ascorbic-acid and phenethyl-isothiocyanate

Isothiocyanates are plant-derived compounds that may be beneficial in the prevention of certain chronic diseases. Yet, by stimulating the production of reactive oxygen species (ROS), isothiocyanates can be genotoxic. Whether antioxidants influence isothiocyanate-induced genotoxicity is unclear, but this situation was clarified appreciably herein. In HCT116 cells, phenethyl isothiocyanate (PEITC) increased ROS production, which was inhibited by N-acetylcysteine (NAC) and deferoxamine (DFO) but not by ascorbic acid (ASC) and trolox (TRX) that were found to be more potent radical scavengers. Surprisingly, ASC and TRX each intensified the DNA damage that was caused by PEITC, but neither ASC nor TRX by themselves caused any DNA damage. In contrast, NAC and DFO each not only attenuated PEITC-induced DNA damage but also attenuated the antioxidant-intensified, PEITC-induced DNA damage. To determine if the DNA damage could be related to possible changes in the major antioxidant defence system, glutathione (GSH) was investigated. PEITC lowered GSH levels, which was prevented by NAC, whereas ASC, TRX and DFO neither inhibited nor enhanced the GSH-lowering effect of PEITC. The GSH synthesis inhibitor, buthionine sulphoxime, intensified PEITC-induced DNA damage, although by itself buthionine sulphoxime did not directly cause DNA damage. The principal findings suggest that ASC and TRX make PEITC more genotoxic, which might be exploited in killing cancer cells as one approach in killing cancer cells is to extensively damage their DNA so as to initiate apoptosis.

Topics: Apoptosis; Ascorbic Acid; Biphenyl Compounds; Chromans; DNA Damage; Drug Evaluation, Preclinical; Free Radical Scavengers; Glutathione; HCT116 Cells; HT29 Cells; Humans; Isothiocyanates; Mutagens; Picrates; Reactive Oxygen Species

The aim of this study was to investigate the protective effect of isothiocyanates alone or in combination with vitamin C towards N-nitrosodibutylamine (NDBA) or N-nitrosopiperidine (NPIP)-induced oxidative DNA damage in the single cell gel electrophoresis (SCGE)/HepG2 assay. Phenethyl isothiocyanate (PEITC) and indole-3-carbinol (I3C) alone showed a weak protective effect towards NDBA (0.1 microm, 26-27%, respectively) or NPIP (1 microm, 26-28%, respectively)-induced oxidative DNA damage. Allyl isothiocyanate (AITC) alone did not attenuate the genotoxic effect provoked by NDBA or NPIP. In contrast, HepG2 cells simultaneously treated with PEITC, I3C and AITC in combination with vitamin C showed a stronger inhibition of oxidative DNA-damage induced by NDBA (0.1 microm, 67%, 42%, 32%, respectively) or NPIP (1 microm, 50%, 73%, 63%, respectively) than isothiocyanates (ITCs) alone. One feasible mechanism by which ITCs alone or in combination with vitamin C exert their protective effects towards N-nitrosamine-induced oxidative DNA damage could be by the inhibition of their cytochrome P450 dependent bioactivation. PEITC and I3C strongly inhibited the p-nitrophenol hydroxylation (CYP2E1) activity (0.1 microm, 66-50%, respectively), while the coumarin hydroxylase (CYP2A6) activity was slightly reduced (0.1 microm, 25-37%, respectively). However, the ethoxyresorufin O-deethylation (CYP1A1) activity was only inhibited by PEITC (1 microm, 55%). The results indicate that PEITC and I3C alone or PEITC, I3C and AITC in combination with vitamin C protects human-derived cells against the oxidative DNA damaging effects of NDBA and NPIP, two food carcinogenic compounds.

Topics: Anticarcinogenic Agents; Aryl Hydrocarbon Hydroxylases; Ascorbic Acid; Carcinogens; Carcinoma, Hepatocellular; Cell Line, Tumor; Comet Assay; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; DNA Breaks; DNA-Formamidopyrimidine Glycosylase; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Indoles; Isothiocyanates; Liver Neoplasms; Microsomes, Liver; Mixed Function Oxygenases; Nitrosamines; Oxidative Stress

Initiation activity of phenylethyl isothiocyanate (PEITC) was examined in a two-stage urinary bladder carcinogenesis model. Male 6-week-old Fischer 344 rats were fed diet containing 0.1% PEITC for 12 or 24 weeks, with or without subsequent administration of 5% sodium l-ascorbate (Na-AsA) in diet until week 48, or for the entire experimental period. After 12 weeks of PEITC-treatment, both simple hyperplasia and papillary or nodular (PN) hyperplasia had developed in all animals, but the majority of these lesions had disappeared at week 48, irrespective of the Na-AsA-treatment. The same lesions after 24 weeks of PEITC-treatment had progressed to dysplasia and carcinoma, in a small number of cases by week 48 (6% in incidence for each lesion), but enhancement by the Na-AsA-treatment was evident only with simple hyperplasias (from 56 to 100% in incidence) and PN hyperplasias (from 19 to 56%). The results suggest a limited initiation activity of PEITC with induction of irreversible lesions by 24 weeks of exposure.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinoma; Diet; Hyperplasia; Isothiocyanates; Male; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Watercress (Nasturtium officinale R.Br.) is the richest source of glucosinolate nasturtiin, which on hydrolysis produces phenethyl isothiocyante (PEITC). Interest in growing watercress is stimulated since demonstration of the role of PEITC in protection against cancers associated with tobacco specific carcinogens. Twenty-one days old watercress seedlings were transplanted into growth chambers (16-h days/8-h nights of 25/22 degrees C and photosynthetic photon flux (PPF) of approximately 265 micromol m(-2) s(-)(1)). The study was replicated three times. Leaves were analyzed for PEITC and ascorbic acid concentrations at transplant, and harvested at 10-days intervals until 60 days after transplant. The PEITC and ascorbic acid concentrations were the highest in leaves harvested at 40 days and the lowest at transplant. Leaves harvested at 40 days produced about 150% higher PEITC concentrations compared to the leaves at transplant. Both PEITC and ascorbic acid concentrations of leaves increased linearly with age until 40 days after transplant after which there was no significant increase. Seedlings at transplant had the lowest dry mass and leaf area, while plants harvested at 60 days had the highest dry mass and leaf area.

Topics: Ascorbic Acid; Isothiocyanates; Nasturtium; Photoperiod; Plant Leaves; Seedlings

The effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), phenylethylisothiocyanate (PEITC), 3-O-ethylascorbic acid, 3-O-dodecylcarbomethylascorbic acid and n-heptadecane-8, 10-dione were analyzed in a rat multiorgan carcinogenesis model. Groups of 15 animals were given a single intraperitoneal (i.p.) injection of diethylnitrosamine and 4 i.p. injections of N-methylnitrosourea as well as N-butyl-N-(4-hydroxybutyl) nitrosamine in the drinking water during the first 2 weeks. Then 4 subcutaneous (s.c.) injections of dimethylhydrazine and 2,2'-dihydroxy-di-n-propylnitrosamine were given in the drinking water over the next 2 weeks for initiation. Test compounds were administered during the initiation or post-initiation periods. The dietary dose was 1% except for n-heptadecane-8, 10-dione and PEITC (0.1%). Complete autopsy was performed at the end of experimental week 28. All 5 compounds reduced the number of lung hyperplasia, particularly PEITC when given during the initiation period. In addition, HTHQ lowered the incidence of esophageal hyperplasia in the initiation period, and of small and large intestinal adenomas in the post-initiation period. However, it also enhanced the development of hyperplasia and papilloma in the forestomach and tongue. PEITC lowered the induction of esophageal hyperplasia, kidney atypical tubules and liver glutathione S-transferase placental form (GST-P)-positive foci when given during the initiation period but enhanced the development of liver GST-P positive foci and urinary bladder tumors in the post-initiation period. Moreover, it induced hyperplasia of the urinary bladder. Our results indicate minor adverse effects for HTHQ in the forestomach and tongue, and demonstrate that PEITC, which inhibits carcinogenesis at the initiation stage in several organs, also exhibits promotion potential in liver and urinary bladder in the post-initiation stage under the present experimental conditions.

Topics: Animals; Anticarcinogenic Agents; Ascorbic Acid; Glutathione Transferase; Hydroquinones; Isothiocyanates; Male; Neoplasm Staging; Neoplasms, Experimental; Organ Specificity; Precancerous Conditions; Rats; Rats, Inbred F344

The effects of a synthetic phenolic antioxidant, 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), two novel synthetic ascorbic acid derivatives, 3-O-ethyl ascorbic acid (EAsA) and 3-O-dodecylcarbomethylascorbic acid (DAsA), and phenylethyl isothiocyanate (PEITC) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis were examined in female Sprague-Dawley rats. Groups of 20, 7 week-old rats received an intra-gastric dose (50 mg/kg, b.w.) of DMBA, and starting one week thereafter received powdered diet containing 1.0% HTHQ, 1.0% EAsA, 1.0% DAsA, 0.1% PEITC or a basal diet alone for 35 weeks. Although the final incidences of mammary adenocarcinomas did not significantly differ among the DMBA-treated groups, multiplicities were significantly lowered in the EAsA (1.6+/-1.6 per rat, P < 0.01) and HTHQ (2.6+/-1.9, P < 0.05) animals as compared with the basal diet case (4.1+/-2.9). The average carcinoma volumes were also significantly smaller in rats given EAsA (2.1+/-3.8 cm3, P < 0.05), DAsA (2.5+/-5.3, P < 0.05) or PEITC (2.4+/-5.9, P < 0.05) than in those receiving DMBA alone (4.9+/-9.2). The results indicate that HTHQ, EAsA and PEITC all exert chemopreventive influence on the promotion/progression stage of DMBA-induced rat mammary carcinogenesis, with EAsA being particularly effective. To our knowledge this is the first documented example of an ascorbic acid derivative possessing chemopreventive potential against mammary cancer in vivo.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Carcinogens; Cell Transformation, Neoplastic; Chemoprevention; Diet; Female; Hydroquinones; Isothiocyanates; Mammary Neoplasms, Experimental; Rats; Rats, Sprague-Dawley