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Annals of Human Biology 2001The ability to taste the bitter compound phenylthiocarbamide (PTC) and related chemicals is bimodal, and all human populations tested to date contain some people who can... (Review)
Review
The ability to taste the bitter compound phenylthiocarbamide (PTC) and related chemicals is bimodal, and all human populations tested to date contain some people who can and some people who cannot taste PTC. Why this trait has been maintained in the population is uncertain but this polymorphism may influence food selection, nutritional status or thyroid metabolism. The gene product that gives rise to this phenotype is unknown, and its characterization would provide insight into the mechanism of bitter taste perception. Although this trait is often considered a simple Mendelian trait, i.e. one gene two alleles, a recent linkage study found a major locus on chromosome 5p15 and evidence for an additional locus on chromosome 7. The development of methods to identify these genes will provide a good stepping-stone between single-gene disorders and polygenic traits.
Topics: Antimetabolites; Genetics, Population; Humans; Phenotype; Phenylcarbamates; Propylthiouracil; Structure-Activity Relationship; Taste; Thiocarbamates
PubMed: 11293722
DOI: 10.1080/03014460151056310 -
Current Medicinal Chemistry 2017Nicotinic acetylcholine receptors (nAChRs) of insects play a key role in fast excitatory neurotransmission. Several classes of insecticides target insect nAChRs, which... (Review)
Review
BACKGROUND
Nicotinic acetylcholine receptors (nAChRs) of insects play a key role in fast excitatory neurotransmission. Several classes of insecticides target insect nAChRs, which are composed of subunit members of a family of multiple subunit encoding genes. Alternative splicing and RNA A-to-I editing can add further to receptor diversity. Native and recombinant receptors have been explored as sites of insecticide action using radioligands, electrophysiology and site-directed mutagenesis.
METHODS
We have reviewed the properties of native and recombinant insect nAChRs, the challenges of functional recombinant insect nAChR expression, nAChR interactions with ligands acting at orthosteric and allosteric sites and in particular their interactions with insecticides.
RESULTS
Actions on insect nAChRs of cartap, neonicotinoids, spinosyns, sulfoxamines, butenolides and mesoionic insecticides are reviewed and current knowledge of their modes of action are addressed. Mutations that add to our understanding of insecticide action and those leading to resistance are discussed. Co-crystallisation of neonicotinoids with the acetylcholine binding protein (AChBP), a surrogate for the nAChR ligand binding domain, has proved instructive. Toxicity issues relating to insecticides targeting nAChRs are also considered.
CONCLUSION
An overview of insecticide classes targeting insect nAChRs has enhanced our understanding of these important receptors and their insecticide binding sites. However, the subunit composition of native nAChRs remains poorly understood and functional expression still presents difficulties. These topics together with improved understanding of the precise sites of insecticide actions on insect nAChRs will be the subject of future research.
Topics: Animals; Drug Resistance; Humans; Insecticides; Macrolides; Neurons; Nicotine; Protein Binding; Pyridines; Pyrimidinones; Receptors, Nicotinic; Recombinant Proteins; Thiocarbamates
PubMed: 28176635
DOI: 10.2174/0929867324666170206142019 -
Cells May 2020Drug repurposing appears to offer an attractive alternative in finding new anticancer agents. Their applicability seems to have multiple benefits, among which are the...
Drug repurposing appears to offer an attractive alternative in finding new anticancer agents. Their applicability seems to have multiple benefits, among which are the potential of immediate efficacy assessment in clinical trials and the existence of patient safety and tolerability evidence. Nevertheless, their effective application in terms of tumor-type targeting requires accurate knowledge of their exact mechanism of action. In this review, we present such a successful drug, namely Disulfiram (commercially known as Antabuse), and discuss its recently uncovered mode of anticancer action through DNA damage.
Topics: Animals; Cell Proliferation; DNA Damage; Disulfiram; Drug Repositioning; Humans; Neoplasms
PubMed: 32414147
DOI: 10.3390/cells9051210 -
Mini Reviews in Medicinal Chemistry Oct 2012Over the past 30 years dithiocarbamate ligands have found application in radiopharmaceutical metal-ligand complexes to image a range of disease states. The vast majority... (Review)
Review
Over the past 30 years dithiocarbamate ligands have found application in radiopharmaceutical metal-ligand complexes to image a range of disease states. The vast majority of research and applications, and the widest range of complex structures, have involved radionuclides of technetium and rhenium. Considering the extent of coordination chemistry of dithiocarbamate ligands described elsewhere in this issue, the extent of radiopharmaceutical application with metallic radionuclides is surprisingly narrow. Here we summarise the types of radiopharmaceutical complexes studied and the uses, and potential uses, to which they have been put in nuclear medicine.
Topics: Bismuth; Cobalt; Coordination Complexes; Copper; Diagnostic Imaging; Gold; Humans; Radiopharmaceuticals; Rhenium; Technetium; Thallium; Thiocarbamates
PubMed: 22931590
DOI: 10.2174/138955712802762112 -
Biosensors Dec 2020Dithiocarbamate fungicides (DTFs) are widely used to control various fungal diseases in crops and ornamental plants. Maximum residual limits in the order of ppb-ppm are... (Review)
Review
Dithiocarbamate fungicides (DTFs) are widely used to control various fungal diseases in crops and ornamental plants. Maximum residual limits in the order of ppb-ppm are currently imposed by legislation to prevent toxicity problems associated with excessive use of DTFs. The specific analytical determination of DTFs is complicated by their low solubility in water and organic solvents. This review summarizes the current analytical procedures used for the analysis of DTF, including chromatography, spectroscopy, and sensor-based methods and discusses the challenges related to selectivity, sensitivity, and sample preparation. Biosensors based on enzymatic inhibition demonstrated potential as analytical tools for DTFs and warrant further research, considering novel enzymes from extremophilic sources. Meanwhile, Raman spectroscopy and various sensors appear very promising, provided the selectivity issues are solved.
Topics: Biosensing Techniques; Fungicides, Industrial; Thiocarbamates
PubMed: 33396914
DOI: 10.3390/bios11010012 -
Biochemical Pharmacology Dec 2020Hydrogen sulfide (HS) is an endogenous mammalian gasotransmitter. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase...
BACKGROUND
Hydrogen sulfide (HS) is an endogenous mammalian gasotransmitter. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) are the principal enzymes responsible for its biogenesis. A recent yeast screen suggested that disulfiram (a well-known inhibitor of aldehyde dehydrogenase and a clinically used drug in the treatment of alcoholism) may inhibit CBS in a cell-based environment. However, prior studies have not observed any direct inhibition of CBS by disulfiram. We investigated the potential role of bioconversion of disulfiram to bis(N,N-diethyldithiocarbamate)-copper(II) complex (CuDDC) in the inhibitory effect of disulfiram on HS production and assessed its effect in two human cell types with high CBS expression: HCT116 colon cancer cells and Down syndrome (DS) fibroblasts.
METHODS
HS production from recombinant human CBS, CSE and 3-MST was measured using the fluorescent HS probe AzMC. Mouse liver homogenate (a rich source of CBS) was also employed to measure HS biosynthesis. The interaction of copper with accessible protein cysteine residues was evaluated using the DTNB method. Cell proliferation and viability were measured using the BrdU and MTT methods. Cellular bioenergetics was evaluated by Extracellular Flux Analysis.
RESULTS
While disulfiram did not exert any significant direct inhibitory effect on any of the HS-producing enzymes, its metabolite, CuDDC was a potent inhibitor of CBS and CSE. The mode of its action is likely related to the complexed copper molecule. In cell-based systems, the effects of disulfiram were variable. In colon cancer cells, no significant effect of disulfiram was observed on HS production or proliferation or viability. In contrast, in DS fibroblasts, disulfiram inhibited HS production and improved proliferation and viability. Copper, on its own, failed to have any effects on either cell type, likely due to its low cell penetration. CuDDC inhibited HS production in both cell types studied and exerted the functional effects that would be expected from a CBS inhibitor: inhibition of cell proliferation of cancer cells and a bell-shaped effect (stimulation of proliferation at low concentration and inhibition of these responses at higher concentration) in DS cells. Control experiments using a chemical HS donor showed that, in addition to inhibiting CBS and CSE, part of the biological effects of CuDDC relates to a direct reaction with HS, which occurs through its complexed copper.
CONCLUSIONS
Disulfiram, via its metabolite CuDDC acts as an inhibitor of CBS and a scavenger of HS, which, in turn, potently suppresses HS levels in various cell types. Inhibition of HS biosynthesis may explain some of the previously reported actions of disulfiram and CuDDC in vitro and in vivo. Disulfiram or CuDDC may be considered as potential agents for the experimental therapy of various pathophysiological conditions associated with HS overproduction.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Animals; Cell Survival; Chelating Agents; Copper; Cystathionine beta-Synthase; Disulfiram; Ditiocarb; Dose-Response Relationship, Drug; Female; HCT116 Cells; Humans; Liver; Mice; Mice, Inbred BALB C; Organometallic Compounds
PubMed: 33035509
DOI: 10.1016/j.bcp.2020.114267 -
Ecotoxicology and Environmental Safety Jan 2019The Amphibian Metamorphosis Assay (AMA) is a screening test for detecting chemicals with thyroid activity. There is little experience in data interpretation and in using...
The Amphibian Metamorphosis Assay (AMA) is a screening test for detecting chemicals with thyroid activity. There is little experience in data interpretation and in using AMA data for screening, testing and identifying endocrine disruptors. To investigate the sensitivity of different endpoints of the AMA, the publically available data for 57 thyroid active and inactive chemicals were compiled and analyzed. Endpoints body weight and length appeared as sensitive as apical thyroid responsive endpoints hind limb length (HLL) and developmental stage (DS) for 12 thyroid active chemicals. The sensitivity of body weight, length and HLL was comparable, which is higher than that of DS for 45 thyroid inactive chemicals. The decision logic of the AMA suggests that an advanced development alone indicates thyroid activity. The analysis here showed that advanced development at day 7 could indicate thyroid activity of a chemical. However, advanced development at day 21 may be influenced by thyroid inactive chemicals. Among 39 thyroid inactive chemicals, which affected one or more endpoints, 33% and 77% induced changes in HLL and/or DS at day 7 and 21, respectively; only 10% influenced thyroid histology. These results showed that apical thyroid responsive endpoints HLL and DS are influenced by thyroid active chemicals as well as thyroid inactive chemical. Both endpoints should be combined with thyroid histology for the identification of thyroid active chemicals. The use of the AMA in a testing strategy to identify chemicals with thyroid activity is discussed.
Topics: Acetanilides; Amphibians; Animals; Benzothiazoles; Biological Assay; Endocrine Disruptors; Endpoint Determination; Metamorphosis, Biological; Thiocarbamates; Thyroid Gland; Toxicity Tests; Triazines; Xenopus laevis
PubMed: 30384058
DOI: 10.1016/j.ecoenv.2018.10.028 -
Systematic Reviews Jun 2022Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and...
BACKGROUND AND OBJECTIVES
Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Disulfiram (DSF), as an anti-alcoholic drug, kills the cancer cells by inducing apoptosis. Several preclinical and clinical studies have examined the potential of repurposing DSF as an anticancer treatment. This systematic review aimed to assess evidence regarding the antineoplastic activity of DSF in in vitro and in vivo models, as well as in humans.
METHODS
Two authors independently conducted this systematic review of English and Chinese articles from the PubMed, Embase, and the Cochrane Library databases up to July 2019. Eligible in vitro studies needed to include assessments of the apoptosis rate by flow cytometry using annexin V/propidium iodide, and studies in animal models and clinical trials needed to examine tumor inhibition rates, and progression-free survival (PFS) and overall survival (OS), respectively. Data were analyzed using descriptive statistics.
RESULTS
Overall, 35 studies, i.e., 21 performed in vitro, 11 based on animal models, and three clinical trials, were finally included. In vitro and animal studies indicated that DSF was associated with enhanced apoptosis and tumor inhibition rates, separately. Human studies showed that DSF prolongs PFS and OS. The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule. There was no noticeable body weight loss after DSF treatment, which indicated that there was no major toxicity of DSF.
CONCLUSIONS
This systematic review provides evidence regarding the anti-tumor activity of DSF in vitro, in animals, and in humans and indicates the optimal forms of treatment to be evaluated in future research.
Topics: Animals; Antineoplastic Agents; Disulfiram; Humans; Neoplasms
PubMed: 35655266
DOI: 10.1186/s13643-021-01858-4 -
ACS Chemical Biology Feb 2019Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One...
Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One important class of triggerable HS donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to HS by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than HS. Here, we report a suite of modular esterase-triggered self-immolative COS donors and include the synthesis, HS release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple HS shuttle in certain biological systems.
Topics: Esterases; HeLa Cells; Humans; Sulfur Oxides; Thiocarbamates
PubMed: 30640440
DOI: 10.1021/acschembio.8b00981 -
Journal of Applied Microbiology Jan 2019Disulfiram (Antabuse™) and its metabolites formed in vivo were evaluated as antibacterial agents against thirty species of Gram-positive and Gram-negative bacteria....
AIMS
Disulfiram (Antabuse™) and its metabolites formed in vivo were evaluated as antibacterial agents against thirty species of Gram-positive and Gram-negative bacteria. The synergistic potential of disulfiram (DSF) and metabolite diethyldithiocarbamate (DDTC) with approved antibiotics were also compared by isobologram (checkerboard) analysis.
METHODS AND RESULTS
Standard microdilution susceptibility testing showed that most DSF metabolites did not possess appreciable antibacterial activity except for DDTC in Bacillus anthracis. Checkerboard studies revealed similarities between the combination drug effects of DSF and DDTC with standard antibiotics.
CONCLUSIONS
It was concluded from the susceptibility data that the metabolites would not extend the antibacterial spectrum of DSF in vivo. The data also suggest that the DDTC by-product of DSF metabolism potentiates the antibacterial activity of DSF as both a standalone and combination agent.
SIGNIFICANCE AND IMPACT OF THE STUDY
The study provides a greater understanding of the antibacterial effects of Antabuse and its metabolites. This research also demonstrates the potential application of DSF as an antibiotic adjuvant for the treatment of resistant staph infections.
Topics: Anti-Bacterial Agents; Disulfiram; Ditiocarb; Gram-Negative Bacteria; Gram-Positive Bacteria
PubMed: 30160334
DOI: 10.1111/jam.14094