Inhibitory action of dithiocarbamates on enzymes of animal tissues

DuBois, Kenneth P.; Raymund, Ann B.; Hietbrink, Bernard E.

doi:10.1016/s0041-008x(61)80009-4

Cited by 46 publications

(6 citation statements)

References 12 publications

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“…In particular, the polymeric dithiocarbamate pesticides affected multiple kinase and phosphatase assays that require divalent cations (magnesium or manganese) and/or have active site cysteine residues sensitive to oxidation. This specific effect was noted previously for maneb, mancozeb, and metiram, consistent with a mechanism of action associated with the inhibition of metal-dependent and sulfhydryl enzymes, , and seems to be specific to these compounds across the broader chemical landscape tested here. Lastly, compounds containing tin (e.g., tributyltin) and mercury (e.g., phenylmercuric acetate) broadly disrupted GPCR ligand-binding activities but not kinase or phosphatase activities.…”

Section: Discussionsupporting

confidence: 89%

Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

Sipes

Martin

Kothiya

et al. 2013

Chem. Res. Toxicol.

173

166

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Understanding potential health risks is a significant challenge due to the large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phases I and II of the U.S. EPA’s ToxCast project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical–assay pairs). Some of the most commonly affected assays were CYPs (CYP2C9 and CYP2C19), transporters (mitochondrial TSPO, norepinephrine, and dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous but distinctly different patterns of activity, whereas many of the pharmaceutical compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical–assay pairs (54) but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical–target combinations clustered with known chemical–target interactions. Results from this large inventory of chemical–biological interactions can inform read-across methods as well as link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.

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Section: Discussionsupporting

confidence: 89%

Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

Sipes

Martin

Kothiya

et al. 2013

Chem. Res. Toxicol.

173

166

View full text Add to dashboard Cite

show abstract

“…Since the enzyme has such a great affinity for disulfiram even in the presence of high concentrations of reduced gluthathione (Kitson, 1981), the necessary concentration of disulfiram itself need not be high. Substances such as cytochrome c, methaemoglobin and xanthine oxidase have the capacity to oxidize diethyldithiocarbamate (DuBois et al, 1961;Stromme, 1963;Fried, 1976 therefore the cyclic scheme shown in Scheme 1 is suggested. In this, depending on the relative rates of re-oxidation and catabolism (Faiman et al, 1978) of diethyldithiocarbamate, a single molecule of disulfiram has the potential to inactivate many enzyme molecules, acting in effect as a redox catalyst.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram

Kitson¹

1983

Biochemical Journal

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Stoicheiometric amounts of [14C]disulfiram react rapidly with sheep liver cytoplasmic aldehyde dehydrogenase to give loss of catalytic activity and incorporation of the expected amount of radioactivity. In a subsequent slower reaction the label is lost from the enzyme without re-emergence of enzymic activity. The results imply that in vivo disulfiram may act as an oxidation-reduction catalyst for the inactivation of aldehyde dehydrogenase.

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“…DE-DTC is a metal-chelating agent [2] and thus could chelate metal ions necessary for cell growth. DE-DTC is also known to react with amino or sulfhydryl groups of proteins [1] and thus could inactivate nutrients for cells. DE-DTC could also possibly react with amino and sulfhydryl groups of cell membranes.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Mechanisms Involved in Sodium Diethyl Dithiocarbamate-Induced Immunomodulation Using the Hydrophilic Analog, Sodium N-Methyl-<i>D</i>-Glucamine Dithiocarbamate

Neveu¹,

Perdoux²

1986

Int Arch Allergy Immunol

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Sodium diethyl dithiocarbamate (DE-DTC) is a lipophilic low molecular weight sulphur compound previously demonstrated to be a potent immunomodulator but cytotoxic in vitro. In this work, we studied the effects on a hydrophilic analog of DE-DTC, sodium N-Methyl-D-glucamine dithiocarbamate (NMG-DTC) on immune responses to a hapten carrier conjugate and on mitogen-induced lymphoproliferation. NMG-DTC, in contrast to DE-DTC, did not modify the responses to a hapten-carrier conjugate. The immunomodulatory activity of DE-DTC appeared to be linked with its lipophilicity. NMG-DTC had a slight inhibitory effect on thymidine incorporation by lymphocytes stimulated by mitogens as compared to that of DE-DTC. DE-DTC was cytotoxic possibly at the cell membrane level; cytotoxicity was not related to the chelating properties of DE-DTC in the culture medium. On the other hand, NMG-DTC appeared to be a less cytotoxic molecule. Therefore it could be useful to study the effects of the dithiocarbamate moiety at the cellular level.

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Inhibitory action of dithiocarbamates on enzymes of animal tissues

Cited by 46 publications

References 12 publications

Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram

Evaluation of the Mechanisms Involved in Sodium Diethyl Dithiocarbamate-Induced Immunomodulation Using the Hydrophilic Analog, Sodium N-Methyl-<i>D</i>-Glucamine Dithiocarbamate

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