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PubMed1999

Analgesic activity and selectivity of isothiocyanate derivatives of fentanyl analogs for opioid receptors.

The analgesic activity and opioid receptor binding characteristics were studied for the isothiocyanate ohmefentanyl (OMFIT), and isothiocyanate carfentanil (CarFIT), isothiocyanate 4-methoxymethylfentanyl (MethoFIT), isothiocyanate 3-methylfentanyl (superFIT) and their amide analogs. Antinociceptive activity was evaluated using the mouse hot plate test; selectivity for opioid receptor was determined in bioassay and binding assay. SuperFIT, CarFIT, OMFIT and MethoFIT exhibited an analgesic ED50 lower than those of their parent compounds without isothiocyanate (SCN) group. Furthermore these compounds exhibited potent inhibitory actions on the electrically evoked contractions of mouse vas deferens, which could be antagonized by naloxone, but their actions were weaker than those of their parent compounds without SC N-group. The inhibitory actions of these compounds on binding of [3H]OMF to mouse brain membrane was weaker than those of their parent compounds without SCN-group. CarFIT and MethoFIT showed weaker inhibitory actions on the binding of [3H] DADLE than their parent compounds without SCN-group, but SuperFIT and OMFIT stronger than their parent compounds, 3-methylfentanyl and ohmefentanyl. The selectivity of these isothiocyanate derivatives for delta opioid receptors increased. In conclusion, introducing isothiocyanato-group into 1-position of phenyl ring of ohmefentanyl and other fentanyl analogs would enhance the selectivity of these compounds for delta-opioid receptors, but decrease their analgesic activity.

Amides↗
PubMed1997

Isothiocyanates and plant polyphenols as inhibitors of lung and esophageal cancer.

A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by both the tobacco-specific nitrosamine, NNK, in A/J mouse lung and the esophageal-specific carcinogen, NMBA, in F344 rat esophagus. In addition, ellagic acid was tested for its ability to inhibit NMBA-induced esophageal tumorigenesis. In the strain A lung tumor model, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 micromol, but was not inhibitory at lower doses. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC, and PHITC was the most potent inhibitor of all. Thus, in the strain A lung tumor model, there was a trend of increased inhibitory efficacy among arylalkyl isothiocyanates with increased alkyl chain length. In the F344 rat esophageal tumor model, PPITC was clearly more potent than PEITC, BITC and PBITC had little inhibitory effect on esophageal tumorigenesis, and in a separate experiment, PHITC actually enhanced esophageal tumorigenesis. Thus, the structure-activity relationships for inhibition of tumorigenesis by arylalkyl isothiocyanates were considerably different in the two animal models. However, the effects of the isothiocyanates on tumorigenesis were well-correlated to their effects on DNA adduct formation in either model. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome p450 enzymes responsible for activation of NNK in mouse lung or NMBA in rat esophagus. Ellagic acid was an effective inhibitor of esophageal tumorigenesis, although not as potent as PEITC or PPITC. Like the isothiocyanates, ellagic acid inhibits cytochrome p450-mediated activation of NMBA.

Adenoma↗
PubMed1989

High-performance size-exclusion chromatographic procedure for the determination of fluoresceinyl isothiocyanate dextrans of various molecular masses in biological media.

A high-performance size-exclusion chromatographic procedure, using Nucleosil Diol, for the quantitative analysis of fluoresceinyl isothiocyanate dextrans of various molecular masses (10,000-150,000) in biological media was developed. The influence of the molecular mass and the degree of substitution of the conjugates on the chromatographic behaviour are discussed. In addition to quantitation, the molecular mass of the conjugates with degree of substitution below 1.6 could be estimated from the chromatograms. Linear standard calibration curves were obtained at concentrations down to 0.050 micrograms ml-1 in rabbit plasma and urine and homogenates of rabbit liver, lymph node and muscle when the derivative (degree of substitution 0.85) was monitored by fluorescence detection (lambda ex = 493 nm, lambda em = 520 mm). The fluoresceinyl isothiocyanate dextrans were found to be stable for more than three days at 37 degrees in all biological media under investigation. A pH-rate profile for the alkaline hydrolysis of fluoresceinyl isothiocyanate dextrans was constructed. The applicability of the method to pharmacokinetic studies was demonstrated by recording the plasma concentration-time profile of a fluoresceinyl isothiocyanate dextran T-70 conjugate following intravenous injection to a rabbit. In relation to future pharmacokinetic investigations on dextran conjugates, the results reported indicate that labelling of the parent dextran with fluoresceinyl isothiocyanate and monitoring of the fluoresceinyl isothiocyanate dextran conjugate throughout the organism using the described method is a promising development.

Animals↗
PubMed1994

Isothiocyanate-substituted kappa-selective opioid receptor ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] phenylacetamide.

The synthesis of isothiocyanate-substituted kappa-selective opioid ligands derived from N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]ethyl]phenylacetami de (8) and their effects in radioligand displacement assays are reported. Ligands 3-5 with the S-absolute configuration were prepared with the isothiocyanate functionality at the 2-, 3-, and 4-positions in the phenylacetamide aromatic ring. The 2-isothiocyanato-4,5-dichlorophenylacetamide 6 was prepared to evaluate the effect of 4,5-dichloro substitution in the same aromatic ring as the 2-isothiocyanate function. N-Methyl-N-[(1S)-1-(4-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl]-3,4-dichlorophenylacetamide (7), with the 4-isothiocyanate function in the 1-phenyl ring, was prepared for comparison with the other compounds in the series. Of the prepared ligands, 7 and 8 (IC50s congruent to 1.4-1.8 nM) were approximately equal in affinity with 2 (ICI-199,441), followed by 3 and 6. All of these compounds were more kappa-selective than 2, as well. The binding characteristics of 8 show that the previously reported 4,5-dichloro substitution is not required for high affinity and kappa-selectivity. All of the synthesized isothiocyanate-substituted ligands irreversibly inhibited radioligand binding to guinea pig brain membrane preparations, including compound 2 (ICI-199,441) which had no isothiocyanate functionality.

Acetamides↗
PubMed2000

Inactivation of cytochrome P450 2B1 by benzyl isothiocyanate, a chemopreventative agent from cruciferous vegetables.

A series of arylalkyl isothiocyanates were evaluated for their ability to inactivate purified cytochrome P450 2B1 in a reconstituted system. Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) occur naturally in several cruciferous vegetables, and the inhibition of cytochrome P450 (P450) enzymes has been implicated in their chemopreventative abilities. The naturally occurring isothiocyanates BITC and PEITC inactivated P450 2B1 in a time- and concentration-dependent manner, whereas the synthetic isothiocyanates phenylpropyl and phenylhexyl isothiocyanate did not result in inactivation, but were potent competitive inhibitors of P450 2B1 activity. The kinetics of inactivation of P450 2B1 by BITC were characterized. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of P450 2B1 was inactivated in a mechanism-based manner. The loss of O-deethylation activity followed pseudo-first-order kinetics, was saturable, and required NADPH. The BITC concentration required for half-maximal inactivation (K(I)) was 5.8 microM, and the maximal rate constant for inactivation was 0.66 min(-)(1) at 23 degrees C. BITC was a very efficient inactivator of P450 2B1 with a partition ratio of approximately 9. The mechanism of BITC-mediated inactivation of P450 2B1 was also investigated. More than 80% of the catalytic activity was lost within 12 min with a concomitant loss of approximately 45% in the ability of the reduced enzyme to bind CO. The magnitude of the UV/visible absorption spectrum of the inactivated protein did not decrease significantly, and subsequent HPLC analysis indicated no apparent modification of the heme. HPLC and protein precipitation analyses indicated that the P450 apoprotein was covalently modified by a metabolite of BITC. Determination of the binding stoichiometry indicated that 0.90 +/- 0. 16 mol of radiolabeled metabolite was bound per mole of enzyme that was inactivated, suggesting the modification of a single amino acid residue per molecule of enzyme that was inactivated. The results reported here indicate that BITC is a mechanism-based inactivator of P450 2B1 and that inactivation occurs primarily through protein modification.

Animals↗
PubMed1995

Isothiocyanates as substrates for human glutathione transferases: structure-activity studies.

The catalytic properties of four human glutathione transferases (GSTs), A1-1, M1-1, M4-4 and P1-1, were examined with 14 isothiocyanate (R-NCS) substrates. The compounds include aliphatic and aromatic homologues, some of which are natural constituents of human food, namely sulphoraphane [1-isothiocyanato-4-(methylsulphinyl)butane], erucin [1-isothiocyanato-4-(methylthio)butane], erysolin [1-isothiocyanato-4-(methylsulphonyl)butane], benzyl-NCS, phenethyl-NCS and allyl-NCS. All isothiocyanates investigated were substrates for the four GSTs. The enzymes promote addition of the thiol group of GSH to the electrophilic central carbon of the isothiocyanate group to form dithiocarbamates [R-NH-C(=S)-SG] which have high UV absorption at 274 nm. Molar absorption coefficients and non-enzymic rate constants as well as standardized enzyme assay conditions for all compounds were established. Of the four isoenzymes investigated, GSTs M1-1 and P1-1 were generally the most efficient catalysts, whereas GST M4-4 was the least efficient. Isothiocyanates are among the GST substrates that are most rapidly conjugated. On the basis of rate-enhancement data and binding energies, the isothiocyanates were compared with 4-hydroxyalkenals, another class of natural GST substrates previously subjected to systematic kinetic analysis. The incremental transition-state stabilization attributable to an increased number of methylene groups in homologous alkyl isothiocyanates is similar to that previously noted for homologous 4-hydroxyalkenals.

Absorption↗
PubMed1998

Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates.

Isothiocyanates have strong chemopreventive properties against many carcinogen-induced cancers in experimental animal models. Here, we report that phenylmethyl isocyacyanate (PMITC) and phenylethyl isothiocyanate (PEITC) induced sustained c-Jun N-terminal kinase (JNK) activation in a dose-dependent manner. The sustained JNK activation caused by isothiocyanates was associated with apoptosis induction in various cell types. An inhibitor of the caspase/interleukin-1 beta-converting enzyme blocked isothiocyanate-induced apoptosis without inhibiting the JNK activation, which suggests that JNK activation by isothiocyanates is an event that is independent or upstream of the activation of caspase/interleukin-1 beta-converting enzyme proteases. PEITC-induced apoptosis was suppressed by interfering with the JNK pathway with a dominant-negative mutant of JNK1 or MEKK1 (JNK1(APF) and MEKK1 (KR), respectively), implying that the JNK pathway is required for apoptotic signaling. Isothiocyanate-induced JNK activation was blocked by the antioxidants 2-mercaptoethanol and N-acetyl-L-cysteine, suggesting that the death signaling was triggered by oxidative stress. Overexpression of Bcl-2 suppressed PEITC-induced JNK activation. In addition, Bcl-2 and Bcl-xL suppressed PEITC-induced apoptosis, but failed to protect cells from death induced by overexpression of activated JNK1. These results suggest that Bcl-2 and Bcl-xL are upstream of JNK. Taken together, our results indicate (i) that JNK mediates PMITC- and PEITC-induced apoptosis and (ii) that PMITC and PEITC may have chemotherapeutic functions besides their chemopreventive functions.

Aldehyde Dehydrogenase↗
PubMedDate not supplied

Inhibition of carcinogenesis by isothiocyanates.

Isothiocyanates occur as conjugates in a wide variety of cruciferous vegetables. Consumption of normal amounts of these vegetables results in the uptake of substantial quantities of isothiocyanates. These naturally occurring isothiocyanates as well as many synthetic analogs can be powerful inhibitors of carcinogenesis in laboratory animals. Particularly impressive results have been obtained in animal models of lung and esophageal cancer. This review summarizes available data on inhibition of carcinogenesis by isothiocyanates. The major mechanism of inhibition appears to be selective inhibition of cytochrome P450 enzymes involved in carcinogen metabolic activation. Evidence for this is reviewed. Isothiocyanates also induce Phase II enzymes and enhance apoptosis. These properties may also be involved in their chemopreventive activity. Phenethyl isothiocyanate is a particularly effective inhibitor of lung tumor induction by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and, therefore, is currently being developed as a chemopreventive agent against lung cancer.

Brassicaceae↗
PubMed1995

Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates.

This study was undertaken to evaluate the inhibitory effects of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC) or 4-phenylbutyl isothiocyanate (PBITC) on N-nitrosomethyl-benzylamine (NMBA)-induced esophageal tumorigenesis in male Fischer 344 rats. Groups of 15 male rats were fed modified AIN-76A diet or diet containing the four isothiocyanates at concentrations of 2.5, 1.0 and 0.4 mumol/g diet for 25 weeks. After two weeks, rats were administered 0.5 mg/kg NMBA s.c. once weekly for 15 weeks. Additional controls received modified AIN-76A diet only or diet containing the high concentration of isothiocyanates (2.5 mumol/g) only. No tumors were found in any of the groups that were not administered NMBA. Rats treated with NMBA only developed 6.7 +/- 0.8 tumors/animal. Tumor incidences in rats treated with 2.5 and 1.0 mumol PEITC/g diet, and with all three dietary concentrations of PPITC were inhibited by 60-100% compared to controls. Tumor multiplicities were inhibited by 83-100% by PEITC or PPITC at all dietary concentrations tested. PPITC clearly had a stronger inhibitory effect on NMBA tumorigenesis than did PEITC. Compared to PEITC and PPITC, BITC and PBITC had little inhibitory effect on tumor multiplicity and no effect on NMBA tumor incidence. In general, the occurrence of preneoplastic lesions (acanthoses, hyperkeratoses, leukoplakias and leukokeratoses) was inhibited in a similar manner as tumor incidence and multiplicity, except that no experimental diet resulted in a significant reduction of the incidence of acanthoses and hyperkeratoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Inhibition of N'-nitrosonornicotine-induced esophageal tumorigenesis by 3-phenylpropyl isothiocyanate.

The ability of dietary isothiocyanates to inhibit the esophageal metabolism of N'-nitrosonornicotine (NNN) was examined in F344 rats. Following feeding of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC) or 6-phenylhexyl isothiocyanate for 2 weeks, rats were killed and the esophagi were incubated in vitro with [5-3H]NNN. While dietary BITC, PEITC and PBITC all decreased NNN metabolism, dietary PPITC had the greatest effect, yielding inhibition ranging from 55 to 91% of the control production of various NNN metabolites. To determine the chemopreventive efficacy of PPITC on NNN-induced esophageal tumorigenesis, rats were fed AIN-76A diets containing 0, 1.0 or 2.5 micromol/g PPITC and were given untreated drinking water or drinking water containing 5 p.p.m. NNN. After 87 weeks, the experiment was terminated and the esophageal tumors were counted. Rats that were given untreated drinking water developed no tumors. Rats that were given 5 p.p.m. NNN and unadulterated AIN-76A diet had an esophageal tumor incidence of 71% and a multiplicity of 1.57 tumors/animal. The two dietary concentrations of PPITC reduced the incidence and multiplicity of NNN-induced esophageal tumors by >95%. These results demonstrate the remarkable chemopreventive efficacy of PPITC in the NNN-induced esophageal tumor model.

Animals↗
PubMed2005

Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13: potential for chemoprevention in smokers.

Isothiocyanates have been shown to be potent inhibitors of carcinogenesis in animals exposed to a number of chemical carcinogens including the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study the effects of benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), two naturally occuring isothiocyanates, on P450 2A6 and 2A13 were investigated. P450s 2A6 and 2A13 are thought to be the primary human P450 enzymes responsible for the in vivo metabolism of nicotine and NNK, respectively. In vitro, BITC and PEITC efficiently inhibited P450 2A6- and 2A13-mediated coumarin 7-hydroxylation. The inhibition of P450 2A6 and 2A13 by BITC was non-competitive with KI's of 4.1 and 1.3 microM, respectively. PEITC was a more potent inhibitor of both enzymes than BITC, with a KI of 0.37 microM for P450 2A6 and 0.03 microM for P450 2A13. P450 2A6-mediated metabolism of nicotine and P450 2A13-mediated alpha-hydroxylation of NNK were also inhibited significantly by these two isothiocyanates. Both BITC and PEITC were able to inactivate P450 2A6 and 2A13 in an NADPH-dependent manner potentially through the formation of adducts to the apoprotein. The potent inhibition of P450 2A6- and 2A13-mediated metabolisms together with the ability of BITC and PEITC to inactivate the enzymes suggests the possibility that these isothiocyanates could be developed as chemopreventive agents to protect smokers who are unwilling or unable to quit smoking against lung cancer.

Anticarcinogenic Agents↗
PubMed2004

Allergic contact dermatitis from allyl isothiocyanate in a Danish cohort of 259 selected patients.

Allyl isothiocyanate is present in many plants. Allergic contact dermatitis from allyl isothiocyanate is well known but infrequently reported. The aim of this study was to investigate the prevalence of contact allergy to allyl isothiocyanate in patients with suspected contact dermatitis from vegetables and food. 259 such patients were tested at the Department of Dermatology, Gentofte Hospital, Denmark, from 1994 to 2003. Only 2 patients (0.8%) had a positive reaction (+) to allyl isothiocyanate and 43 patients (16.6%) had a ?+ reaction. One of the patients with a positive reaction provided samples of margarine, salad cream, oil and mayonnaise. These were analysed with high-performance liquid chromatography, and a moderate concentration of allyl isothiocyanate (2.5 ppm) was detected in the sample of margarine. This patient was a professional sandwich maker presenting with fingertip dermatitis mimicking 'tulip fingers' or allergic contact dermatitis from garlic and onions. In conclusion, allergic contact dermatitis from allyl isothiocyanate occurs in only a limited number of cases, despite frequent exposure. The large number of ?+ reactions raises the question as to whether the recommended patch test concentration is too low.

Adult↗
PubMed2003

Anti-tumour and anti-oxidant activity of naturally occurring isothiocyanates.

Two naturally occurring isothiocyanates, Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) were investigated for their antioxidant and anti-tumour peroperties. Both AITC and PITC showed antioxidant and tumour reducing activities when administered intraperitoneally at a dosage of 25 microg/dose/animal for 5 consecutive days. The inhibition of PMA induced superoxide generation by the peritoneal macrophages in AITC and PITC treated animals were 34% and 30.3% respectively. Nitrite production by the peritoneal macrophages was also inhibited by the administration of both AITC (51.6%) and PITC (34.53%). Administration of these naturally occurring isothiocyanates also inhibited the lipid peroxidation (AITC - 47.4%; PITC-25.9%) in mice liver homogenate. Both isothiocyanates also scavenged hydroxyl radicals (OH-) in vitro. Percentage inhibition of OH-production in AITC treated animals were 61.9% and that of PITC treated animals were 69.7%. Treatment with these isothiocyanates reduced the solid tumour development induced by Dalton's lymphoma ascites (DLA) tumour cells. The life span of Ehrlich ascites tumour bearing animals was also significantly enhanced to 152.4% and 95.2% by the treatment with PITC and AITC, respectively, implicating the anti-tumour activity of these compounds.

Animals↗
PubMed1994

Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms.

Organic isothiocyanates block the production of tumors induced in rodents by diverse carcinogens (polycyclic aromatic hydrocarbons, azo dyes, ethionine, N-2-fluorenylacetamide, and nitrosamines). Protection is afforded by alpha-naphthyl-, beta-naphthyl-, phenyl-, benzyl-, phenethyl-, and other arylalkyl isothiocyanates against tumor development in liver, lung, mammary gland, forestomach, and esophagus. Many isothiocyanates and their glucosinolate precursors (beta-thioglucoside, N-hydroxysulfate) occur naturally and sometimes abundantly in plants consumed by humans, e.g., cruciferous vegetables. Nevertheless, the possible contributions of isothiocyanates and glucosinolates to the well recognized protective effects against cancer of high consumptions of vegetables are unclear. The anticarcinogenic effects of isothiocyanates appear to be mediated by tandem and cooperating mechanisms: (a) suppression of carcinogen activation by cytochromes P-450, probably by a combination of down-regulation of enzyme levels and direct inhibition of their catalytic activities, which thereby lower the levels of ultimate carcinogens formed; and (b) induction of Phase 2 enzymes such as glutathione transferases and NAD(P)H: quinone reductase, which detoxify any residual electrophilic metabolites generated by Phase 1 enzymes and thereby destroy their ability to damage DNA. Since isothiocyanates block carcinogenesis by dual mechanisms and are already present in substantial quantities in human diets, these agents are ideal candidates for the development of effective chemoprotection of humans against cancer.

Animals↗
PubMed1987

Inhibition of rat liver microsomal Ca2+-ATPase by fluorescein-5'-isothiocyanate.

Rat liver microsomal fraction was incubated at pH 8.8 with fluorescein-5'-isothiocyanate in a Tris-buffered sucrose medium. This treatment completely inhibited ATP-dependent Ca2+ transport, Ca2+-ATPase activity, and Ca2+-ATPase phosphoenzyme intermediate formation. Inhibition of Ca2+ transport and phosphoenzyme intermediate formation by fluorescein-5'-isothiocyanate was partially prevented by including ATP in the treatment medium. These data taken together are consistent with the proposal that fluorescein-5'-isothiocyanate binds the Ca2+-ATPase ATP-binding site, suggesting the presence of a lysine residue in this domain. Fluorescein-5'-isothiocyanate labeling of microsomal proteins had no measurable effect on the basal, Mg2+-ATPase activity. Using fluorescein-5'-isothiocyanate-labeled microsomal fraction, we demonstrated that the Mg2+-ATPase activity was inhibited by Ca2+.

Adenosine Triphosphate↗
PubMed1990

Glutathione S-transferase subunit induction patterns of Brussels sprouts, allyl isothiocyanate and goitrin in rat liver and small intestinal mucosa: a new approach for the identification of inducing xenobiotics.

Effects of Brussels sprouts (2.5-30%), allyl isothiocyanate (0.03 and 0.1%) and goitrin (0.02%), in the diet, on the glutathione S-transferase subunit pattern in the liver and small intestinal mucosa of male Fisher rats were investigated. A statistically significant linear relationship was found between the amount of Brussels sprouts in the diet and the induction of glutathione S-transferase subunits in two experiments. Increases in total activity of glutathione S-transferases towards 1-chloro-2,4-dinitrobenzene ranged from about 15% (2.5% Brussels sprouts in the diet) to 180% (30% Brussels sprouts in the diet) in the liver, and from 3% (2.5% Brussels sprouts) to 150% (30% Brussels sprouts) in the small intestinal mucosa. There were similar increases in the total amounts of glutathione S-transferase subunits. In the first experiment, when the average sinigrin and progoitrin levels found in the sprouts were 1835 and 415 mumol/kg, respectively, subunit induction patterns in both the liver and the small intestinal mucosa were very similar to the pattern observed after feeding allyl isothiocyanate. In the second experiment, when the average sinigrin level found in the sprouts was as low as the progoitrin level (both about 540 mumol/kg), a goitrin-like induction pattern was observed. The most pronounced difference between the glutathione S-transferase subunit induction patterns due to administration of allyl isothiocyanate and goitrin is the much stronger enhancement of subunit 2 by allyl isothiocyanate. The induction patterns of both experiments indicate that in Brussels sprouts at least two compounds, probably allyl isothiocyanate and goitrin, are responsible for the induction of glutathione S-transferases.

Animals↗
PubMedDate not supplied

Synthesis of isothiocyanate-derived mercapturic acids.

Twelve mercapturic acids derived from saturated and unsaturated aliphatic and aromatic isothiocyanates were synthesised, by adding isothiocyanate to a solution of N-acetyl-L-cysteine and sodium bicarbonate, in a typical yield of 77%. Isothiocyanates were synthesised first by adding the corresponding alkyl bromide to phthalimide potassium salt. The obtained N-alkyl-phthalimide was hydrazinolysed yielding the alkyl amine, which subsequently was reacted with thiophosgene yielding the isothiocyanate with an overall yield of 16%. Mercapturic acids in urine can serve as a biomarker of intake to determine the health promoting potential of isothiocyanates present in cruciferous vegetables.

Acetylcysteine↗
PubMed2000

Modifying effects of 4-phenylbutyl isothiocyanate on N-nitrosobis(2-oxopropyl)amine-induced tumorigenesis in hamsters.

The modifying effects of dietary 4-phenylbutyl isothiocyanate (PBITC), given during the initiation stage of carcinogenesis, were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). A total of 120 female 5-week-old hamsters were divided into six groups. Animals in groups 1-3, each consisting of 30 hamsters, were given BOP by two subcutaneous injections, 1 week apart, at a dose of 20 mg/kg body weight, plus 0, 10 or 100 micromol/animal of PBITC in corn oil by gavage 2 h prior to each carcinogen treatment. Ten animals in group 4 served as a vehicle control, and animals in groups 5 and 6, each consisting of ten hamsters, were given 10 and 100 micromol of PBITC alone in corn oil. Sacrifice was 52 weeks after the first BOP injection. The PBITC treatments significantly (P<0.05) inhibited the development of pancreatic ductal dysplasias and adenocarcinomas. Also, lung tumors (adenomas and adenocarcinomas) were significantly (P<0.05) reduced in a dose-dependent manner. In contrast, both hepatocellular and cholangiocellular tumors (adenomas and carcinomas) tended to be or were significantly increased by PBITC. These results, taken together with our previous findings, indicate that the natural isothiocyanate, phenethyl isothiocyanate (PEITC), has a more potent chemopreventive action against BOP-induced tumorigenesis than synthetic isothiocyanates with longer alkyl chains, such as 3-phenylpropyl isothiocyanate (PPITC) and PBITC. Thus, their lipophilicity does not necessarily reflect the chemopreventive potential because the strength of lipophilicity is PEITC<PPITC<PBITC.

Adenocarcinoma↗