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PubMedDate not supplied

Protective effects of isothiocyanates towards N-nitrosamine-induced DNA damage in the single-cell gel electrophoresis (SCGE)/HepG2 assay.

The aim of this study was to investigate the protective effect of isothiocyanates towards N-nitrosamine-induced DNA damage in the single-cell gel electrophoresis (SCGE)/HepG2 assay. None of the isothiocyanates (ITCs) concentrations tested in the presence or absence of formamidopyrimidine-DNA glycosylase (Fpg) caused DNA damage per se. Combined treatments of HepG2 cells with phenethyl isothiocyanate (PEITC), allyl isothiocyanate (AITC) or indol-3-carbinol (I3C) and N-nitrosopyrrolidine (NPYR) or N-nitrosodimethylamine (NDMA) reduced the genotoxic effects of the N-nitrosamines in a dose-dependent manner. The protective effect of the three ITCs tested was higher towards NPYR-induced oxidative DNA damage than against NDMA. The greatest protective effect towards NPYR-induced oxidative DNA damage was shown by I3C (1 microM, 79%) and by PEITC (1 microM, 67%) and I3C (1 microM, 61%) towards NDMA (in presence of Fpg enzyme). However, in absence of Fpg enzyme, AITC (1 microM, 72%) exerted the most drastic reduction towards NPYR-induced oxidative DNA damage, and PEITC (1 microM, 55%) towards NDMA. Our results indicate that ITCs protect human-derived cells against the DNA damaging effect of NPYR and NDMA, two carcinogenic compounds that occur in the environment.

Anticarcinogenic Agents↗
PubMedDate not supplied

Protective effects of isothiocyanates towards N-nitrosamine-induced DNA damage in the single-cell gel electrophoresis (SCGE)/HepG2 assay.

The aim of this study was to investigate the protective effect of isothiocyanates towards N-nitrosamine-induced DNA damage in the single-cell gel electrophoresis (SCGE)/HepG2 assay. None of the isothiocyanates (ITCs) concentrations tested in the presence or absence of formamidopyrimidine-DNA glycosylase (Fpg), caused DNA damage per se. Combined treatments of HepG2 cells with phenethyl isothiocyanate (PEITC), allyl isothiocyanate (AITC) or indol-3-carbinol (I3C) and N-nitrosopyrrolidine (NPYR) or N-nitrosodimethylamine (NDMA) reduced the genotoxic effects of the N-nitrosamines in a dose-dependent manner. The protective effect of the three ITCs tested was higher towards NPYR-induced oxidative DNA damage than against NDMA. The greatest protective effect towards NPYR-induced oxidative DNA damage was shown by I3C (1 microm, 79%) and by PEITC (1 microm, 67%) and I3C (1 microm, 61%) towards NDMA (in the presence of Fpg enzyme). However, in the absence of Fpg enzyme, AITC (1 microm, 72%) exerted the most drastic reduction towards NPYR-induced oxidative DNA damage, and PEITC (1 microm, 55%) towards NDMA. The results indicate that ITCs protect human-derived cells against the DNA damaging effect of NPYR and NDMA, two carcinogenic compounds which occur in the environment.

Antimutagenic Agents↗
PubMed2002

C-terminal sequence analysis of peptides using triphenylgermanyl isothiocyanate.

The Schlack-Kumpf degradation, also called the isothiocyanate method, is thought to be a promising approach to chemical C-terminal sequencing of peptides and proteins. The derivatizing reagent is most crucial to this method. A new derivatizing reagent, triphenylgermanyl isothiocyanate (TPG-ITC), has been synthesized and applied to C-terminal peptide sequencing. The chemistry involves activation with acetic anhydride, derivatization with TPG-ITC, and cleavage of the derivatized C-terminal amino acid thiohydantoin with sodium hydroxide. A series of reaction conditions, including activation reagent volume, activation time, and derivatization temperature and time, have been investigated using a model peptide covalently attached to 1,4-phenylene diisothiocyanate (DITC)-glass beads. This procedure has been successfully used to sequence eight C-terminal residues of a model peptide at low nanomole levels. TPG-ITC is a white solid with relatively long shelf-life. According to our previous article (B. Mo, J. Li, and S. P. Liang, 1997, Anal. Biochem. 252, 169-176), TPG-ITC is a type II derivatizing reagent. Compared with acetyl isothiocyanate and trimethylsilyl isothiocyanate, TPG-ITC is much more stable and efficient for use in peptide C-terminal sequencing.

Animals↗
PubMed1995

Reversible conjugation of isothiocyanates with glutathione catalyzed by human glutathione transferases.

Rates were determined for the nonezymatic (second order rate constants) and enzyme-catalyzed conjugations with glutathione of four isothiocyanates that are present in edible plants (allyl-, benzyl-, phenethyl-isothiocyanates, and sulforaphane). Of four cloned human glutathione transferases studied, GSTP1-1 and GSTM1-1 were the most efficient catalysts. GSTA1-1 was less efficient, and GSTM2-2 was the least efficient. Conjugation of benzyl-NCS is the most rapid and that of sulforaphane [CH3S(O)(CH2)4-NCS] is the slowest. The large enzymatic rate enhancements and the abundance of the enzymes suggest that the glutathione transferases play important roles in the metabolic disposition of isothiocyanates in humans. Enzymatic cleavage of the GSH conjugates of isothiocyanates (dithiocarbamates) is catalyzed by glutathione transferases. The importance of these reverse reactions is probably limited because they are slow and inhibited by high intracellular concentrations of glutathione.

Glutathione↗
PubMed1990

Effect of dietary aromatic isothiocyanates fed subsequent to the administration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumorigenicity in mice.

Naturally-occurring aromatic isothiocyanates, benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), were tested for their post-treatment effects on lung tumorigenicity by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. Mice at 7 weeks of age were administered a single i.p. dose of NNK (10 mumol/mouse). One week after NNK dosing, mice were placed on AIN-76A diet containing 1 or 3 mumol/g diet of BITC or PEITC. The control group was maintained on AIN-76A diet after NNK administration. Mice were killed 16 weeks after NNK treatment and lung adenomas were counted. The results showed mice fed control diet developed 7.8 tumors/mouse. Mice fed PEITC at concentrations of 1 or 3 mumol/g diet had 8.2 or 6.1 tumors/mouse, respectively. Feeding BITC at 1 mumol/g diet resulted in a tumor yield of 8.0 tumors/mouse, whereas BITC diet at 3 mumol/g diet gave 5.2 tumors/mouse, a small but significant inhibition. However, in the high BITC dose group, a loss in weight gain due to reduced food intake was noted. The results of this study showed that post-treatment of aromatic isothiocyanates had little, if any, effect on NNK lung tumorigenicity in A/J mice. This is in contrast to our previous findings in which pretreatment with PEITC greatly inhibited lung tumor induction by NNK in A/J mice and suggests that tumor inhibition by PEITC is due to inhibition of NNK metabolic activation.

Animals↗
PubMed1987

Determination of N-acetyl-S-(N-alkylthiocarbamoyl)-L-cysteine, a principal metabolite of alkyl isothiocyanates, in rat urine.

A simple and rapid analytical procedure is described for N-acetyl-S-(N-alkylthiocarbamoyl)-L-cysteine (alkyl = benzyl, allyl, methyl, ethyl or n-butyl), a mercapturic acid with an unstable dithiocarbamic acid ester structure, which is found in rat urine as the principal metabolite of the corresponding alkyl isothiocyanate. Because such mercapturic acids decompose at pH values greater than 5 to N-acetylcysteine and alkyl isothiocyanate, the free isothiocyanate is converted with n-butylamine into the corresponding disubstituted thiourea, and, after extraction, measured by high-performance liquid chromatography using an ultraviolet detector. The recovery is ca. 100% and the precision is very good. The lower limit of detection is ca. 0.5 microgram of thiourea. The 24-h renal excretion of these mercapturic acids was determined in rats after administration of benzyl, allyl, methyl, ethyl or n-butyl isothiocyanate.

Animals↗
PubMed2004

Isothiocyanates as novel cytotoxic and cytostatic agents: molecular pathway on human transformed and non-transformed cells.

Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Recently, isothiocyanates, natural products found in the diet of humans, has been shown to function as cancer chemopreventive agents. They are strong inhibitors of phase I enzymes and inducers of phase II enzymes. They can also induce apoptosis and modulate cell-cycle progression of highly proliferating cancer cells. This commentary will review the mechanism of apoptosis and growth inhibition mediated by different isothiocyanates. Particular attention will be given to the effects of the new isothiocyanate 4-(methylthio)butylisothiocyanate (MTBITC). Since selective targeting and low toxicity for normal host tissues are fundamental requisites for proposed chemopreventive agents, we will also review the effects of different isothiocyanates on non-transformed human cells.

Antineoplastic Agents↗
PubMed2005

Raphanus sativus and its isothiocyanates inhibit vascular smooth muscle cells proliferation and induce G(1) cell cycle arrest.

Mu (Raphanus sativus, Korean White Radish) crude extract (Mu-CE) has been studied for its anti-proliferative activity on mouse aortic smooth muscle cells. The abnormal growth of vascular smooth muscle cells (VSMC) is a prominent feature of vascular disease, including atherosclerosis, restenosis after angioplasty. We examined the mechanisms of the action of Mu-CE on VSMC proliferation. The viability of VSMC decreased to 35% at 24 h of treatment with Mu-CE. Treatment of Mu-CE showed potent inhibitory effects on the DNA synthesis of cultured VSMC. In addition, Mu-CE induced apoptosis using cell death ELISA assay. These inhibitory effects were associated with G1 cell cycle arrest. Treatment of Mu-CE, which induced a cell-cycle arrest in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 by Mu-CE was not observed. Then, total isothiocyanates (ITC) including four different 4-(Methylthio)-3-butenyl isothiocyanate (MTBITC), allyl isothiocayanate (AITC), benzyl isothiocyanate (BITC), and phenethyl isothiocyanate (PEITC) was isolated from n-hexane extracts of Mu. When the VSMC were treated with ITC, the cell viability was significantly decreased. These findings indicate the efficacy of Mu-CE in inhibiting cell proliferation, G1- to S-phase cell-cycle progress on VSMC.

Animals↗
PubMed2004

Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms.

Chemoprevention is a cancer preventive strategy to inhibit, delay or reverse carcinogenesis using naturally occurring or synthetic chemical agents. Numerous epidemiological studies as well as experimental animal studies clearly demonstrate that high intake of cruciferous vegetables protects against tumorigenesis. Thus, cruciferous vegetables have been of great interest for potential use in the chemoprevention of cancer. Cruciferous vegetables are rich source of glucosinolates, which are degraded into isothiocyanates by enzymatic action of plant-specific myrosinase or intestinal flora in the body. It appears that significant portion of the chemopreventive effects of isothiocyanates may be associated with the inhibition of the metabolic activation of carcinogens by cytochrome P450s (Phase I), coupled with strong induction of Phase II detoxifying and cellular defensive enzymes. Inductions of Phase II cellular enzymes are largely mediated by the antioxidant responsive element (ARE), which is regulated by the transcriptional factor, Nrf2. Additional potent regulatory mechanisms of Nrf2 include the different signaling kinase pathways (MAPK, PI3K, PKC and PERK) as well as other non-kinase dependent mechanisms. Moreover, apoptosis and cell cycle perturbations appear to be yet another potential chemopreventive mechanisms elicited by isothiocyanates, especially with respect to the effects on pre-initiated or initiated tumor cells. Finally, modulation of other critical signaling mediators, including the NF-kappaB and AP-1 by a wide array of chemopreventive agents including isothiocyanates may also contribute to the overall chemopreventive mechanisms.

Animals↗
PubMed2005

Comparison of phenethyl and 6-phenylhexyl isothiocyanate-induced toxicity in rat esophageal cell lines with and without glutathione depletion.

Phenethyl isothiocyanate (PEITC) and its synthetic homolog, 6-phenylhexyl isothiocyanate (PHITC), are both potent inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung mice tumorigenesis. However, unlike PEITC, PHITC enhanced N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. These findings imply that due to its unique chemical properties, PHITC's effects on esophageal cells are procarcinogenic rather than chemopreventive. Relative to PEITC, PHITC is more lipophilic and less reactive, which could result in higher PHITC intracellular levels. Due to ITCs' inherently high level of thiol reactivity, increased intracellular levels of PHITC have the potential to deplete intracellular glutathione (GSH) reserves. Since GSH is a primary intracellular antioxidant and cytoprotective enzyme cofactor, preservation of intracellular GSH status is crucial for cytoprotection. Despite the recognized importance of isothiocyanate structure with the potential for toxicity, no studies have yet investigated the association between the primary intracellular free thiol, GSH, and isothiocyanate-induced toxicity in this target cell population. The present study investigated whether PEITC and PHITC display unique cytotoxic profiles in cultured rat esophageal cells, and also monitored the effects of ITC challenge on cellular GSH status. A final series of experiments investigated the converse i.e., affects of modulation of intracellular GSH status on ITC-mediated toxicity. Dose-response curves revealed that PEITC was significantly more toxic in tumorigenic and non-tumorigenic cells relative to PHITC. The ITC-GSH interaction studies demonstrated comparable GSH levels following either PEITC or PHITC challenge, and also showed that GSH depletion did not augment ITC-mediated cellular toxicity. While our data demonstrate structure related differences in ITC-mediated cytotoxicities, these differences do not appear to be directly attributable to cellular GSH pools.

Animals↗
PubMed1988

Superoxide anion measurement by sulfonated phenyl isothiocyanate cytochrome c.

Sulfonated phenyl isothiocyanate cytochrome c is suggested as a new scavenger for superoxide anion. The efficiency of the modified cytochrome c in measurements is compared with that of phenyl isothiocyanate cytochrome c and acetylated cytochrome c. Sulfonated phenyl isothiocyanate cytochrome c is water and salt soluble. Autooxidability of the pigment is not observed. The primary advantage of sulfonate phenyl isothiocyanate cytochrome c is that it appears to be specifically reduced by O2 radicals without interferences by other reactions in complex biological systems.

Acetylation↗
PubMed2001

Monitoring of isothiocyanates emanating from Arabidopsis thaliana upon paraquat spraying.

Arabidopsis thaliana plants were sprayed with the superoxide-generating herbicide paraquat. The headspace of sprayed plants was characterized by a number of compounds, which were absent in the headspace of untreated plants. They were identified as isothiocyanates (ITCs) with 4-methylthiobutyl isothiocyanate as main compound. After identification, a GC-system, based on PDMS sorption, was used to continuously monitor the ITC emissions. The specificity of isothiocyanate emission was also determined by subjecting the Arabidopsis thaliana plants to in vitro mechanical wounding. Again, 4-methylthiobutyl isothiocyanate was the main component, but the emission profile was completely different since the compound was emitted immediately, i.e., during wounding itself.

Arabidopsis↗
PubMed2001

Benzyl isothiocyanate is the chief or sole anthelmintic in papaya seed extracts.

Papaya (Carica papaya) seeds were extracted in an aqueous buffer or in organic solvents, fractionated by chromatography on silica and aliquots tested for anthelmintic activity by viability assays using Caenorhabditis elegans. For all preparations and fractions tested, anthelmintic activity and benzyl isothiocyanate content correlated positively. Aqueous extracts prepared from heat-treated seeds had no anthelmintic activity or benzyl isothiocyanate content although both appeared when these extracts were incubated with a myrosinase-containing fraction prepared from papaya seeds. A 10 h incubation of crude seed extracts at room temperature led to a decrease in anthelmintic activity and fractionated samples showed a lower benzyl isothiocyanate content relative to non-incubated controls. Benzyl thiocyanate, benzyl cyanide, and benzonitrile were not detected in any preparations and cyanogenic glucosides. which were present, could not account for the anthelmintic activity detected. Thus, our results are best explained if benzyl isothiocyanate is the predominant or sole anthelmintic agent in papaya seed extracts regardless of how seeds are extracted.

Animals↗
PubMed2003

Effect of naturally occurring allyl and phenyl isothiocyanates in the inhibition of experimental pulmonary metastasis induced by B16F-10 melanoma cells.

The effect of naturally occurring allyl and phenyl isothiocyanates in the inhibition of B16F-10 melanoma cells-induced metastasis has been studied in C57BL/6 mice. The two compounds were administered by three different modalities. Simultaneous administration of the compounds with tumour induction was found to produce significant reduction in the lung tumour nodule formation; of the two compounds studied, allyl isothiocyanate have shown to be more effective and it produced 93% inhibition of tumour nodules while phenyl isothiocyanate has an inhibition of 77.3%. Prophylactic administration also produces considerable effect but no effect was observed by their administration after the tumour development. Lung collagen hydroxyproline, lung uronic acid, lung hexosamine content, serum sialic acid and serum GGT levels were also estimated and the enhanced levels of these parameters in the control animals were found to be reduced by the simultaneous administration of these isothiocyanates; these data were also correlated with the inhibition of lung tumour nodules produced and the increase in life span of the animals.

Animals↗
PubMed2001

Oligothiophene isothiocyanates as a new class of fluorescent markers for biopolymers.

The regioselective synthesis of fluorescent oligothiophene isothiocyanates is described. The isothiocyanates were reacted with bovine serum albumin (BSA) following standard procedures and the optical properties of the oligothiophene-BSA conjugates were analyzed as a function of oligomer concentration, time, and irradiation power. The oligothiophene-BSA conjugates were chemically very stable and their photoluminescence characteristics persisted unaltered for several months. Photoluminescence data relative to the conjugate of an oligothiophene-S,S-dioxide isothiocyanate with monoclonal anti-CD8 antibody are reported. No fluorescence quenching was observed following the binding of the isothiocyanate to the antibody and the conjugate displayed high chemical stability and photostability.

Antibodies, Monoclonal↗
PubMed2001

Decomposition rates of isothiocyanate conjugates determine their activity as inhibitors of cytochrome p450 enzymes.

Thiol conjugates of isothiocyanates (thiol-ITCs) are metabolites of ITCs formed in the mercapturic acid pathway in mammals. They are effective chemopreventive agents in mouse lung tumor bioassays and in other models. Thiol-ITCs are inhibitors of P450s, but it has not been determined if P450 inhibition is due to conjugates themselves or to parent ITCs released by deconjugation reactions. In studies of mechanism of chemopreventive action of thiol-ITCs, rates of deconjugation of Cys, GSH, and N-acetyl-L-cysteine (NAC) conjugates of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 6-phenylhexyl isothiocyanate (PHITC), and sulforaphane (SFN), expressed as the first-order rate constant k(1) and the half-life of decomposition Dt(1/2), were measured in aqueous solutions at pH 7.4 and 37 degrees. The Dt(1/2)s for the Cys conjugates were severalfold shorter than the Dt(1/2)s for respective GSH conjugates, while the Dt(1/2)s for the NAC conjugates were the longest. Cleavage of thiol conjugates was pH dependent, much slower under acidic conditions than at pH 7.4. Inhibition of P450 enzymes by thiol-ITCs was followed using PROD (pentoxyresorufin O-dealkylation) for P450 2B1 and EROD (ethoxyresorufin O-dealkylation) for P450 1A1. The inhibition of PROD and EROD by aqueous thiol-ITCs increased with preincubation time and was roughly parallel to the extent of decomposition of the conjugate that had occurred, indicating that both potency of the respective parent ITC and the rate of reductive cleavage of the conjugate influenced enzyme inhibition. In the presence of 250-1000 microM GSH, comparable to physiological levels, rates of deconjugation of thiol-ITCs were markedly reduced; inhibition of PROD was also proportionately reduced. Slow rates of decomposition of thiol-ITCs anticipated in plasma and tissues suggests that inhibition of P450 enzymes involved in carcinogen activation by ITCs released from thiol-ITCs may not be a principal mechanism for their tumor inhibitory activity; other mechanisms probably contribute to their chemopreventive activity.

Animals↗
PubMed1987

Re-examination of hexose-transporter inhibition and labelling by hexose isothiocyanates.

We have re-examined hexose-transport inhibition by hexose isothiocyanates and find that the inhibition is incomplete, probably because of decomposition of the reagent. The inhibition type is 'mixed', because hexose-transporter ligands such as maltose and cytochalasin B only give partial protection from inhibition. This suggests that a liganded-transporter-hexose isothiocyanate ternary complex is formed. We have compared the labelling of red-blood-cell membranes by [14C]MITC (D-maltose isothiocyanate) with the labelling obtained using a photoaffinity probe (ASA-BMPA [2-N-(4-azidosalicyloyl)-1,3-bis-(D-mannos-4'-yloxy)-2 -propylamine]) which gives specific labelling of the hexose transporter in band 4.5. [14C]MITC gives a partially D-glucose-displaceable labelling of a band 3 component in the same cell preparations which show ASA-BMPA labelling of band 4.5. This eliminates the possibility that band 4.5 labelling can only occur when the HITC (hexose isothiocyanate) binding protein in band 3 is proteolysed. HITC pretreatment does not decrease ASA-BMPA labelling of the exofacial site of band 4.5. This is also consistent with the formation of ternary complex. However, HITC pretreatment inhibits both reversible and photoactivated covalent [3H]cytochalasin B binding to band 4.5. These results suggest that, in the intact cell, interactions between a band 3 HITC-binding component and the inside cytochalasin B-binding site on the hexose transporter in band 4.5 may occur.

Affinity Labels↗
PubMed1995

Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates.

The reversible reaction of GSH with two dietary anticarcinogens, benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), has been studied in the absence and presence of human glutathione S-transferases (GSTs). The spontaneous reaction at pH 7.4 and 37 degrees C yielded values for k2 of 17.9 and 6.0 M-1.s-1 for GSH conjugation of BITC and PEITC respectively (forward reaction), and k1 values of 6.9 x 10(-4) and 2.4 x 10(-4) s-1 for dissociation of the respective GSH conjugates, BITC-SG and PEITC-SG (reverse reaction). GSTs A1-1, A2-2, M1a-1a and P1-1 catalysed both the forward and reverse reactions with specific activities (mumol/min per mg at 30 microM isothiocyanate or GSH conjugate) ranging from 23.1 for the GSH conjugation of BITC by GST P1-1 to 0.03 for the dissociation of BITC-SG by GST A1-1. When present at similar concentration to substrates (12 microM), GSTs A1-1 and A2-2 but not GST M1a-1a shifted the equilibrium in favour of BITC-SG or PEITC-SG. Kinetic studies confirmed that GST A1-1 interacted selectively with the GSH conjugates in the micromolar range (Km 6.9 microM, Ki 4.3 microM), whereas GST M1a-1a interacted with BITC-SG and PEITC-SG with approx. 5-fold lower affinity. In conclusion, GSTs are true catalysts; at high intracellular concentration they also sequester GSH conjugates, promoting GSH conjugation, whereas trace extracellular GSTs promote dissociation of effluxed organic isothiocyanate-GSH conjugates.

Anticarcinogenic Agents↗