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

Three species of marine bivalve molluscs (Chamelea gallina, Ruditapes decussatus, and Crassostrea gigas) have been studied in order to evaluate the levels of pollution on the South Atlantic Spanish littoral. Several transition metals (Cu, As, Cd, Sn, Hg, Pb) were determined as a general index of total contamination. Animals from putative contaminated areas exhibited higher metal contents than those from cleaner waters. C. gigas showed 5-20-fold higher total metal content than the other two species. The mutagenicity of ethanolic extracts was assayed by using both the His reversion and the Ara forward mutation tests. Mollusc tissues from the three species did not contain genotoxins active on TA98 (frameshift mutations) or TA100 (mainly G:C base-pair substitutions), but did contain direct-acting genotoxins of a polar nature and oxidative type. This was based on the following observations: 1) mammalian metabolic activation was not required for mutagenicity, 2) mutagens were eluted with the polar fraction from XAD-2 columns, and 3) mutagenic responses were observed with Salmonella typhimurium TA102 (A:T base-pair substitutions; sensitive to oxidative damages) and Escherichia coli catalase-deficient (AraR forward mutations) strains. No relevant differences were found in the mutagenicity of mollusc extracts from areas with different pollution levels. Otherwise, our data suggest that, in general, animals living in contaminated environments had fewer genotoxins of oxidative type than those from less polluted areas. Such a result might be explained by the observation of increased levels of a number of detoxifying and antioxidant enzymes, such as glutathione-S-transferase, glutathione-peroxidase, catalase, and superoxide dismutase. Thus, contaminated animals seem to be better protected against the oxidative damages induced by metals, in agreement with their lower malondialdehyde levels. To what extent the responsible mutagenic compounds are of endogenous origins, or "Nature's pesticides" (the major toxic chemicals ingested by phytoplankton filter-feeders), and/or the result of human activities remains to be determined.
Environ Mol Mutagen 1992
PMID:Metal, mutagenicity, and biochemical studies on bivalve molluscs from Spanish coasts. 154 Dec 52

Escherichia coli K-12 strains completely lacking catalase activity due to mutations in katG, katE, and katF genes were constructed in order to assess the role of hydrogen peroxide in mutagenesis. Mutagenesis was monitored by selecting forward mutations to L-arabinose resistance. Lethality was measured at experimental conditions equivalent to those of the mutant yield by using a mixed culture of pairs of isogenic strains distinguished by their differential nutritional requirements. Deficiency in katG, katE, and katF genes leads to an enhanced spontaneous mutation rate as well as an enhanced sensitivity to both the lethal and mutagenic effects of hydrogen peroxide or an H2O2-generating mixture of compounds, such as coffee. To compare further the responses of the catalase-deficient bacteria to those of catalase-proficient counterparts, other genotoxins were analyzed. Both catalase-deficient and catalase-proficient strains were equally mutated by MMS, 4-NQO, and ultraviolet light. It is concluded that the bacterial strains and the mutagenicity tests described in the paper represent a useful tool to study the role of H2O2 in mutagenesis.
Environ Mol Mutagen 1990
PMID:Mutagenesis in Escherichia coli lacking catalase. 219 82

Weak mutagenic activity was detected in several commercially available edible palm and corn oils using liquid incubation bioassays with Salmonella typhimurium TA1537. Chromatographic fractionation of unrefined palm oil established that mutagenic activity was present in three fractions that also contained fatty acyl hydroperoxides. Similar weak mutagenic activity was also demonstrated for linoleic and linolenic acid hydroperoxides. In all cases, the mutagenicity was abolished by exogenous catalase, implying that the observed activity was moderated by hydrogen peroxide.
Teratog Carcinog Mutagen 1989
PMID:Mutagenic lipid peroxides from edible oils. 257 Apr 68

Cigarette smoke has been reported to contain free radicals and free radical generators in both the gas and particulate phases. Studies in our laboratory have shown that both cigarette smoke condensate (CSC) and smoke bubbled through phosphate buffered saline solution (smoke-PBS) increased sister chromatid exchanges (SCE) in Chinese hamster ovary cells in a dose-dependent manner. Since oxygen free radicals have been shown to cause SCEs and other chromosomal damage, we investigated the role of these radicals in the induction of SCEs by CSC and smoke-PBS. Addition of the antioxidant enzymes catalase and superoxide dismutase or the oxygen-radical scavenger ascorbic acid failed to reduce the SCE frequency in the presence of either CSC or smoke-PBS. Additional studies indicated that the quantity of hydrogen peroxide produced in CSC or smoke-PBS is too small to account for the observed SCE induction. It appears, therefore, that SCE induction by CSC or smoke-PBS does not involve the participation of oxygen free radicals.
Environ Mol Mutagen 1989
PMID:Role of oxygen free radicals in the induction of sister chromatid exchanges by cigarette smoke. 264 5

Day 9.5 rat embryos were exposed in culture to xanthine/xanthine oxidase generated active oxygen species. Growth and development were assessed after 46 hr of culture. The treatment induced abnormalities of the neural suture, the severity of which increased in a dose-related manner with the concentration of substrate or enzyme. Glutathione (10 mM) or catalase (50 micrograms/ml) either partially or completely abolished the effects of xanthine/xanthine oxidase, whereas the addition of superoxide dismutase (50 micrograms/ml) or desferrioxamine (1mM) did not reduce the number of malformed embryos. These findings suggest that hydrogen peroxide and/or hydroxyl radicals are responsible for the effects of xanthine and xanthine oxidase.
Teratog Carcinog Mutagen 1986
PMID:Malformations induced in cultured rat embryos by enzymically generated active oxygen species. 288 69

Sister chromatid exchange (SCE) induction by ultraviolet (UV) light was studied in both human and pig whole blood cultures (WBC) and plasma leukocyte cultures (PLC). No variation in SCE frequency was observed between pig WBC and PLC in control as well as in treated cells. Conversely, SCE frequencies of human PLC were consistently higher than those of WBC in control and UV-exposed cells. Thus, red blood cells (RBCs) do not influence the sensitivity of lymphocytes to UV light exposure, and there must be some different culture condition(s) in the induction of SCEs between human WBC and PLC but not in swine lymphocyte cultures. Since the BrdUrd/lymphocyte ratio of WBC was halved in PLC, the effect of BrdUrd concentration in inducing the SCE baseline frequency of PLC may be ruled out. Also, Ficoll-Hypaque-separated human mononuclear leukocytes in culture (MLC), but not pig MLC, showed a two-fold increase in SCE frequency over WBC values. Thus, neither the cell separation technique nor polymorphonuclear leukocytes had a significant role in the elevated SCE frequency of human PLC or MLC. Experiments where human RBCs were titrated into human PLC showed that the induction of an elevated SCE frequency of PLC was suppressed in a dose-dependent manner by the presence of RBCs in the culture medium. Since the incorporation of pig or human RBCs into human PLC as well as into MLC reduced the SCE frequency to that of WBC, a common component and/or function existing in these cells is suggested. Analysis of different RBC components showed that RBCs, specifically RBC ghosts, release a diffusible but not dialyzable "corrective" factor into culture medium that is able to reduce the SCE frequencies of PLC. Antioxidant enzymes such as catalase and horseradish peroxidase were unable to reduce the SCE frequency of human PLC to WBC values.
Environ Mutagen 1986
PMID:Variation in sister chromatid exchange frequencies between human and pig whole blood, plasma leukocyte, and mononuclear leukocyte cultures. 373 96

The mechanisms by which two quinone-forming compounds, hydroquinone (HQ) and tert-butyl-hydroquinone (tBHQ), induce chromosomal loss and breakage in a prostaglandin H synthase-containing V79 cell line have been investigated using the cytokinesis-block micronucleus assay with CREST antibody staining. Increased frequencies of CREST-positive micronuclei (indicating chromosome loss) and CREST-negative micronuclei (indicating chromosome breakage) were observed following exposure of cells to HQ and tBHQ. The formation of micronuclei by HQ, but not tBHQ, was dependent on arachidonic acid supplementation, indicating activation by prostaglandin H synthase. Since the oxidation of hydroquinones can result in the generation of oxygen radicals, the contribution of oxygen radicals to the formation of chromosomal alterations induced by HQ and tBHQ was investigated. In the presence of a superoxide-generating system consisting of hypoxanthine and xanthine oxidase, a significant increase in micronucleated cells was observed. These induced micronuclei consisted exclusively of CREST-negative micronuclei and their formation was completely inhibited by pretreatment with catalase. Catalase also significantly inhibited the CREST-negative micronuclei induced by HQ and tBHQ. In addition, glutathione treatment inhibited both CREST-positive and negative micronuclei induced by these phenolic compounds. These results indicate that both chromosome loss and breakage are induced by these two quinone-forming agents. Reactive oxygen species contribute to the chromosomal breakage induced by HQ and tBHQ but the observed chromosomal loss appears to result from other mechanisms such as an interference of quinone metabolites with spindle formation.
Environ Mol Mutagen 1994
PMID:Role of oxygen radicals in the chromosomal loss and breakage induced by the quinone-forming compounds, hydroquinone and tert-butylhydroquinone. 785 41

Benzene and five of its known metabolites--muconic acid, hydroquinone, catechol, p-benzoquinone, and benzentriol--were examined for DNA damage in human lymphocytes using the alkaline Comet assay, and conditions were optimised to determine responses. Metabolic activation (S-9 mix) was included in the assay for varying times to try to enhance effects. In addition, the effects of catalase were investigated as it is known to be present in S-9 mix reducing oxidative damage, and some benzene metabolites are known to react through oxygen radical mechanisms. Effects were also examined in cycling cells to determine whether they were more sensitive to damage then noncycling cells. Comets were measured either by eye or by image analysis. Data have been presented according to length of treatments. When Comets were measured by eye after treatment with hydrogen peroxide (H2O2), the positive control, and each compound for 0.5 hr, only H2O2 and benzenetriol induced pronounced DNA damage without metabolic activation. The effect of catechol was moderate compared with that of benzenetriol. There was a very weak effect of benzene in the absence of rat liver S-9 mix. In the presence of S-9 mix, benzene was not activated. The effect of benzenetriol was greatly reduced by the external metabolising system, but p-benzoquinone became activated to some extent. Catalase abolished the effect of benzenetriol, suggesting that H2O2 formed during autoxidation may be responsible for the DNA-damaging ability of this metabolite. The presence of catalase in S-9 mix may explain the detoxification of benzenetriol and the failure to detect consistent benzene responses. Mitogen-stimulated cycling cells were less sensitive to H2O2 and benzenetriol than unstimulated G0 lymphocytes. When comets were measured by image analysis, a 0.5-hr treatment with H2O2 and benzenetriol and catechol confirmed results analysed by eye, with S-9 mix greatly reducing responses. When treatments were increased to 1 hr in the presence and absence of S-9 mix, benzene at a 5-fold increased dose produced a significant positive response but not at the lower dose. When treatment times were increased to 2 and 4 hr, doses were also increased, and muconic acid, hydroquinone, catechol, and benzoquinone in the presence of S-9 mix showed positive time and dose-related responses, and at the highest dose of benzoquinone the morphology of the nucleus was affected. Effects tended to become more pronounced at high doses and after longer exposures, although this was not always consistent from experiment to experiment. In conclusion, benzene and all metabolites investigated gave positive responses. Where altered responses were observed, they were significantly different from the corresponding controls.
Environ Mol Mutagen 1995
PMID:An investigation of the DNA-damaging ability of benzene and its metabolites in human lymphocytes, using the comet assay. 857 19

In this study we examined the potential for environmental levels of ozone (03) to degrade arachidonic acid (AA), a polyunsaturated fatty acid abundantly present in the lung, into products that can produce DNA single strand breaks (ssb) in cultured human lung cells. Human lung fibroblasts were incubated with 60 microM AA that had been previously exposed to and degraded by 0.4 ppm 03 (1 hr.) Incubation of the cells with 03-exposed AA (but not with vehicle alone) for 1 hr at 4 degrees C and 37 degrees C produced 555 and 245 rad-equivalents of DNA ssb, respectively, as determined by the DNA alkaline elution technique. These breaks were completely eliminated when the ozonized AA solution was incubated with catalase prior to cell treatment, indicating that h202 was solely responsible for damaging DNA. Superoxide dismutase bovine serum albumin, or heat-inactivated catalase showed little, if any, inhibitory activity. The H202 content of the ozonized AA (31 +/- 4 microM) could account for only about 40% of the observed breaks. Potentiation of the H202-induced DNA ssb persisted after removal of the carbonyl substances by chromatographic procedures, suggesting that the non-carbonyl component of ozonized AA was the responsible component for inducing augmentation of the observed increases in DNA ssb. Ozonized AA also induced DNA ssb in cultures of the human bronchial epithelial cell line BEAS-2B. Again, these breaks were shown to exceed levels that could be attributed to the presence of H202 alone. These results indicate that products of ozonized AA can interact to potentiate DNA ssb in human lung cells.
Environ Mol Mutagen 1996
PMID:Products of ozonized arachidonic acid potentiate the formation of DNA single strand breaks in cultured human lung cells. 862 54

Glutathione is activated to a mutagen by gamma-glutamyl transpeptidase. Other thiols, such as cysteine, penicillamine, cysteine ethylester, and cysteinylglycine, are direct mutagens in the Ames Salmonella mutagenicity test. Thiol mutagenesis is oxidative in nature and involves H2O2 and possibly hydroxyl radicals. Transition metals are crucial for thiol autoxidation. The role of copper and ceruloplasmin (CP) in thiol-dependent mutagenesis was studied in Salmonella typhimurium strain TA102. Cu and CP at low concentrations enhanced thiol-dependent mutagenesis in the presence, but not in the absence, of added Fe. The degree of enhancement depended on the type of thiol. At high Cu or CP concentrations, thiol mutagenesis was inhibited. Cu also decreased the mutagenicity of H2O2. Cu- and CP-enhanced mutagenesis were inhibited by radical scavengers, catalase, and peroxidase but not by superoxide dismutase. The effects of Cu and CP on thiol-dependent mutagenesis were similar to their effects on thiol-driven lipid peroxidation. The results indicate that the role of Cu and CP in the enhancement of thiol mutagenesis is the facilitation of the transfer of electrons from a thiol to iron, rather than in catalysis of the Fenton reaction.
Environ Mol Mutagen 1997
PMID:Role of copper and ceruloplasmin in oxidative mutagenesis induced by the glutathione-gamma-glutamyl transpeptidase system and by other thiols. 902 Mar 9


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