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PubMed2006

Allyl isothiocyanate and its N-acetylcysteine conjugate suppress metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in SK-Hep 1 human hepatoma cells.

Cruciferous vegetables contain a series of relatively unique secondary metabolites of amino acids, called glucosinolates. Sinigrin, the predominant aliphatic glucosinolate in cruciferous vegetables, is hydrolyzed to yield allyl isothiocyanate (AITC), which, after absorption and metabolism in humans, is excreted in the urine as an N-acetylcysteine (NAC) conjugate. We have determined the inhibitory effects of AITC and its NAC conjugate on cell proliferation, the expression of matrix metalloproteinases (MMPs), adhesion, invasion, and migration in SK-Hep 1 human hepatoma cells. Our results demonstrate that AITC and NAC-AITC suppress SK-Hep 1 cell proliferation in a dose-dependent manner; by 25% and 30% for 10 microM AITC and 10 microM NAC-AITC, respectively. We examined the influence of AITC and NAC-AITC on the gene expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). Gelatin zymography also revealed a significant downregulation of MMP-2/-9 expression in SK-Hep1 cells treated with 0.1-5 microM AITC and NAC-AITC compared with controls. Reverse transcriptase polymerase chain reaction revealed dose-dependent decreases in MMP-2/-9 messenger RNA levels in both AITC-treated and NAC-AITC-treated cells. TIMP-1/-2 activities were unaffected by treatment with AITC or NAC-AITC in our experiments. NAC-AITC inhibited cancer cell adhesion and invasion much more potently than its parent compound. NAC-AITC at 5 microM caused excellent inhibition of cell migration for 48 hrs. These results demonstrate the potential of AITC and NAC-AITC as chemopreventive agents.

Acetylcysteine↗
PubMed1980

Short time bleaching of fluorescein isothiocyanate. A possible parameter for the specific binding of conjugates in immunofluorescence.

The fluorescence kinetics of fluorescein isothiocyanate (FITC)-antibody conjugates during short (0.01 sec) laser excitations were analyzed for possible information about the immunological specificity of binding to antigenic substrates in direct immunofluorescence assays with antigen-coated Sephadex beads. First results of these investigations suggest marked differences in the bleaching characteristics of specifically and nonspecifically bound FITC conjugates: FITC-anti-bovine serum albumin (BSA) and FITC-anti-rabbit immunoglobulin (Ig) were found to fade significantly more slowly when bound to the respective homologous antigen (anti-BSA to BSA, and anti-rabbit Ig to rabbit Ig) as compared to nonspecifically adherent anti-BSA to rabbit Ig, and anti-rabbit Ig to BSA. Possible implications of these data for discrimination of nonspecific staining in immunofluorescence are discussed.

Antigens↗
PubMed2001

Dose-dependent promotion by phenylethyl isothiocyanate, a known chemopreventer, of two-stage rat urinary bladder and liver carcinogenesis.

The effects of phenylethyl isothiocyanate (PEITC) on urinary bladder and liver carcinogenesis were analyzed in a rat model. Diets containing 0.1%, 0.05%, or 0.01% PEITC were administered for 32 wk to male Fischer 344 rats with and without pretreatment with an injection of diethylnitrosamine (200 mg/kg body wt i.p.) and 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk for initiation. In the initiated groups, PEITC administration significantly increased the incidences of papillary or nodular hyperplasia, dysplasia, and transitional cell carcinomas at higher doses of 0.01%, 0.01%, and 0.05%, respectively, compared with the control group, given initiation alone, in a dose-dependent manner. Without initiation, administration of 0.1% and 0.05% PEITC induced simple and papillary or nodular hyperplasia and dysplasia in the urinary bladder. In the liver, induction of glutathione S-transferase placental form-positive foci was dose dependently enhanced by PEITC administration, but the incidences of liver tumors were not different among the groups. From the present experiment, we can conclude that > 0.01% PEITC enhances rat urinary bladder carcinogenesis, while weakly promoting hepatocarcinogenesis. In addition, it is suggested that > 0.05% PEITC has tumorigenic potential.

Animals↗
PubMed2002

Simultaneous treatment with benzyl isothiocyanate, a strong bladder promoter, inhibits rat urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Effects of benzyl isothiocyanate (BITC) on urinary bladder carcinogenesis were examined in rats simultaneously treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Groups of 20 6-wk-old Fischer 344 male rats were given 10, 100, or 1,000 ppm BITC in the diet or a basal diet with 50 ppm BBN in the drinking water for 40 wk and then killed for autopsy. Additional groups consisting of 10 or 9 rats were similarly given BITC or the basal diet alone without BBN treatment. With BBN treatment, dysplasia, papilloma, and carcinoma incidences and multiplicities were dramatically decreased by simultaneous treatment with BITC in a clear dose-dependent manner. In contrast, epithelial hyperplasia was induced in rats treated with 100 and 1,000 ppm BITC without BBN. These results clearly indicate that although BITC may have weak carcinogenic potency, it is a potent chemopreventive agent against bladder tumor induction by BBN.

Animals↗
PubMed2004

Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n-pentylnitrosamine depentylation by rat esophageal microsomes, human and rat CYP2E1, and Rat CYP2A3.

Garlic and Cruciferae are associated with reduced risks of several human cancers, and some of their constituents are anticarcinogenic in animals. Here we studied inhibition of in vitro metabolism of the rat esophageal carcinogen methyl-n-pentylnitrosamine (MPN) by garlic-derived allyl sulfides and by Cruciferae-derived phenethyl isothiocyanate (PEITC) and sulforaphane. The test inhibitors were incubated with [3H]-MPN, NADPH-generating system and rat esophageal microsomes (REM) or a cytochrome P450 (CYP). [3H]-MPN activation by depentylation was assayed by HPLC with radiometric determination of [3H]-pentaldehyde 2,4-dinitrophenylhydrazone. IC50 for depentylation of 40 microM MPN by rat CYP2E1 was 5-12 microM for diallyl sulfide (DAS), diallyl disulfide (DADS), and PEITC and 10-20 microM for diallyl sulfone, allyl mercaptan, and diallyl trisulfide. Maximum inhibition required preincubation of rat CYP2E1 with DAS for 15 min and with DADS for 30 min. Using these preincubation times, Ki for MPN depentylation by REM, rat and human CYP2E1, and rat CYP2A3 was 0.6-1.6 microM for inhibition by DAS and 1.7-70 microM for inhibition by DADS. With PEITC, Ki for MPN depentylation by REM, rat CYP2E1, and rat CYP2A3 was 0.4-4.6 microM. These low Ki and IC50 values may help explain how garlic and Cruciferae inhibit carcinogenesis.

Allyl Compounds↗
PubMed2006

Evaluation of isothiocyanates as potent inducers of carcinogen-detoxifying enzymes in the urinary bladder: critical nature of in vivo bioassay.

Deficiency of carcinogen-detoxifying phase 2 enzymes, such as glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), increases bladder cancer risk in humans. We report that several isothiocyanates (ITCs) that have not been previously examined, 1-methylbutyl ITC in particular, potently and preferentially induce both GST and NQO1 in the rat bladder. Comparison of 25 ITCs that are closely related in chemical structures showed that a 3-5-carbon aliphatic side chain with a methyl group attached to the alpha carbon was crucial for maximal inducer activity in the bladder. Surprisingly, cell-based bioassays failed to predict the phase 2 enzyme-inducing activity of the ITCs in the bladder. Furthermore, although ITCs are principally metabolized in vivo to dithiocarbamates (DTCs), which are believed to serve as the carriers of ITCs and are rapidly eliminated and concentrated in the urine, the total urinary levels of ITC plus DTC did not correlate with the degree of GST and NQO1 induction by the ITCs in the bladder of rats. Thus, several underappreciated ITCs are exceedingly potent inducers of GST and NQO1 in the rat bladder but were predicted neither by in vitro bioassays of phase 2 enzyme induction nor by their appearance or concentration in urine in vivo.

Animals↗
PubMed1981

Fluorescein-isothiocyanated insulin interactions with human platelets.

The interactions of fluorescein-isothiocyanated porcine insulin (FITC-insulin) with human platelets were examined by a fluorescence polarization technique. The degree of polarization of the incubation mixture of FITC-insulin and platelets was changed by the ratio of bound to free insulin. This method enabled us to follow the time course of the reaction in the homogeneous assay system without separating the insulin-receptor complex, and it was shown to be useful in the study of insulin binding and dissociation. Insulin binding to trypsinized platelets was considered to be nonspecific, since this fraction remained relatively constant during the incubation period at 25 C. Specific binding was evaluated by subtracting the nonspecific binding from the binding to untreated platelets; specific binding reached a plateau at 60 min. Scatchard analysis was conducted by adding increasing amounts of FITC-insulin to a platelet suspension. Furthermore, some of the prerequisites in analyzing insulin-receptor interaction were examined by this method.

Binding, Competitive↗
PubMed1993

Uptake of fluorescein isothiocyanate (FITC)-fractionated heparin by rat parenchymal hepatocytes in primary culture.

The distribution of fractionated heparin in a primary culture of rat parenchymal hepatocytes was investigated optically using the fluorescence labelled drug and confocal imaging system with an inverted fluorescence microscope. The cell-associated fluorescein isothiocyanate (FITC)-fractionated heparin was observed to increase in conjunction with incubation time and also to localize, suggesting an internalization to cell organella with the exception of the nuclei.

Animals↗
PubMed1995

Percutaneous penetration of fluorescein isothiocyanate-dextrans and the mechanism for enhancement effect of enhancers on the intercellular penetration.

To identify the mechanism involved in the enhancement effect of enhancers on the intercellular penetration of large polar molecules, the skin penetration of fluorescein isothiocyanate (FITC)-dextrans (average molecular weight; 4400, 9400, and 69000 Da) and the lipid removal from the intercellular spaces by enhancers were studied using hairless rat skin. Pretreatment of hairless rat skin with enhancers such as n-octanol (20%), laurocapram (2%), isopropylmyristate (IPM, 20%), oleic acid (5%) and cineol (2%), which are water-immiscible, significantly enhanced the flux of FITC-dextrans, while pretreatment with water-miscible enhancers, i.e. dimethyl sulfoxide (DMSO, 5%) and N-methyl-2-pyrrolidone (NMP) did not increase the flux compared with the control. The penetration of FITC-dextrans was approximately size dependent. n-Octanol, laurocapram, IPM and oleic acid dramatically removed ceramides which are the intercellular lipids, whereas NMP and DMSO partly extracted the sphingolipids. A linear relationship was observed between the flux and removal of ceramides (p < 0.01), indicating that the removal of intercellular lipids would cause dramatic dilations between adherent cornified cells and enhance the penetration through the intercellular pathways. When the penetration of FITC-dextrans through Wistar rat skin was compared with that via hairless rat skin, the steady state flux of FITC-dextrans through Wistar rat skin pretreated with water-immiscible enhancers was 1.2- to 4.9-fold higher, suggesting that the penetration of large polar molecules through follicles may play at least some role in the percutaneous absorption.

Animals↗
PubMed2003

The effects of calcium chloride and sodium chloride on the electroporation-mediated skin permeation of fluorescein isothiocyanate (FITC)-dextrans in vitro.

We previously reported the substantial synergic effects of electroporation and electrolytes, particularly those containing CaCl(2) on the skin permeation of the model low-molecular weight compound, calcein. We then investigated the effects of electroporation (300 V, 10 msx10 times) and 150 mM NaCl or CaCl(2) on skin permeation of higher molecular weight compounds, fluorescein isothiocyanate (FITC)-dextrans (FD-4, FD-10 and FD-40; average molecular weight, 4.4, 9.6 and 35.6 kDa, respectively) using excised hairless rat skin. The observed steady state flux of FD-4 was 1.3 pmol/cm(2)/h after electroporation without NaCl or CaCl(2). The flux did not differ greatly from that without electroporation. In contrast, a much higher steady state flux was observed after electroporation with NaCl or CaCl(2) (2.5 and 8.2 pmol/cm(2)/h, respectively). For FD-10 and FD-40, no flux was detected with electroporation in water (without electrolytes) or without electroporation. On the other hand, high skin permeation was observed after electroporation in NaCl or CaCl(2) solution (FD-10: 7.5 and 18.2 pmol/cm(2)/h, FD-40: 4.5 and 9.3 pmol/cm(2)/h in NaCl and CaCl(2), respectively). The effects of CaCl(2) on FD permeation were greater than those of NaCl. The present finding suggests that electroporation application in the presence of electrolytes, particularly CaCl(2), was very effective in increasing transdermal delivery of water-soluble macromolecules.

Animals↗
PubMed2006

Efficient synthesis of isothiocyanates based on the tandem Staudinger/aza-Wittig reactions and mechanistic consideration of the tandem reactions.

The tandem and stepwise Staudinger/aza-Wittig reactions of several azides were examined in detail. The tandem reaction method (Method I) exhibited superior results in the yield of the corresponding isothiocyanates bearing an electron-withdrawing group than the conventional stepwise method (Method II) which involves the sequential treatment of the azides with triphenylphosphine and then carbondisulfide. The mechanistic consideration for both reaction methods was proposed on the basis of the 1H-NMR analyses.

Azides↗
PubMed1994

Gas-phase microsequencing of peptides and proteins with a fluorescent Edman-type reagent, fluorescein isothiocyanate.

A fluorescent Edman-type reagent, fluorescein isothiocyanate (FITC), was adapted to a gas-phase sequencer fitted with a miniature reaction chamber. Fluorescein thiohydantion amino acids were identified by on-line gradient HPLC with fluorescence monitoring. The optimized protocol for the coupling reaction using FITC and phenylisothiocyanate, and the degree of washing to remove the excess reagents were established. Myoglobin (5 pmol) and lysozyme (5 pmol) were analyzed by the sequencer to obtain a 35-51% initial yield (I.Y.) and 82-88% repetitive yield (R.Y.) for the former, and 51-66% I.Y. and 91-92% R.Y. for the latter. These figures permitted 20-25 amino acid residues to be identified from the N-terminus of 5 pmol samples applied to the sequencer.

Amino Acid Sequence↗
PubMed1998

Effects of synthetic hydroxy isothiocyanates on microbial systems.

Hydroxy isothiocyanates (ITCs), including some new derivatives of naturally occurring compounds, were synthesized and their minimum inhibitory, minimum fungicidal, and minimum bactericidal concentrations for Aspergillus niger, Aspergillus fumigatus, Staphylococcus aureus, and Escherichia coli were estimated. These compounds were strongly antimicrobial; for example, 2-(4-hydroxyphenyl) ethyl ITC inhibited growth of all strains examined at concentrations of 7.8 to 15.6 micrograms/ml. The ATP concentration in E. coli was markedly reduced when cells were treated with 2-(4-hydroxyphenyl)ethyl ITC. Inhibition of the growth of E. coli by 2-(4-hydroxyphenyl)ethyl ITC was decreased in the presence of cysteine. Streptolysin S production in washed cells of Streptococcus equisimilis was extremely sensitive to this ITC derivative and this inhibition also was counteracted by cysteine. The results showed that the ITC compounds had antimicrobial effects by blocking sulfhydryl groups.

Adenosine Triphosphate↗
PubMed2000

Kinetic and thermodynamic analysis of the cyclodextrin-allyl isothiocyanate inclusion complex in an aqueous solution.

The decomposition of allyl isothiocyanate (AITC) in an aqueous solution was depressed in the presence of cyclodextrin (CD), it's suppression effect increasing in the order of none < beta-CD < alpha-CD. The results of kinetic and thermodynamic analysis of the CD-AITC inclusion complexes showed that the inclusion process was mostly governed by an enthalpy change (delta H degree) rather than by an entrophy change (delta S degree), and that Van der Waals forces played a primary role int he inclusion. Steric factors were important for the reaction activity of AITC inclusion into the CD cavity, especially significant being the stereospecificity between the size of the CD cavity and the AITC molecule which is the main factor concerning it's activity. Our results suggest that the association stability and activity of the included AITC molecule are important factors in the suppression mechanism for CDs. Therefore, both these factors would make an alpha-CD-AITC system more advantageous than a beta-CD-AITC system, and the marked suppression effect of alpha-CD on the decomposition of AITC can be attributed to the formation of inclusion complexes in an aqueous solution.

Cyclodextrins↗
PubMed2004

Effects of isothiocyanates on tumor necrosis factor-alpha production by J774A.1 (BALB/c macrophage) cells.

The effects of isothiocyanates (ITCs) on tumor necrosis factor-alpha (TNF-alpha) production by the J774A.1 mouse macrophage cell line stimulated with lipopolysaccharide (LPS) were examined. Some individual ITCs examined showed a priming effect, which was expressed as pre-activation, but also inhibited the production of TNF-alpha with concomitant stimulation by LPS, as a triggering stimulant of TNF production. These results suggest that ITCs exert opposing activities that can enhance or inhibit the host defense system.

Animals↗
PubMed2004

Effects of ionized cyclodextrin on decomposition of allyl isothiocyanate in alkaline solutions.

The secondary hydroxyl ion (alkoxide) ion for cyclodextrin (CD) may affect the decomposition of allyl isothiocyanate (AITC) in alkaline solutions. The equilibrium and kinetic parameters involved in the reaction processes were measured. It was found that the interaction between the alkoxide ion for CD and the included AITC occurred more than pKa 12.7. From the identified kinetic parameters and discussion, it was suggested that the reaction site of AITC was located in the vicinity of one of the secondary hydroxyl groups of CD in the cavity.

Alkalies↗
PubMed2005

Dietary isothiocyanates modify mitochondrial functions through their electrophilic reaction.

We found that both benzyl isothiocyanate (ITC) and phenyl ITC inhibited respiration in the mitochondria in an electrophilic reaction-dependent manner. ITC-induced mitochondrial swelling and cytochrome c release were prevented by cyclosporin A, indicating that they are mediated through the ITC moiety-dependent reaction to critical thiol groups for the opening of membrane permeability transition-dependent pores.

Animals↗
PubMed1994

Oxidative conversion of isothiocyanates to isocyanates by rat liver.

This report describes the oxidative metabolism of isothiocyanates to isocyanates catalyzed by rat liver microsomes. Incubation of 2-naphthylisothiocyanate, microsomes, and NADPH yielded either N,N'-di-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ureas were formed by the production of the known genotoxicant, 2-naphthylisocyanate, 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 because 2-aminonaphthalene reacted with the substrate. Urea formation was dependent on the microsomes, NADPH, and oxygen. Use of microsomes from rats previously treated with Aroclor 1254 increased urea formation greater than 10-fold. The enzyme activity was inhibited by alpha-napthoflavone, flavone, or CO, and slightly inhibited by metyrapone, 7-ethoxycoumarin, or SKF-525A. It was not inhibited by methimazole or paraoxon, suggesting that neither flavin-containing monooxygenase nor hydrolytic enzyme was involved. These data are consistent with a cytochrome P450-dependent, oxidative desulfuration of 2-naphthylisothiocyanate to yield 2-naphthylisocyanate. Further studies with the isomeric 1-naphthylisothiocyanate and the dietary benzylisothiocyanate showed that they can also be metabolized to their isocyanates, as evidenced by the trapping of isocyanates with 2-aminofluorene to form the mixed ureas.

1-Naphthylisothiocyanate↗