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At least 217 records · Page 12Linked to original sources
PubMed1988

Effects of capsaicin and isothiocyanate on thermogenesis of interscapular brown adipose tissue in rats.

To clarify whether capsaicin or isothiocyanate, which are found in common spices, activate brown adipose tissue (BAT) function, BAT temperature, mitochondrial guanosine diphosphate (GDP) binding (a thermogenic indicator), and mitochondrial oxygen consumption were measured in interscapular brown adipose tissue (IBAT) of rats. Intramuscular injection of capsaicin (0.7 mg/kg) or isothiocyanate (3.0 mg/kg) increased significantly IBAT temperature without affecting the rectal temperature, a possible side effect, and increased significantly GDP binding and mitochondrial oxygen consumption in IBAT, as did administration of ephedrine (0.375 mg/kg). Therefore, the administration of capsaicin or isothiocyanate activates BAT function in rats.

Adipose Tissue, Brown↗
PubMed2000

Induction of NADPH:quinone oxidoreductase in murine hepatoma cells by methylsulfinyl isothiocyanates: methyl chain length-activity study.

Methylsulfinyl isothiocyanates (MITC) are a class of isothiocyanates occurring in a variety of cruciferous vegetables showing anticarcinogenic activity. To develop analogues of methylsulfinyl isothiocyanate with less toxicity and better biological activity, four types of methyl chain length (designated as 2-, 4-, 6- and 8-MITC) were synthesized. The murine hepatoma cells (Hepa 1c1c7) were treated with various concentrations of MITC, and then assessed for cell growth, enzyme activity and mRNA expression of the detoxifying enzyme NADPH:quinone oxidoreductase (QR). All of four MITC augmented the induction of QR activity and the expression of QR mRNA in a dose-dependent manner. In the non-toxic concentration range, an increase in the methyl chain length resulted in a higher QR induction in both activity and mRNA expression. However, increasing cytotoxicity was also observed by an increase in the methyl chain length. Our results suggested that 4- and 6-MITC as QR inducers appeared to be less toxic and even more potent.

Animals↗
PubMed2000

"Lysine is the Lord", thought some scientists in regard to the group interacting with fluorescein isothiocyanate in ATP-binding sites of P-type ATPases but, is it not cysteine?

Isothiocyanates are recognized inhibitors acting on ATP-binding sites of P-type ATPases. Detailed studies with modification of proteins in molecules of purified ATPases by fluorescein isothiocyanate (FITC) and consequent tryptic hydrolysis followed by isolation and sequencing of the respective peptide fragments revealed FITC bound to a lysine residue. This residue was then indicated to be essential for the interaction of ATP with the P-type ATPases. Nevertheless, upon an exchange by site directed mutagenesis of lysine, believed to be essential, the expected total inhibition of ATPase activity was missing. In addition, in the case of the plasma membrane Ca2+-ATPase, the residual activity still remained sensitive to FITC. It was attempted to explain the latter finding by hypothetical existence of some other lysine residue essential for the ATPase activity. On the contrary, in our previous studies we have shown that, based on the reactivity of isothiocyanates, the primary target of FITC in P-type ATPases has to be the SH group of a cysteine residue. However, later on, in altered conditions during trypsinolysis and sequencing, FITC may become transferred from its original site of interaction to a lysine residue and this may lead to final identification of the label on a false place. The present study represents all attempt of elucidating the controversy whether it is lysine or cysteine that represents the FITC-sensitive group truly responsible for the recognition by the active site of P-type ATPases of ATP and its binding.

Adenosine Triphosphatases↗
PubMed2004

Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells.

Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, offers significant protection against cancer in animals induced by a variety of carcinogens. The present study demonstrates that PEITC suppresses proliferation of PC-3 cells in a dose-dependent manner by causing G(2)-M-phase cell cycle arrest and apoptosis. Interestingly, phenyl isothiocyanate (PITC), which is a structural analogue of PEITC but lacks the -CH(2) spacers that link the aromatic ring to the -N=C=S group, neither inhibited PC-3 cell viability nor caused cell cycle arrest or apoptosis. These results indicated that even a subtle change in isothiocyanate (ITC) structure could have a significant impact on its biological activity. The PEITC-induced cell cycle arrest was associated with a >80% reduction in the protein levels of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C (Cdc25C; 24 h after treatment with 10 micro M PEITC), which led to an accumulation of Tyr(15) phosphorylated (inactive) Cdk1. On the other hand, PITC treatment neither reduced protein levels of Cdk1 or Cdc25C nor affected Cdk1 phosphorylation. The PEITC-induced decline in Cdk1 and Cdc25C protein levels and cell cycle arrest were significantly blocked on pretreatment of PC-3 cells with proteasome inhibitor lactacystin. A 24 h exposure of PC-3 cells to 10 micro M PEITC, but not PITC, resulted in about 56% and 44% decrease in the levels of antiapoptotic proteins Bcl-2 and Bcl-X(L), respectively. However, ectopic expression of Bcl-2 failed to alter sensitivity of PC-3 cells to growth inhibition or apoptosis induction by PEITC. Treatment of cells with PEITC, but not PITC, also resulted in cleavage of procaspase-3, procaspase-9, and procaspase-8. Moreover, the PEITC-induced apoptosis was significantly attenuated in the presence of general caspase inhibitor and specific inhibitors of caspase-8 and caspase-9. In conclusion, our data indicate that PEITC-induced cell cycle arrest in PC-3 cells is likely due to proteasome-mediated degradation of Cdc25C and Cdk1, and ectopic expression of Bcl-2 fails to confer resistance to PEITC-induced apoptosis. Furthermore, the results of the present study point toward involvement of both caspase-8- and caspase-9-mediated pathways in apoptosis induction by PEITC.

Acetylcysteine↗
PubMed2006

The phenylhexyl isothiocyanate induces apoptosis and inhibits leukemia cell growth in vivo.

Isothiocyanates are potent chemopreventive agents for carcinogen-induced cancers in rodents. The major mode of action for chemoprevention is cytoprotection i.e. inducing detoxifying enzymes to remove the carcinogens, thus blocking the initiation of carcinogenesis. Analysis has indicated that isothiocyanates also act at the post-initiation levels of carcinogenesis. We have also reported that the phenylhexyl isothiocyanate (PHI) induced growth arrest and apoptosis in human leukemia HL-60 cells in culture. Since then we have investigated the in vivo efficacy of PHI. The effects of PHI were evaluated in immunodeficient mice, with xenografts of human leukemia HL-60 cells. The maximum tolerated dose (MTD) was determined. The experimental mice received 80% of the MTD. Oral feedings of PHI significantly reduced tumor incidence (p<0.05) without overt toxicity. PHI inhibited cell cycle progression through the down-regulation of cyclin expression, Rb phosphorylation and the up-regulation of the cdk-inhibitors. Apoptosis was significantly increased in the treated tumors but not in the normal mouse tissues. In conclusion, PHI induced apoptosis and inhibited the growth of xenografts by targeting the cell cycle regulators. PHI induced selective apoptosis effects in the rapidly growing tumor cells but not in the normal tissues.

Animals↗
PubMed1991

Inhibition of tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) tumorigenesis with aromatic isothiocyanates.

4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogenic nitrosamine. At low doses, it induces primarily lung tumours in mice, hamsters and rats, regardless of the route of administration. Its unique organ specificity and potency suggest its possible role in the high incidence of lung cancer in smokers. The goal of this study was to find agents that would potentially prevent NNK tumorigenesis. Previous results led us to test phenethyl isothiocyanate (PEITC) on NNK tumorigenesis in a two-year bioassay in Fischer 344 rats. The NNK-treated group developed 80% lung tumour incidence, whereas NNK-treated rats fed PEITC diets had only 40% lung tumour incidence. Incidences in other organs were not affected by this treatment. We also tested PEITC in a 16-week, short-term bioassay against NNK-induced lung adenomas in A/J mice. Pretreatment of mice with PEITC by gavage at four daily doses of 5 mumol or 25 mumol reduced the formation of NNK-induced lung adenomas by 70% or 100%, respectively. Interestingly, benzyl isothiocyanate and phenyl isothiocyanate, the lower homologues of PEITC, were inactive in this bioassay. Using a protocol similar to that used in the bioassays, PEITC was shown to decrease DNA methylation by NNK in the lungs of rats and mice and suppress the metabolism of NNK by mouse lung microsomes. These results are consistent with the previous data, suggesting that the inhibition of NNK-induced lung tumour formation by PEITC is a consequence of reduced DNA methylation caused by inhibition of NNK metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effects of disulfiram, diethyldithiocarbamate, bisethylxanthogen, and benzyl isothiocyanate on glutathione transferase activities in mouse organs.

Four sulfur compounds known to inhibit tumorigenic effects of chemical carcinogens were administered to female CD-1 mice at 0.5% of the diet for 14 days, and their effects on cytosolic glutathione transferase (EC 2.5.1.18) specific activities were examined in liver, lung, kidney, urinary bladder, forestomach, proximal small intestine, and colon. Disulfiram, sodium diethyldithiocarbamate, bisethylxanthogen, and benzyl isothiocyanate elevated glutathione transferase specific activities in most of the organs examined. The four sulfur compounds differed in the extents and organ specificities of their effects on these enzyme activities. In the liver, bisethylxanthogen and benzyl isothiocyanate increased glutathione transferase activities to at least 3 times control levels and caused differential increases in the isozyme patterns observed after isoelectric focusing of the cytosols. Bisethylxanthogen also increased immunoreactive glutathione transferase in liver cytosol. Recrystallized disulfiram was less effective in enhancing hepatic glutathione transferase activities than was commercial (97%) disulfiram. Among the six extrahepatic organs examined, the small intestine and the forestomach exhibited the greatest response of glutathione transferase activities to each of the four sulfur compounds. Benzyl isothiocyanate was most effective in these "portal of entry" organs but less effective than bisethylxanthogen in the other extrahepatic organs examined. Bisethylxanthogen elicited significant increases in glutathione transferase activities in liver, lung, and small intestine even when administered at 0.01% to 0.05% of the diet, suggesting that this compound may have considerable potential as an inhibitor of carcinogens susceptible to enzymatic conjugation with glutathione.

Animals↗
PubMed1983

Selective and reversible inhibition of heart sarcolemmal (Na+ + K+)-ATPase by p-bromophenyl isothiocyanate. Evidence for a sulfhydryl group in the ATP-binding site of the enzyme.

Isothiocyanates are potent modifiers of thiol groups, and they have been successfully applied in studying the active site structure of renal (Na+ + K+)-ATPase. However, very little has been known on interactions of isothiocyanates with myocardial sarcolemmal ATPases. In the present study the mode of interaction and inhibitory effect of p-bromophenyl isothiocyanate (BPITC) on isolated rat heart sarcolemmal preparation ATPase activities not exhibiting (Mg-Ca)-ATPase activity was investigated. BPITC in concentrations of 10(-7)-10(-4) mol . l-1 inhibited selectively and non-competitively the (Na+ + K+)-ATPase activity in the sarcolemma with an ID50 around 2.10(-7) mol . l-1. The non-specific interaction of BPITC with bivalent cations, namely with Mg2+ and Ca2+, in the reaction system was eliminated by preincubation of membranes with BPITC keeping the ratio of inhibitor to membrane protein concentration constant. Under these conditions no considerable inhibitory effects were observed on Mg2+-ATPase or the low-affinity Ca2+-ATPase of sarcolemma. Preincubation of membranes with 2 mmol . l-1 ATP protected (Na+ + K+)-ATPase activity against inhibition by BPITC. The interaction of BIPTC with the sarcolemma proved to be reversible in the presence of beta-mercaptoethanol or dithiothreitol.

Adenosine Triphosphate↗
PubMed1996

Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetylcysteine for lung tumorigenesis in Fischer rats.

The purpose of this study is to evaluate the efficacy of three promising sulfur-containing compounds, 6-phenylhexyl isothiocyanate (PHITC), phenethyl isothiocyanate (PEITC), and N-acetylcysteine (NAC), as chemopreventive agents in a long-term bioassay for lung tumorigenesis in F344 rats. PEITC occurs as a constituent of certain cruciferous vegetables, PHITC is a synthetic homologue, and NAC is an endogenous substance. Male F344 rats were treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.c. injection at a dose of 1.5 mg/kg body weight three times weekly for 20 weeks. This dose regimen induced a 67% tumor incidence in the lung, a major target organ of NNK. PHITC or PEITC administered in the diet for 22 weeks, a period covering from 1 week before to 1 week after the NNK treatment, exhibited significant inhibition of lung tumorigenesis induced by NNK. The lung tumor incidences in the NNK-treated groups, fed a diet containing 4 mmol/kg (876 ppm) or 2 mmol/kg (438 ppm) PHITC, were 24 and 19% and were 9 and 17% in groups fed PEITC at concentrations of 8 mmol/kg (1304 ppm) or 4 mmol/kg (652 ppm), respectively. In contrast to isothiocyanates, NAC given in the diet at 80 mmol/kg (13056 ppm) or 40 mmol/kg (6528 ppm) exerted no inhibitory effects on the NNK-induced lung tumorigenesis. At the dose studied, NNK did not induce liver and pancreatic tumors in the treated animals, but a significant increase of nasal cavity tumor incidence was observed in the NNK-treated group. However, none of the test compounds showed any effect on the tumorigenesis in this tissue. This study demonstrated that PHITC and PEITC were potent chemopreventive agents for the NNK-induced lung tumorigenesis in F344 rats, whereas NAC was not active at all. These results support further evaluation of these compounds in chemoprevention studies.

Acetylcysteine↗
PubMed1978

Kinetic analysis of the inhibition of sulfate transport in human red blood cells by isothiocyanates.

A kinetic analysis of anion self-exchange in human red blood cells, in the presence of an irreversible inhibitor, is presented and applied to the study of the inactivation of sulfate transport by three isothiocyanates: 3-isothiocyano-1,5-naphthalenedisulfonic acid, disodium salt (INDS), 1-isothiocyano-4-naphthalene sulfonic acid, sodium salt, monohydrate (INS), and 1-isothiocyano-4-benzenesulfonic acid, sodium salt, monohydrate (IBS). The time dependence of the inhibition of sulfate transport by the isothiocyanates used could be described by a single exponential and could be shown to contain a reversible and an irreversible component. In each case a portion of sulfate efflux was found to be resistant to inactivation. The residual portion of the sulfate efflux varied with inhibitor: 4% for INS, 16% for INDS, and 34% for IBS. INS showed the largest reversible inhibitory effect (12% of the flux remaining at 0.2 mM inhibitor concentration), while INDS showed the weakest effect (92% of the flux remaining at 0.3 mM inhibitor concentration). IBS had the highest rate of inactivation while INDS had the lowest. The kinetic analysis further suggests that all three isothiocyanates bind reversibly to an inhibitory site on the membrane before they bind covalently, and therefore irreversibly, to the same site on the membrane. The equilibrium constant for the dissociation of the reversibly-bound complex, Ki, and the rate of irreversible inactivation after all membrane sites are reversibly bound, kmax, have been computed for all three inhibitors: INDS (Ki = 420 micron, kmax = 5.04 hr-1), INS (Ki = 148 micron, kmax = 6.48 hr-1), and IBS (Ki = 208 micron, k(max) = 8.11 hr-1).

Biological Transport, Active↗
PubMed1988

Etoxadrol-meta-isothiocyanate: a potent, enantioselective, electrophilic affinity ligand for the phencyclidine-binding site.

Etoxadrol-meta-isothiocyanate (2S,4S,6S-2-ethyl-2-(3-isothiocyanatophenyl)-2-piperidyl)1,3-dioxolane, 4a) has been synthesized and characterized as an irreversible ligand for the phencyclidine (PCP)-binding site. It is the first chiral electrophilic affinity ligand for this site to have been described. This affinity ligand is based upon etoxadrol, a 1,3-dioxolane known to have PCP-like effects in vivo and in vitro. Etoxadrol-meta-isothiocyanate was found to be four-five times more potent in vitro than metaphit (1-[1-(3- isothiocyanatophenyl)cyclohexyl]piperidine), the only previously known electrophilic affinity ligand for the PCP-binding site. The binding was shown to be highly enantioselective for etoxadrol-meta-isothiocyanate (4a). The 2R,4R,6R-enantiomer of 4a was essentially inactive. The ability of the 2S,4S,6S-enantiomer (4a) to interact with the benzodiazepine, muscarinic, and mu opioid receptor systems was also examined, and it was found not to interact with these receptor systems. It seems likely that 4a will prove to be a valuable tool in the study of structure and function of the PCP-binding site.

Acylation↗
PubMed1990

Effect of aromatic isothiocyanates on the functional properties of human hemoglobin. Role of the stereochemistry of the charged group.

The effect of chemical modification of hemoglobin with six derivatives of benzene isothiocyanate has been studied. The negatively charged reagents (isothiocyanates of benzoic and benzenesulfonic acids) markedly inhibit the interaction of hemoglobin with allosteric effectors such as H+, Cl- and organic phosphates; the affinity for heme ligands in the absence of effectors is reduced but cooperativity is maintained, making these modified hemoglobins suitable models for a possible 'blood substitute'. The only uncharged reagent tested (isothiocyanate of benzenesulfonamide) increases the oxygen affinity of hemoglobin and affects only slightly the interaction with heterotropic ligands; its potential use as an antisickling drug is under study.

Benzene Derivatives↗
PubMed1977

Reactions of cellulose isothiocyanates with thiol and amino compounds.

A cellulose isothiocyanate has been prepared by treatment of cellulose with 2,4-di-isocyanatotoluene followed by hydrolysis and reaction of the resulting amine with thiophosgene. The cellulose isothiocyanate was characterized by its binding capacity with respect to [14C]-glycine, [131 I]-human serum albumin, and 2-mercaptoethanol. An analytical method for binding capacity, based on reaction with [35 S]-alpha-toluenethiol, was developed. Because of the aromatic character of the NCS group of the cellulose isothiocyanate, the covalently bonded thiol can be quantitatively liberated.

Binding Sites↗
PubMed1993

Synthesis and binding properties of MK-801 isothiocyanates; (+)-3-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine hydrochloride: a new, potent and selective electrophilic affinity ligand for the NMDA receptor-coupled phencyclidine binding site.

Three new site-directed irreversible (wash-resistant) ligands for the high-affinity phencyclidine (PCP) binding site associated with the N-methyl-D-aspartate (NMDA) receptor were synthesized and their binding characteristics were studied. (+)-3- And (+)-2-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycl ohepten-5,10 - imine hydrochloride ((+)-8a,b.HCl) were prepared in four steps from the corresponding nitro derivatives (+)-4a,b, which were obtained by nitration of (+)-3 (MK-801). In the same way the optical antipode (-)-8a.HCl was synthesized from (-)-3. At a concentration of 100 nM, the 3-isothiocyanate derivative (+)-8a irreversibly labeled approximately 50% of the (+)-[3H]-3 binding sites, compared to 20 microM needed for its optical antipode (-)-8a and the 2-isothiocyanate (+)-8b. The apparent Ki values for reversible inhibition of (+)-[3H]-3 binding by (+)- and (-)-8a and (+)-8b were 37,838, and 843 nM, respectively. In contrast, metaphit (1b) and etoxadrol m-isothiocyanate (2b), two previously reported irreversible ligands for the PCP binding site, label about 50% of the (+)-[3H]-3 binding sites at 100 microM and 250 nM, respectively, with apparent Ki values for reversible inhibition of 535 and 94 nM. Compound (+)-8a is also a selective affinity ligand, displaying little or no irreversible in vitro affinity at 100 microM for opioid, benzodiazepine, muscarinic, and dopamine receptors. At a 25 microM concentration, (+)-8a caused an irreversible 52% reduction of binding to sigma 1-receptors. Compound (+)-8a is the most potent known electrophilic affinity label for the PCP binding site. Its potency and selectivity should enable it to be a valuable tool for the elucidation of the structure and function of the NMDA receptor-associated PCP binding site in the mammalian central nervous system.

Animals↗
PubMedDate not supplied

Oxidative conversion by rat liver microsomes of 2-naphthyl isothiocyanate to 2-naphthyl isocyanate, a genotoxicant.

The present study investigated the oxidative metabolism of 2-naphthyl isothiocyanate catalyzed by rat liver microsomes. Incubation of 2-naphthyl isothiocyanate, microsomes, and NADPH yielded either N,N'-di-2-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ureas were formed by the production of 2-naphthyl isocyanate, which reacted with its hydrolysis product, 2-aminonaphthalene, to yield the symmetrical urea or, with 2-aminofluorene, to form the mixed urea. Formation of N,N'-di-2-naphthylthiourea was also observed, since 2-aminonaphthalene reacted with the substrate. Urea formation was dependent on microsomes, NADPH, and O2. Use of microsomes from rats previously treated with Aroclor increased urea formation > or = 10-fold. The enzyme activity was inhibited by alpha-naphthoflavone, flavone, or CO and slightly inhibited by metyrapone, 7-ethoxycoumarin, or SKF-525A. It was not inhibited by methimazole or paraoxon. These data are consistent with a cytochrome P-450-dependent, oxidative desulfuration of the isothiocyanate to yield an isocyanate.

1-Naphthylisothiocyanate↗
PubMed1976

4-NN-dimethylaminoazobenzene 4'-isothiocyanate, a new chromophoric reagent for protein sequence analysis.

4-NN-Dimethylaminoazobenzene 4'-isothiocyanate was synthesized for the purpose of improving the ease and sensitivity of peptide sequence analysis. The method of 4-NN-dimethylaminoazobenzene 4'-isothiocyanate synthesis, the preparation of 24 4-NN-dimethylaminoazobenzene-4'-thiohydantoins of amino acids and their t.l.c. separation are described. All the thiohydantoins, except those of leucine and isoleucine, could be satisfactorily separated by chromatography on a two-dimensional polyamide sheet. The sensitive azo group permits the detection of 4-NN-dimethylaminoazobenzene-4'-thiohydantoins of amino acids as red spots down to pmol amounts directly on the sheet. A simple sensitive method for sequencing dipeptides and the first two or three N-terminal amino acids of proteins is also reported. The colour change of the spots from purple to blue to red after being exposed to HCl vapour, corresponding to the chemical change from 4-NN-dimethylaminoazobenzene-4' isothiocyanate to the 4-NN-dimethylaminoazobenzene-4'-thiocarbamoyl amino acid derivative to the 4-NN-dimethylaminoazobenzene-4'-thiohydantoin amino acid derivative, reveals a very interesting and valuable feature of this reagent.

Amino Acid Sequence↗
PubMed1993

Chemotaxis away from thiocyanic and isothiocyanic esters in Pseudomonas aeruginosa.

Negative chemotaxis, the movement of organisms away from chemicals, was investigated in Pseudomonas aeruginosa using a rapid videotape method. Digital image processing was used to detect changes in bacterial numbers near the mouth of a capillary containing a test chemical. P. aeruginosa was found to be repelled by thiocyanic and isothiocyanic esters including allyl isothiocyanate, ethyl thiocyanate, methyl isothiocyanate and methyl thiocyanate. Particularly, the movement of bacteria away from methyl thiocyanate was so drastic that bacterial numbers near the mouth of the capillary decreased by approximately 80% within 30 s after the start of observation. Mutant strains, fully motile but lacking positive chemotaxis, did not escape away from the esters, suggesting a common mechanism between positive and negative chemotaxes in this organism.

Chemotaxis↗