Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:APRD00249 (Mutagen)
 5,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The modulatory effect of vitamin C (Vit C) on the mutagenic effect of the antineoplastic drug cyclophosphamide (CP) was assessed in the in vivo micronucleus test in Swiss mice. Simultaneous oral administration of Vit C with i.p. administration of CP was found to decrease the frequency of micronucleated polychromatic erythrocytes elevated by CP. Vit C exhibited a significant antimutagenic effect over a wide dose range (1.56-200 mg/kg). The dose-response relationship was highly significant. These results demonstrated the ability of the in vivo micronucleus test to detect in vivo modulation of CP mutagenicity by Vit C. Our earlier results and those from other laboratories also indicate that this model system is suitable for primary in vivo screening of modulation of mutagenesis.
Teratog Carcinog Mutagen 1992
PMID:Modulation of cyclophosphamide mutagenicity by vitamin C in the in vivo rodent micronucleus assay. 135 96

The effects of retinoids (vitamin A analogs) and vitamins C and E on the aflatoxin B1 (AFB1)-induced mutagenesis in Salmonella typhimurium TA-98 and TA-100 were investigated. The bioassay was performed under conditions that permitted the effects of vitamins on carcinogen metabolism to be assessed separately from effects on the expression of the mutated bacterial cell. Both retinoic acid and retinol inhibited (up to 50%) AFB1-induced mutagenesis in S. typhimurium TA-98, but only retinol inhibited (up to 75%) mutagenesis in TA-100. Retinoic acid inhibition of mutagenesis in S. typhimurium TA-98 was pronounced over a wide concentration range (i.e., 2 X 10(-10) to 2 X 10(-8) M) however, at the higher concentrations (i.e., 2 X 10(-8) to 2 X 10(-6) M range) the predominant effect was the inhibition of the metabolism of AFB1 to its mutagenic metabolites. Vitamin E was more potent in inhibiting the expression of AFB1-induced mutagenesis than vitamin C. However, the major inhibitory effects of vitamin E were related to the metabolism of AFB1, whereas vitamin C was inhibitory at both metabolic and the post-metabolic levels of the AFB1 mutagenesis assay. The results of these investigations suggest that vitamins A, C, or E inhibit both AFB1 metabolism to its mutagenic metabolites as well as the expression of AFB1-induced mutated bacterial cells.
Teratog Carcinog Mutagen 1985
PMID:Effects of vitamins A, C, and E on aflatoxin B1-induced mutagenesis in Salmonella typhimurium TA-98 and TA-100. 285 59

This study examines sister chromatid exchange (SCE) induction by ascorbate, a weak in vitro SCE inducer which acts through free radical intermediates, and low doses of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a potent SCE inducer which acts primarily through DNA interstrand cross-links. A small dose-dependent increase in SCE was observed in human peripheral lymphocytes exposed to ascorbate in the 0.5-10 mM dose range for 59 hours, with significant slowing of cell cycle kinetics at concentrations at and above 5 mM. CCNU concentration was selected to approximate the maximal increase in SCE induced by ascorbate. SCE frequencies in cells exposed sequentially to both agents were not significantly different from expectations under an additivity-of-effect model based on SCE response to each agent individually. Despite clear differences in the types of lesions induced, ascorbate and CCNU appear to act independently to induce SCE in a manner consistent with, though not exclusive to, Painter's replicon cluster model.
Teratog Carcinog Mutagen 1988
PMID:Sister chromatid exchange in human lymphocytes exposed to ascorbic acid and the cancer chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. 290 45

Cell-cell communication through chemical messengers is a fundamental event required for the differentiation of embryonal cells. Interference with this process by xenobiotics may disrupt embryogenesis. Chinese hamster cells (V79) which display a specific form of cell-cell communication called metabolic cooperation were cultured in the presence of structurally diverse chemical teratogens. Among them were 12-O-tetradecanoyl-phorbol-13-acetate (TPA), diphenylhydantoin (DPH), warfarin, and a series of monoalkyl ethers of ethylene glycol with alcohol chain lengths from methyl to butyl. Sodium saccharin and ascorbic acid were examined to represent two chemicals which have been thoroughly tested for teratogenic effects in laboratory animals and cause no birth defects. Recovery of 100 6-thioguanine-resistant V79 (6-TGr) cells in coculture with 400,000 6-thio-guanine-sensitive V79 (6-TGs) cells in the presence of 6-thioguanine (6-TG) and the chemical agent was measured. In amounts that neither interfered with colony forming ability nor caused cytostasis when 100 6-TGr cells were plated alone, all of the substances except for saccharin and vitamin C increased the number of surviving 6-TGr cells in a concentration-related manner. The recovery was increased by the presence of TPA (to 100% by 4 ng/ml), DPH (from 26% at 91 microM to 43% at 274 microM), warfarin (from 15.5% at 162 microM to 44.5% at 487 microM) and to variable extents by all five glycol ethers. The most efficacious in the latter group of compounds was the isopropyl ether which raised 6-TGr recovery from 8% at 0.017 M to 66% at 0.087 M. Based on the evidence accumulated by previous studies involving TPA, we postulate that the teratogens employed inhibited metabolic cooperation. These observations suggest that V79 cells may be suitable to study inhibition of cell-cell communication as a mechanism of teratogenesis.
Teratog Carcinog Mutagen 1984
PMID:Inhibition of metabolic cooperation between Chinese hamster V79 cells by structurally diverse teratogens. 614 27

Sorbic acid and potassium sorbate are widely used Generally Recognized as Safe (GRAS) food additives with an extremely high (25 mg/kg) acceptable daily intake level. Some children between the ages of 6-24 months may actually ingest this amount. While presently not permitted to be added directly to meat and poultry products in the US, potassium sorbate has been proposed as a preservative for bacon, as an additive in conjunction with nitrite and ascorbate or erythorbate. Sorbate and nitrite form several species of direct-acting mutagens and genotoxic agents when present together at pH's mimicking gastric conditions. Two of the mutagens have been identified as ethylnitrolic acid and 1,4-dinitro-2-methylpyrrole. Mutagen formation is blocked by ascorbate at low pH. Ascorbate at eightfold molar excess leads to inactivation of 1,4-dinitro-2-methylpyrrole near neutral pH but does not destroy the mutagenic nitro compound at low pHs. The combination of sorbate with nitrite represents a potential health risk in the absence of adequate inactivating levels of ascorbate (vitamin C).
Environ Mutagen 1983
PMID:Review: putative mutagens and carcinogens in foods. II: sorbate and sorbate-nitrite interactions. 686 25

Recent reports suggest that ascorbic acid (vitamin C) inhibits tumorigenesis as well as exerts a protective effect against mutagenesis in vitro; however, there is no information on its ability to affect gene mutations induced in vivo. In this study, we have investigated the antimutagenic effects of ascorbic acid on the frequency of 6-thioguanine-resistant (6-TGr) T-lymphocytes produced in Fischer 344 rats dosed with the direct-acting alkylating agent, N-ethyl-N-nitrosourea (ENU). The frequency of 6-TGr T-lymphocytes from the spleen measured five weeks after ENU treatment indicated that ENU produced a substantial mutagenic response. Pretreatment and/or post-treatment of rats with ascorbic acid administered in the drinking water appeared to inhibit the response, but the inhibition was statistically significant only when data from the various dosing schedules were pooled. In addition, there was no clear dose-dependency to the inhibitory effect of ascorbic acid. To further evaluate the time effects of the vitamin supplement on ENU mutagenicity, rats were exposed to the mutagen together with ascorbic acid, which was given continuously for the entire duration of the experiment. At specific times after ENU treatment, the frequency of 6-TGr T-cells was determined in lymphocytes isolated from the spleen and the thymus. Time-dependent increases in the frequency of 6-TGr T-cells were observed with ENU treatment; ascorbic acid significantly reduced the ENU-mediated mutagenic responses, most dramatically in the spleen at weeks 6 and 8 (P < 0.0001), and to a lesser extent in the thymus (P < 0.01 at week 6 and P < 0.006 at week 8). Our data suggest that ascorbic acid intake affects the in vivo mutagenicity of ENU, a direct-acting mutagen/carcinogen, and that the reported inhibitory effects of the antioxidant on carcinogenesis may be partially mediated by its effects on mutagenesis. Although it is difficult to extrapolate from rodent studies to humans, the results presented suggest an explanation for epidemiological data that link vitamin C ingestion with decreased cancer risk.
Environ Mol Mutagen 1994
PMID:Ascorbic acid (vitamin C) modulates the mutagenic effects produced by an alkylating agent in vivo. 795 25

The modulatory effect of higher doses of vitamin C (ascorbic acid) on the genotoxicity of the three pesticides (endosulfan, phosphamidon, and mancozeb) was assessed in the in vivo micronucleus test in Swiss albino mice. Concurrent administration of the vitamin in a dose (20 mg/kg bwt/day) equivalent to double the human therapeutic one, along with each of the three pesticides, was most effective as an antimutagen. The therapeutic dose (10 mg/kg bwt/day) was comparatively less so, and the quadruple (40 mg/kg bwt/day) of it did not show any further amelioration.
Teratog Carcinog Mutagen 1994
PMID:Impact of higher doses of vitamin C in modulating pesticide genotoxicity. 799 29

The effects of dietary exposure to sodium L-ascorbate (Na-AsA), butylated hydroxyanisole (BHA), and diphenyl on the development of urinary bladder tumors in a mouse two-stage carcinogenesis model were examined. Male B6C3F1 mice received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water for 4 weeks and were then treated with 5% Na-AsA, 1% BHA, or 1% diphenyl for 32 weeks. None of these chemicals enhanced the development of either preneoplastic or neoplastic lesions in the urinary bladder. Furthermore, DNA synthesis levels of urinary bladder epithelium in mice treated with each substance alone for 8 weeks were not elevated significantly, although Na-AsA was associated with a significant increase in the urinary pH value and Na+ concentration. The results indicate that Na-AsA, BHA, and diphenyl do not exert an enhancing influence on mouse bladder carcinogenesis, in clear contrast to the case in the rat.
Teratog Carcinog Mutagen 1993
PMID:Lack of promotion of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in mice by rat cancer promoters. 810 12

A human volunteer study was conducted to test the effect of vitamin C supplementation on biomarkers of oxygen radical-mediated damage in individuals with a range of serum cholesterol levels. A group of 48 non-smokers, 24 men and 24 women, was selected from a panel of over 100 volunteers to give as wide a range of serum cholesterol levels as possible. None of the volunteers was taking medication to control cholesterol levels and they maintained their normal dietary habits so as not to compromise their cholesterol status. Volunteers were allocated to three groups of 16, each consisting of four males with low cholesterol levels (< 6 mmol/L) matched for age and build with four males with high cholesterol levels (> 6 mmol/L) and eight females matched in the same way. A three-treatment, three-treatment period, cross-over design was adopted to take account of any temporal differences in response. The three treatments given were placebo, 60 mg vitamin C/day (the recommended daily allowance) and 6 g vitamin C/day. Each treatment was given for 14 days with 6 weeks between the treatment periods. All procedures were performed to the standards of Good Clinical Practice. Blood samples were taken at the end of each treatment period. Serum was assayed for cholesterol whilst vitamin C, total antioxidant capacity, lipid peroxidation breakdown products and ras p21 protein levels were measured in plasma. Lymphocytes were examined for DNA damage using the Comet assay and chromosome aberration test. The Comet assay was conducted with and without challenge with hydrogen peroxide and the chromosome aberration test with and without challenge with bleomycin. Vitamin C supplementation caused a statistically significant increase in plasma vitamin C concentrations and total antioxidant capacity but did not affect cholesterol levels or ras p21 protein levels. There was a non-significant dose-related decrease in lipid peroxidation breakdown products with vitamin C supplementation. No effect on DNA damage was observed in the Comet assay, either with or without hydrogen peroxide challenge, or in the chromosome aberration test without bleomycin. However, a statistically significant increase in bleomycin-induced aberrations was found after vitamin C supplementation. This may be due to effects of vitamin C on iron status. Comparison of male and female subjects showed statistically significant differences in plasma vitamin C levels, the antioxidant capacity of the plasma and the number of chromosome aberrations induced by bleomycin challenge of lymphocytes in vitro. The results were the same for both low and high cholesterol subjects. This study provides no evidence of a beneficial effect on any of the biomarkers studied of vitamin C supplementation over a short-term supplementation period of 2 weeks in a population of healthy, non-smoking individuals eating a nutritionally adequate diet.
Environ Mol Mutagen 1997
PMID:The effects of vitamin C supplementation on biomarkers of oxygen radical generated damage in human volunteers with "low" or "high" cholesterol levels. 932 41

Several phenothiazine derivatives have been shown to cause reproductive toxicity. The biochemical mechanisms responsible for these effects are not fully understood at present. In this study, we investigated hydrogen peroxide-dependent oxidation of seven phenothiazines by purified human term placental peroxidase. Promazine was employed as the prototype phenothiazine drug. Promazine was easily oxidized to a cation radical (absorption maximum at 513 nm) when incubated under acidic conditions with human term placental peroxidase in the presence of hydrogen peroxide. The rate of the radical formation was 350 +/- 30 nmol/min/mg protein when 30 micrograms of the purified peroxidase was incubated with 10 mM promazine and 1.0 mM hydrogen peroxide in acetate buffer pH 3.5. The reaction was linear with respect to time, exhibited dependence on the amount of enzyme, and the concentration of promazine and hydrogen peroxide. Collectively, the results suggest an enzymatic nature of the reaction. Reduced glutathione, ascorbate, and NADH suppressed the rate of promazine radical formation presumably by its reduction back to promazine in a concentration-dependent manner. Concomitantly, NADH was co-oxidized. The cation radical formation and NADH oxidation declined significantly by potassium cyanide and sodium azide, the known peroxidase inhibitors. The enzyme also oxidized chlorpromazine, triflupromazine, trifluoperazine, trimeprazine, fluphenazine, and perphenazine in the presence of hydrogen peroxide. The evidence gathered in this study suggests that peroxidative bioactivation of phenothiazines to their corresponding cation radical species by the human placental peroxidase may represent one of the biochemical mechanisms responsible for the reported developmental toxicity of these chemicals.
Teratog Carcinog Mutagen 1997
PMID:Oxidation of phenothiazines by human term placental peroxidase in non-smokers. 943 63


1 2 3 Next >>