deadly hazardous to the workers under chronic or acute exposure. However, the toxicity mechanisms of CS2 are still unclear due to the scarcity of biocompatible donors, which can release CS2 in cells. Here we developed the first bioorthogonal CS2 delivery system based on the "click-and-release" reactions between mesoionic 1,3-thiazolium-5-thiolates (TATs) and strained cyclooctyne exo-BCN-OH. We successfully realized intracellular CS2 release and investigated the causes of CS2-induced hepatotoxicity, including oxidative stress, proteotoxic stress and copper-dependent cell death. It is found that CS2 can be copper vehicles bypassing copper transporters after reacting with nucleophiles in cytoplasm, and extra copper supplementation will exacerbate the loss of homeostasis of cells and ultimately cell death. These findings inspired us to explore the anticancer activity of CS2 in combination with copper by introducing a copper chelating group in our CS2 delivery system.

Carbon disulfide. Just toxic or also bioregulatory and/or therapeutic?

The overview presented here has the goal of examining whether carbon disulfide (CS2) may play a role as an endogenously generated bioregulator and/or has therapeutic value. The neuro- and reproductive system toxicity of CS2 has been documented from its long-term use in the viscose rayon industry. CS2 is also used in the production of dithiocarbamates (DTCs), which are potent fungicides and pesticides, thus raising concern that CS2 may be an environmental toxin. However, DTCs also have recognized medicinal use in the treatment of heavy metal poisonings as well as having potency for reducing inflammation. Three known small molecule bioregulators (SMBs) nitric oxide, carbon monoxide, and hydrogen sulfide were initially viewed as environmental toxins. Yet each is now recognized as having intricate, though not fully elucidated, biological functions at concentration regimes far lower than the toxic doses. The literature also implies that the mammalian chemical biology of CS2 has broader implications from inflammatory states to the gut microbiome. On these bases, we suggest that the very nature of CS2 poisoning may be related to interrupting or overwhelming relevant regulatory or signaling process(es), much like other SMBs.

Mechanosensitivity below Ground: Touch-Sensitive Smell-Producing Roots in the Shy Plant Mimosa pudica.

The roots of the shy plant Mimosa pudica emit a cocktail of small organic and inorganic sulfur compounds and reactive intermediates into the environment, including SO2, methanesulfinic acid, pyruvic acid, lactic acid, ethanesulfinic acid, propanesulfenic acid, 2-aminothiophenol, S-propyl propane 1-thiosulfinate, phenothiazine, and thioformaldehyde, an elusive and highly unstable compound that, to our knowledge, has never before been reported to be emitted by a plant. When soil around the roots is dislodged or when seedling roots are touched, an odor is detected. The perceived odor corresponds to the emission of higher amounts of propanesulfenic acid, 2-aminothiophenol, S-propyl propane 1-thiosulfinate, and phenothiazine. The mechanosensitivity response is selective. Whereas touching the roots with soil or human skin resulted in odor detection, agitating the roots with other materials such as glass did not induce a similar response. Light and electron microscopy studies of the roots revealed the presence of microscopic sac-like root protuberances. Elemental analysis of these projections by energy-dispersive x-ray spectroscopy revealed them to contain higher levels of K(+) and Cl(-) compared with the surrounding tissue. Exposing the protuberances to stimuli that caused odor emission resulted in reductions in the levels of K(+) and Cl(-) in the touched area. The mechanistic implications of the variety of sulfur compounds observed vis-à-vis the pathways for their formation are discussed.

Evolution of a new enzyme for carbon disulphide conversion by an acidothermophilic archaeon.

Extremophilic organisms require specialized enzymes for their exotic metabolisms. Acid-loving thermophilic Archaea that live in the mudpots of volcanic solfataras obtain their energy from reduced sulphur compounds such as hydrogen sulphide (H(2)S) and carbon disulphide (CS(2)). The oxidation of these compounds into sulphuric acid creates the extremely acidic environment that characterizes solfataras. The hyperthermophilic Acidianus strain A1-3, which was isolated from the fumarolic, ancient sauna building at the Solfatara volcano (Naples, Italy), was shown to rapidly convert CS(2) into H(2)S and carbon dioxide (CO(2)), but nothing has been known about the modes of action and the evolution of the enzyme(s) involved. Here we describe the structure, the proposed mechanism and evolution of a CS(2) hydrolase from Acidianus A1-3. The enzyme monomer displays a typical ß-carbonic anhydrase fold and active site, yet CO(2) is not one of its substrates. Owing to large carboxy- and amino-terminal arms, an unusual hexadecameric catenane oligomer has evolved. This structure results in the blocking of the entrance to the active site that is found in canonical ß-carbonic anhydrases and the formation of a single 15-Å-long, highly hydrophobic tunnel that functions as a specificity filter. The tunnel determines the enzyme's substrate specificity for CS(2), which is hydrophobic. The transposon sequences that surround the gene encoding this CS(2) hydrolase point to horizontal gene transfer as a mechanism for its acquisition during evolution. Our results show how the ancient ß-carbonic anhydrase, which is central to global carbon metabolism, was transformed by divergent evolution into a crucial enzyme in CS(2) metabolism.

Estimates of metabolic rate and major constituents of metabolic demand in fishes under field conditions: Methods, proxies, and new perspectives.

Metabolic costs are central to individual energy budgets, making estimates of metabolic rate vital to understanding how an organism interacts with its environment as well as the role of species in their ecosystem. Despite the ecological and commercial importance of fishes, there are currently no widely adopted means of measuring field metabolic rate in fishes. The lack of recognized methods is in part due to the logistical difficulties of measuring metabolic rates in free swimming fishes. However, further development and refinement of techniques applicable for field-based studies on free swimming animals would greatly enhance the capacity to study fish under environmentally relevant conditions. In an effort to foster discussion in this area, from field ecologists to biochemists alike, we review aspects of energy metabolism and give details on approaches that have been used to estimate energetic parameters in fishes. In some cases, the techniques have been applied to field conditions; while in others, the methods have been primarily used on laboratory held fishes but should be applicable, with validation, to fishes in their natural environment. Limitations, experimental considerations and caveats of these measurements and the study of metabolism in wild fishes in general are also discussed. Potential novel approaches to FMR estimates are also presented for consideration. The innovation of methods for measuring field metabolic rate in free-ranging wild fish would revolutionize the study of physiological ecology.

Role of Thiobacillus thioparus in the biodegradation of carbon disulfide in a biofilter packed with a recycled organic pelletized material.

This study reports the biodegradation of carbon disulfide (CS2) in air biofilters packed with a pelletized mixture of composted manure and sawdust. Experiments were carried out in two lab-scale (1.2 L) biofiltration units. Biofilter B was seeded with activated sludge enriched previously on CS2-degrading biomass under batch conditions, while biofilter A was left as a negative inoculation control. This inoculum was characterized by an acidic pH and sulfate accumulation, and contained Achromobacter xylosoxidans as the main putative CS2 biodegrading bacterium. Biofilter operation start-up was unsuccessfully attempted under xerophilic conditions and significant CS2 elimination was only achieved in biofilter A upon the implementation of an intermittent irrigation regime. Sustained removal efficiencies of 90-100 % at an inlet load of up to 12 g CS2 m(-3) h(-1) were reached. The CS2 removal in this biofilter was linked to the presence of the chemolithoautotrophic bacterium Thiobacillus thioparus, known among the relatively small number of species with a reported capacity of growing on CS2 as the sole energy source. DGGE molecular profiles confirmed that this microbe had become dominant in biofilter A while it was not detected in samples from biofilter B. Conventional biofilters packed with inexpensive organic materials are suited for the treatment of low-strength CS2 polluted gases (IL <12 g CS2 m(-3) h(-1)), provided that the development of the adequate microorganisms is favored, either upon enrichment or by inoculation. The importance of applying culture-independent techniques for microbial community analysis as a diagnostic tool in the biofiltration of recalcitrant compounds has been highlighted.

Bacterial CS2 hydrolases from Acidithiobacillus thiooxidans strains are homologous to the archaeal catenane CS2 hydrolase.

Carbon disulfide (CS(2)) and carbonyl sulfide (COS) are important in the global sulfur cycle, and CS(2) is used as a solvent in the viscose industry. These compounds can be converted by sulfur-oxidizing bacteria, such as Acidithiobacillus thiooxidans species, to carbon dioxide (CO(2)) and hydrogen sulfide (H2S), a property used in industrial biofiltration of CS(2)-polluted airstreams. We report on the mechanism of bacterial CS(2) conversion in the extremely acidophilic A. thiooxidans strains S1p and G8. The bacterial CS(2) hydrolases were highly abundant. They were purified and found to be homologous to the only other described (archaeal) CS(2) hydrolase from Acidianus strain A1-3, which forms a catenane of two interlocked rings. The enzymes cluster in a group of ß-carbonic anhydrase (ß-CA) homologues that may comprise a subclass of CS(2) hydrolases within the ß-CA family. Unlike CAs, the CS(2) hydrolases did not hydrate CO(2) but converted CS(2) and COS with H(2)O to H(2)S and CO(2). The CS(2) hydrolases of A. thiooxidans strains G8, 2Bp, Sts 4-3, and BBW1, like the CS(2) hydrolase of Acidianus strain A1-3, exist as both octamers and hexadecamers in solution. The CS(2) hydrolase of A. thiooxidans strain S1p forms only octamers. Structure models of the A. thiooxidans CS(2) hydrolases based on the structure of Acidianus strain A1-3 CS(2) hydrolase suggest that the A. thiooxidans strain G8 CS(2) hydrolase may also form a catenane. In the A. thiooxidans strain S1p enzyme, two insertions (positions 26 and 27 [PD] and positions 56 to 61 [TPAGGG]) and a nine-amino-acid-longer C-terminal tail may prevent catenane formation.

Diversity and ecophysiology of new isolates of extremely acidophilic CS2-converting Acidithiobacillus strains.

Biofiltration of industrial carbon disulfide (CS2)-contaminated waste air streams results in the acidification of biofilters and therefore reduced performance, high water use, and increased costs. To address these issues, we isolated 16 extremely acidophilic CS2-converting Acidithiobacillus thiooxidans strains that tolerated up to 6% (vol/vol) sulfuric acid. The ecophysiological properties of five selected strains (2Bp, Sts 4-3, S1p, G8, and BBW1) were compared. These five strains had pH optima between 1 (2Bp) and 2 (S1p). Their affinities for CS2 ranged between 80 (G8) and 130 (2Bp) µM. Strains S1p, G8, and BBW1 had more hydrophobic cell surfaces and produced less extracellular polymeric substance than did strains 2Bp and Sts 4-3. All five strains converted about 80% of the S added as CS2 to S(0) when CS2 was supplied in excess. The rate of S(0) consumption varied between 7 (Sts 4-3) and 63 (S1p) nmol O2 min(-1) ml culture(-1). Low S(0) consumption rates correlated partly with low levels of cell attachment to externally produced S(0) globules. During chemostat growth, the relative amount of CS2 hydrolase in the cell increased with decreasing growth rates. This resulted in more S(0) accumulation during CS2 overloads at low growth rates. Intermittent interruptions of the CS2 supply affected all five strains. Strains S1p, G8, and BBW1 recovered from 24 h of starvation within 4 h, and strains 2Bp and Sts 4-3 recovered within 24 h after CS2 was resupplied. We recommend the use of mixtures of Acidithiobacillus strains in industrial biofilters.

Carbon disulfide exposure induced lung function reduction partly through oxidative protein damage: A cross-sectional and longitudinal analysis.

Carbon disulfide (CS2) exposure has been associated with lung function reduction in occupational population. However, evidence on the general population with relatively low CS2 exposure is lacking and the mechanism involved remains largely unknown. Urinary CS2 metabolite (2-mercaptothiazolidine-4-carboxylic acid, TTCA) and lung function were determined in the urban adults from the Wuhan-Zhuhai cohort at baseline in 2011-2012 and were repeated every 3 years. Cross-sectional and longitudinal associations between TTCA and lung function were estimated using linear mixed models. Inflammation and oxidative damage biomarkers in blood/urine were measured to evaluate their potential mediating roles involved. Cross-sectionally, participants in the highest quartile of TTCA level showed a 0.64% reduction in FEV1/FVC and a -308.22 mL/s reduction in PEF, compared to those in the lowest quartile. Longitudinally, participants with consistently high TTCA level had annually -90.27 mL/s decline in PEF, compared to those with consistently low TTCA level. Mediation analysis revealed that plasma protein carbonyl mediated 49.89% and 22.10% of TTCA-associated FEV1/FVC and PEF reductions, respectively. Conclusively, there was a cross-sectional and longitudinal association between CS2 exposure and lung function reduction in the general urban adults, and protein carbonylation (oxidative protein damage) partly mediated lung function reduction from CS2 exposure.

Could houseplants improve indoor air quality in schools?

Previous studies performed by the National Aeronautics Space Administration (NASA) indicated that plants and associated soil microorganisms may be used to reduce indoor pollutant levels. This study investigated the ability of plants to improve indoor air quality in schools. A 9-wk intensive monitoring campaign of indoor and outdoor air pollution was carried out in 2011 in a primary school of Aveiro, Portugal. Measurements included temperature, carbon dioxide (CO2), carbon monoxide (CO), concentrations of volatile organic compounds (VOC), carbonyls, and particulate matter (PM10) without and with plants in a classroom. PM10 samples were analyzed for the water-soluble inorganic ions, as well for carbonaceous fractions. After 6 potted plants were hung from the ceiling, the mean CO2 concentration decreased from 2004 to 1121 ppm. The total VOC average concentrations in the indoor air during periods of occupancy without and with the presence of potted plants were, respectively, 933 and 249 µg/m³. The daily PM10 levels in the classroom during the occupancy periods were always higher than those outdoors. The presence of potted plants likely favored a decrease of approximately 30% in PM10 concentrations. Our findings corroborate the results of NASA studies suggesting that plants might improve indoor air and make interior breathing spaces healthier.

Extremely acidophilic sulfur-oxidizing bacteria applied in biotechnological processes for gas purification.

Extreme acidophilic (pH ~ 0.25) microorganisms have been studied and applied to treat volatile sulfur emissions like carbon disulfide. These microorganisms provide opportunities for biomass control and recycling of sulfuric acid using extremely low pH operating conditions as shown in 70 L bench-scale bioreactors. Applying the extreme acidophilic bacteria in full-scale bioreactors treating carbon disulfide in combination with hydrogen sulfide emissions from industrial processes like the viscose industry was shown to be effective with average total sulfur removal efficiency above 90%.

Prodrugs of Persulfides, Sulfur Dioxide, and Carbon Disulfide: Important Tools for Studying Sulfur Signaling at Various Oxidation States.

Significance: Bioactive sulfur species such as hydrogen sulfide (H2S), persulfide species (R-SnSH, n ≥ 1), hydrogen polysulfide (H2Sn, n ≥ 2), sulfur dioxide (SO2), and carbon disulfide (CS2) participate in various physiological and/or pathological pathways such as vasodilation, apoptosis, inflammation, and energy metabolism regulation. The oxidation state of the individual sulfur species endows them unique biological activities. Recent Advances: There have been great strides made in achieving molecular understanding of the sulfur-signaling processes. Critical Issues: The development of various chemical tools that deliver reactive sulfur species in a controllable manner has played an important role in understanding the different roles of various sulfur species. In this review, we focus on three types of sulfur species, including persulfide, SO2, and CS2. Starting with a brief introduction of their physiological functions, we will then assess the various drug delivery strategies to generate persulfide species, SO2, and CS2 as research tools and potentially as therapeutic agents. Future Directions: Development of donors of various sulfur species that respond to distinct stimulus is critical for this field. Another key to the long-term success of this field is the identification of an area of unmet medical need that can be addressed with these sulfur species.

Neutral hydrolyses of carbon disulfide: An ab initio study of water catalysis.

The water-catalyzed hydrolysis reaction of carbon disulfide (CS(2)) has been investigated at the levels of HF and MP2 with the basis set of 6-311++G(d,p) using the combined supramolecular/continuum models, in which up to six water molecules are involved in the hydrolysis and the effect of water bulk solvent is taken into account according to the polarizable continuum model (PCM). The activation Gibbs free energies in water solution, DeltaG(sol) (not equal) (298 K), for the rate-determining steps of one up to six water hydrolyses are 247.9, 184.2, 152.3, 141.8, 134.4, and 118.9 kJ/mol, respectively. The most favorable hydrolysis path of CS(2) involves a sort of eight-membered ring transition structure formed by six water molecules, among which three water molecules are not involved in the proton transfer, two near to the nonreactive sulfur atom, and one below the parent carbon disulfide. This suggests that the hydrolysis of CS(2) can be mediated with the water molecule(s) and be significantly facilitated by the cooperative effects of the water molecule(s) in the nonreactive region. The catalytic effects of water molecule(s) due to the alleviation of ring strain in the proton transfer process may result from the synergistic effects of rehybridization and charge reorganization from the prereaction complex to the rate-determining transition state structure induced by water molecule(s). PCM solvation models could significantly lower the rate-determining activation Gibbs free energies by 20-38 kJ/mol when two up to six explicit water molecules involved in the neutral hydrolysis of CS(2).

A breath test to assess compliance with disulfiram.

AIMS: To evaluate the ability of a hand-held breath analyser, the Zenalyser((R)) (Zenics Medical), to identify alcohol-dependent patients receiving disulfiram therapy and to assess the sensitivity and specificity of the instrument at different time intervals post-disulfiram dosing. DESIGN: Breath samples were taken from two groups of alcohol-dependent patients, one group on a daily disulfiram regimen and one group receiving no disulfiram. The breath samples were analysed for the combined concentration of carbon disulphide and acetone produced from the metabolism of disulfiram. From these data, two reference ranges were prepared and used for sensitivity and specificity assessments. SETTING: Breath samples for the reference ranges were obtained from patients at Shelton Hospital, Shrewsbury. Breath samples used to assess the sensitivity and specificity of the instrument were obtained from patients at the Edinburgh Alcohol Problems Clinic. PARTICIPANTS: Twenty in-patients from Shelton Hospital receiving a daily 200 mg disulfiram regimen and 20 in-patients receiving no disulfiram. At the Edinburgh Clinic, 54 patients taking a thrice-weekly disulfiram regimen and 22 patients not on disulfiram. MEASUREMENTS: A total of 489 breath samples from Shelton Hospital and 391 breath samples from the Edinburgh Clinic were analysed for the combined concentrations of carbon disulphide and acetone. FINDINGS: The breath analyser produced results that distinguished between the disulfiram-treated and untreated groups (P < 0.001). At 1 day post-dose, the sensitivity was 100% and the specificity was 100%. At 2 and 3 days post-dose, the sensitivities and specificities were 84.6% and 100% and 88.2% and 100%, respectively. CONCLUSION: The breath analyser can improve the assessment of the compliance status of patients receiving a daily dose regimen of disulfiram, but is less useful for this purpose if disulfiram is taken on a thrice-weekly regimen.

Abiotic synthesis of organic compounds from carbon disulfide under hydrothermal conditions.

Abiotic formation of organic compounds under hydrothermal conditions is of interest to bio, geo-, and cosmochemists. Oceanic sulfur-rich hydrothermal systems have been proposed as settings for the abiotic synthesis of organic compounds. Carbon disulfide is a common component of magmatic and hot spring gases, and is present in marine and terrestrial hydrothermal systems. Thus, its reactivity should be considered as another carbon source in addition to carbon dioxide in reductive aqueous thermosynthesis. We have examined the formation of organic compounds in aqueous solutions of carbon disulfide and oxalic acid at 175 degrees C for 5 and 72 h. The synthesis products from carbon disulfide in acidic aqueous solutions yielded a series of organic sulfur compounds. The major compounds after 5 h of reaction included dimethyl polysulfides (54.5%), methyl perthioacetate (27.6%), dimethyl trithiocarbonate (6.8%), trithianes (2.7%), hexathiepane (1.4%), trithiolanes (0.8%), and trithiacycloheptanes (0.3%). The main compounds after 72 h of reaction consisted of trithiacycloheptanes (39.4%), pentathiepane (11.6%), tetrathiocyclooctanes (11.5%), trithiolanes (10.6%), tetrathianes (4.4%), trithianes (1.2%), dimethyl trisulfide (1.1%), and numerous minor compounds. It is concluded that the abiotic formation of aliphatic straight-chain and cyclic polysulfides is possible under hydrothermal conditions and warrants further studies.

Loss of 3-methylcholanthrene-inducible form of cytochrome P-450 in liver microsomes following administration of carbon disulfide in C57BL/6 Cr mice.

Early after administration of CS2 to untreated, phenobarbital (PB)-and 3-methylcholanthrene (3-MC)-pretreated C57BL/6 Cr mice: (1) the loss of cytochrome P-450 was enhanced by pretreatment with both inducers, but to a greater extent with 3-MC; (2) the decrease in 7-ethoxyresorufin (ER) O-deethylation activity was much greater than that of cytochrome P-450 in untreated and PB-pretreated mice, but both paralleled values in 3-MC-pretreated mice, in which ER O-deethylation activity was induced markedly, (3) the peak of the carbon monoxide-difference spectrum of microsomal reduced cytochrome P-450 (about 448 nm) in 3-MC-pretreated mice shifted toward 450 nm after administration of increasing doses of CS2; (4) similar tendencies were observed in vitro in items (1) to (3); (5) electrophoresis of microsomal proteins revealed a loss of each protein band induced by PB and 3-MC following CS2 administration; (6) in the reconstituted monooxygenase system using partially purified cytochrome P-450 and P-448 forms from PB- and 3-MC-treated rats, CS2 suppressed the drug-metabolizing activities exhibited by the P-448 form but had little or no effect on those by the P-450 form; and (7) in n-octylamine difference spectra of microsomes, loss of the 3-MC-induced high spin form of cytochrome P-450 was evident. These results indicate that the 3-MC-inducible form of cytochrome P-450 was more susceptible to CS2 than the PB-inducible form. The hepato-necrogenic action of CS2 was not enhanced by PB or 3-MC pretreatment in mice.

Oxidative metabolism of carbon disulfide by isolated rat hepatocytes and microsomes.

The oxidative metabolism of carbon disulfide (CS2) was investigated in isolated rat hepatocytes and liver microsomes. In microsomes, CS2 metabolism was increased by phenobarbital pretreatment of the rats and decreased with pretreatment of the rats with cobaltous chloride. In both microsomes and hepatocytes, CS2 metabolism was inhibited by SKF-525A. Carbon dioxide (CO2) was the major volatile metabolite of CS2 in hepatocytes, and carbonyl sulfide (COS) was the major volatile metabolite in microsomal incubations. Addition of cytosol to microsomal incubations shifted the predominant volatile metabolite from COS to CO2 but did not change total volatile metabolite formation. Acetazolamide, a carbonic anhydrase inhibitor, significantly decreased COS metabolism but not CS2 metabolism in isolated hepatocytes or microsomes fortified with dialyzed cytosol. When [18O]H2O was included in incubations of microsomes and CS2, a substantial portion of the resulting COS was [18O] enriched, indicating that the oxygen atom was derived from water. These data are consistent with the hypothesis that CS2 is oxidized predominantly by the cytochrome P-450 containing monooxygenase system, and the product of this reaction is an unstable intermediate which reacts with water to form monothiocarbonate and reactive sulfur species. Monothiocarbonate is the hydrated form of COS. In intact hepatocytes, it is metabolized predominantly to CO2 and hydrogen sulfide. Unmetabolized monothiocarbonate can be dehydrated to COS. The majority of the reactive sulfur species and hydrogen sulfide are oxidized to nonvolatile sulfur compounds, including sulfate, but by different mechanisms.

Diethyldithiocarbamate depresses the acoustic startle response in rats.

The relationship between norepinephrine (NE) content in cortex and spinal cord and acoustic startle amplitude was investigated in two experiments. Administration of diethyldithiocarbamate (DDC) depressed startle amplitude at the same time and dose that it most severely depleted NE content. These results support the conclusion that NE facilitates the normal elaboration of the acoustic startle reflex and also support evidence that NE activity in the spinal cord may be of particular importance in the maintenance of normal startle amplitude.

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.

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.