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PubMed1996

Anti-mutagenic agents are also co-recombinogenic and can be converted into co-mutagens.

In experiments using yeast without an external metabolic activation system, the hormones testosterone, beta-estradiol, and diethylstilbestrol were anti-mutagenic and co-recombinogenic. In the presence of Aroclor-induced rat liver S-9 plus cofactors (S9-mix) the same substances acted as co-mutagens and anti-recombinogens. Since an external metabolic activation system was able to convert anti-mutagens into co-mutagens, we studied whether the different metabolism of yeast and mice would lead to different effects. In whole-animal experiments using the mouse spot test, anti-mutagenic effects of vanillin (Imanishi et al., 1990), phenobarbital (Shibuya and Murota, 1984), and tannic acid (Sasaki et al., 1990) have been observed. In our present experiments with yeast, tannic acid and phenobarbital showed anti-mutagenic effects also, whereas vanillin acted as a co-mutagen. Thus, as in the case of the hormones, tannic acid and phenobarbital were anti-mutagenic and co-recombinogenic whereas vanillin was co-mutagenic as well as co-recombinogenic.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Fate of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in Sprague-Dawley rats. I. Mutagens in the urine.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent bacterial mutagen formed during cooking of beef. IQ was administered intravenously to Sprague-Dawley rats at concentrations ranging from 7.5-50 mg/kg body weight. Urine was collected and analyzed for mutagenicity. Urinary mutagens were found which required activation by S9 mix, and reverted Ames test strains TA98 and TA100, but not TA1535 or TA1537. The amount of urinary mutagen(s) were related to IQ dose administered and were excreted within 48 h. Additional mutagenic activity was not released after incubation with beta-glucuronidase or aryl sulfatase. Analysis of urinary mutagens by HPLC indicates that the majority of mutagenic activity is due to unchanged IQ, but a small peak of mutagenic activity may correspond to N-acetyl or 3-N-demethylated metabolite. Since only 1% of the administered mutagenic activity is recovered in the urine, IQ may be readily detoxified in vivo.

Animals↗

PubMed2006

Evaluation of new 2,2'-dimethyl-5,5'-dipropoxybenzidine- and 3,3'-dipropoxybenzidine-based direct dye analogs for mutagenic activity by use of the Salmonella/mammalian mutagenicity assay.

As part of a continuing study aimed at establishing structure-activity relationships and heuristic principles useful for the design of non-genotoxic azo dyes, a series of new direct dyes based on two non-mutagenic benzidine analogs, 2,2'-dimethyl-5,5'-dipropoxybenzidine and 3,3'-dipropoxybenzidine, were evaluated for mutagenic activity in Salmonella typhimurium strains TA98 and TA100. These strains are widely used for mutagenicity screening and have been shown to detect the mutagenic activity of benzidine analogs. While some toxicity was seen with some dyes at high doses, all of the dyes examined were judged non-mutagenic with and without metabolic activation in the standard Salmonella plate-incorporation assay. The results in the standard test are consistent with the properties of the diamines themselves. However, only one of the dyes was non-mutagenic when a reductive-metabolism pre-incubation assay was used. The results of this study suggest that although benzidine analogs are potential replacements for benzidine, there is a need to understand which mutagenic products are produced when reductive metabolism is present. There is also a need to know whether or not metal complexes of these dyes are mutagenic. Such information will allow the development of new non-mutagenic azo dyes.

Animals↗

PubMed1979

Mutagens in a river heavily polluted with paper recycling wastes: results of field and laboratory mutagen assays.

Paper recycling industries generate considerable quantities of waterborne wastes, and thus water pollution constitutes the greatest environmental problem associated with this industrial activity [Hunt and Franklin, 1973]. Generally the impact of this water pollution is considered in terms of aesthetic blight and deterioration of water quality. We present data that document another aspect of this pollution, the environmental contamination of an aquatic ecosystem with mutagenic materials. A natural population of the fern Osmunda regalis growing in a river heavily polluted with paper recycling wastes had a high incidence of chromosome mutations. This population was monitored for four years for the frequency of two-break chromosome mutations. These mutations were postzygotic in origin and suggested the presence of mutagens in the river water. The fern population is downstream from the outfalls of a paper recycling mill, which was discharging 13.3 X 10(6) liters of untreated paper recycling waste per day. In 1977 a waste-water-treatment facility was constructed to remove the solid waste previously discharged into the river. This facility generates 69,300 kg of solid waste daily, which is taken to a landfill. Periodic samples of this solid waste were collected from the waste-treatment facility in the summer of 1978, extracted with various solvents, and the extracts tested for mutagenic activity with the Salmonella/mammalian microsome mutagenicity test [Ames et al, 1975]. A majority of the solid waste samples contained mutagenic materials, but in all cases S-9 activation was required for mutagenic activity. The samples also were assayed with the soybean mitotic crossing-over assay [Vig, 1975]. Four out of six samples were positive. These results document the presence of mutagens in the solid waste generated by a paper recycling industry and the genetic impact of these mutagens on the local biota.

Chromosome Aberrations↗

PubMed1981

Use of nitrous acid-dependent decrease in mutagenicity as an indication of the presence of mutagenic primary aromatic amines. Non-specific reactions with phenols and benzo[alpha]pyrene.

Treatment of mutagenic primary aromatic amines with nitrous acid is known to decrease their mutagenicity. We examined some factors concerning the validity of using decreases in mutagenicity due to nitrous acid treatment as an indication of the presence of mutagenic primary aromatic amines in complex mixtures. We found that treatment of benzo[alpha]pyrene with nitrous acid for the extended periods of time previously employed leads to formation of three nitrobenzo[alpha]pyrene isomers. Some of the isomers are direct-acting mutagens for S. typhimurium with considerably greater mutagenicity than benzo[alpha]pyrene isomers. In attempts to minimize reaction of chemicals other than aromatic amines, we found that only very brief reaction periods are required for complete reaction of nitrous acid with representative aromatic amines, essentially eliminating their mutagenicity. During such brief reaction periods modification of benzo[alpha]pyrene is negligible, but phenols react readily. Chromatographic analysis indicated that reaction of nitrous acid with aromatic amines leads to the formation of families of products, thereby increasing the complexity of the mixtures in which the amines may occur. Thus, experiments examining the effects of nitrous acid on the mutagenic activity of complex mixtures must be carefully designed, and the results must be interpreted cautiously.

Amines↗

PubMed1989

Mutagenic activity and presence of the strong mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2-(5H)-furanone (MX) in chlorinated raw and drinking waters in The Netherlands.

Chlorinated surface and drinking waters in The Netherlands were analysed for mutagenic activity (Ames test) and the strong mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). Mutagenic activity and MX were formed during chlorine treatment of raw surface waters and purified surface water. Mutagenicity was also present in finished drinking waters which had been subjected to post-chlorination, but no MX could be detected. It is proposed that the mutagens responsible for most of the activity are acidic compounds as they were mainly extractable under acidic conditions. The precursors to the mutagenic compounds formed during post-chlorination of drinking water were efficiently removed by use of ozonation/activated carbon filtration. On the other hand, coagulation (Fe(III] in the presence of activated carbon powder seemed to have hardly any effect on the mutagen precursors. The calculated mutagenicity contribution from MX to the observed TA100 activity in the waters studied was less than 20%.

Chlorine↗

PubMed1982

Mutagens in larger fungi. I. Forty-eight species screened for mutagenic activity in the Salmonella/microsome assay.

Specimens of large fungi (mushrooms) were screened for mutagenic activity by the Salmonella/microsome assay, with strains TA98, TA2637 and TA100. Our of 48 species tested, 37 exhibited a significant but for the most part weak activity. The activity observed in the presence of S9 mix was typically between 0 and 50% of that without, and in no case was the activity increased in the presence of microsomal enzymes. Six metabolites reported to occur in some of the species included in this investigation were also tested. Significant mutagenic activity was found with isovelleral (5) from Lactarius sp., agaritine (3) from Agaricus bisporus and related sp. and beta-nitraminoalanine (7) from Agaricus silvaticus. Isovelleral may be a major mutagen in some of the sharp-tasting and mutagenic Russulaceae sp. A. bisporus (cultivated specimen) was weakly mutagenic toward all three strains of S. typhimurium, used, and agaritine was weakly active toward TA2637 alone. This implies that this fungus might contain other mutagenic material as well. beta-Nitraminoalanine was not found in the particular collection of A. silvaticus tested here. The mutagenicity observed for the fungus in this work may therefore be due to other metabolites. Even though many species found to be mutagenic are used as food, it seems premature to make specific recommendations about eventual health risks. Further information is needed about the chemistry and toxicology of the active compounds as well as about the effects of various methods used in preparing mushrooms for food.

Animals↗

PubMed1988

Evaluation of azo food dyes for mutagenicity and inhibition of mutagenicity by methods using Salmonella typhimurium.

The mutagenicity of 4 azo dyes (FD&C Yellow No. 5, FD&C Yellow No. 6, FD&C Red No. 40 and amaranth) that are widely used to color food has been evaluated. 4 different methods were used: (1) the standard Ames plate-incorporation assay performed directly on the dyes in the absence of S9 and in the presence of rat- or hamster-liver S9; (2) application of the standard plate assay to ether extracts of aqueous solutions of the dyes; (3) a variant of the standard assay, using hamster liver S9, preincubation, flavin mononucleotide (FMN) and other modifications designed to facilitate azo reduction; and (4) reduction of the dyes with sodium dithionite, followed by ether extraction and the standard plate assay. Assays that include chemical reduction (methods 3 and 4) were included because azo compounds ingested orally are reduced in the intestine with the release of free aromatic amines. No mutagenic activity was seen for any of the azo dyes tested by using the standard Ames plate assay (method 1). Ether extracts of some samples of FD&C Yellow No. 6, FD&C Red No. 40 and amaranth were active (method 2), but only at high doses, generally 250 mg-equivalents or more per plate. These results indicate the presence of low levels of ether-extractable mutagenic impurities. The FMN preincubation assay (method 3) gave negative results for all dye samples tested. Most batches of FD&C Red No. 40 tested had mutagenic activity that was detectable when the ether extract of less than 1 mg of dithionite-reduced dye was plated in the presence of S9 (method 4). This finding implies that an impurity in these samples of FD&C Red No. 40 can be reduced to yield an ether-extractable mutagen. Dithionite-reduced samples of FD&C Yellow No. 6 and amaranth showed ether-extractable mutagenic activity only at much higher doses than those at which activity was seen with most dithionite-reduced samples of FD&C Red No. 40 (method 4). FD&C Yellow No. 5 showed no mutagenic activity with this method. Mutagenic activity was not detected when FD&C Red No. 40 was tested by using the azo reduction preincubation assay with FMN (method 3).(ABSTRACT TRUNCATED AT 400 WORDS)

Azo Compounds↗

PubMed1990

Mutagenicity of deep-frying fat, and evaluation of urine mutagenicity after consumption of fried potatoes.

Mutagen formation during deep-frying was evaluated using standard frying conditions. Portions of pre-fried, sliced potatoes were fried in a commercial brand of hydrogenated vegetable frying fat, which was used repeatedly and for a prolonged period of time. Concentrations of polar oxidation and degradation products, and of dimeric and polymeric triglycerides, were found to increase in the frying fat as well as in fried potatoes with prolonged use of the fat. Thiobarbituric acid-reactive substances were detectable neither in the frying fat nor in the fried potatoes. Polar fractions of repeatedly used frying fat significantly increased the number of revertants in Salmonella typhimurium strain TA97 without S-9 mix. In the presence of S-9 mix mutagenic activity was reduced. As a consequence of ongoing formation of polar degradation and oxidation products, the mutagenicity of the fat increased after repeated use. Polar fractions of lipids extracted from commercially obtained pre-fried potatoes, as well as from fried potatoes, marginally increased the number of revertants in strain TA97 without S-9 mix. The mutagenicity of the lipid fractions of fried potatoes was not related to the heating time of the fat. Methanol extracts of fat-free residues of fried potatoes significantly increased numbers of revertants in strain TA97 after metabolic activation, which indicated that a different class of mutagens had been isolated. The mutagenicity of methanol extracts was not increased after either prolonged or repeated use of the fat. Urine samples of six healthy, non-smoking volunteers, collected during the 24 hr following consumption of portions of potatoes fried in repeatedly used fat, showed no increase in mutagenicity compared with control samples. Since the exact identity of mutagens formed during deep-frying, as well as their metabolic fate in man, is unclear at present, evaluation of possible adverse biological effects associated with consumption of fried foods will require strictly controlled metabolic studies.

Adult↗

PubMedDate not supplied

Formation of mutagens in cooked foods. V. The mutagen reducing effect of soy protein concentrates and antioxidants during frying of beef.

Cooking beef patties results in the formation of mutagens detectable by Salmonella typhimurium TA98 with metabolic activation. Decreased mutagenic activity results when frying beef with added soy protein concentrates (SPC). The reduction in mutagenicity takes place during the cooking process. Whereas fried beef hamburgers show high mutagenic activity, by comparison, similarly fried soy-hamburgers have much less mutagenic activity. Volumetric effects are responsible partly for the reduction on mutagenicity by SPC. Naturally occurring antioxidants in SPC, such as chlorogenic acid, also play a role. Also, a commonly used antioxidant, butylated hydroxyanisole (BHA), has been found effective in reducing the mutagenicity of fried beef. Thus, the addition of SPC or BHA in beef patties may provide a practical way of reducing mutagen formation during frying of beef.

Animals↗

PubMed2002

Mutagenic activity of the glutathione S-transferase substrate 1-chloro-2,4-dinitrobenzene (CDNB) in the Salmonella mutagenicity assay.

The mutagenicity of the commonly used glutathione S-transferase substrates 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB) was investigated in the Salmonella mutagenicity assay. CDNB induced a concentration-dependent mutagenic response in Salmonella typhimurium strain TA98. Incorporation of an activation system derived from Aroclor 1254-induced rats did not influence mutagenic response. Under the same conditions DCNB failed to display mutagenic activity. The mutagenic activity of CDNB was attenuated in bacterial strains under-expressing nitroreductase or O-acetylase activity but, in contrast, it was exaggerated in an O-acetylase over-expressing strain. It is inferred that CDNB exhibits a mutagenic response following reduction of the nitro-group to the hydroxylamine, which is further acetylated to form the acetoxy derivative that presumably breaks down spontaneously to generate the nitrenium ion, the likely ultimate mutagen.

Animals↗

PubMed1978

The efficiency and extent of mutagenic activity of some new mutagens of base-analogue type.

N4-Hydroxycytidine, 5-methyl-N4-hydroxydeoxycytidine and 2-amino-N6-hydroxyadenine were tested for their mutagenic activity in S. typhimurium and E. coli cells. Reversion analysis of different markers was applied in a plate-test system, and 2-aminopurine was used as a reference mutagen. (i) 2-Amino-N6-hydroxyadenine was the most potent mutagen. In some cases it gave more than 1000 colonies of revertants per plate. (ii) N6-Hydroxycytidine was the least specific mutagen. Almost all the tested markers were inducible to revert by this analogue. (iii) The mutagenic specificity of 5-methyl-N4-hydroxydeoxycytidine seemed to be opposite to that of 2-aminopurine. This suggests that the former can induce transition of CG to TA. (iv) A comparison of the mutagenic actions of N4-hydroxycytidine and 5-methyl-N4-hydroxy-deoxycytidine showed that deoxyriboside analogues are not necessarily more efficient mutagens than ribonucleosides. (v) No purine or pyrimidine deficiency was needed for mutagenesis to occur for any of the mutagens investigated. (vi) The results on bacteria with different repair abilities suggest that base-analogue mutagenesis (except perhaps for BrdUrd) occurs mainly during replication of nucleic acids containing substituted nucleosides with bi-functional specificity.

2-Aminopurine↗

PubMed1993

Binding of polycyclic planar mutagens to chlorophyllin resulting in inhibition of the mutagenic activity.

Chlorophyllin is known to inhibit the mutagenicity of a variety of compounds. Using highly purified samples of chlorophyllin and its family compounds, we studied the mechanism of the inhibition. Since mutagens with polycyclic planar structures are particularly strongly inhibited, it seemed likely that the inhibition arises by trapping of the mutagens by chlorophyllin through complex formation at the planar surfaces of these molecules. To explore this possibility, we prepared a Sepharose bearing covalently linked chlorophyllin as ligand, and the adsorption of mutagens to this Sepharose was measured. Three different chlorophyllin derivatives were used, i.e., copper-chlorin, iron-chlorin and chlorin, to investigate the role of metal in the center of the chlorophyllin chromophore. Adsorption of 37 different compounds, mostly mutagens, in 0.02 M Tris-HCl buffer at pH 8.0 to these chlorophyllin-Sepharose preparations was studied in a quantitative manner. The results showed that most of the compounds having three or more fused rings were strongly adsorbed with apparent dissociation constants of 10(-5)-10(-6) M, whereas those having two fused rings or one ring were only poorly adsorbed. Since the three Sepharose adsorbents gave similar adsorption profiles, it appeared that the central metal in the chlorophyllin molecule does not play a crucial role in the adsorption. We also measured the inhibitory effect of copper-chlorin against the mutagenicity of some of these compounds using the Salmonella assay. The results showed that those mutagens that were strongly adsorbable to copper-chlorin-Sepharose were subject to efficient inhibition by copper-chlorin, whereas many of those only poorly adsorbed were inhibited only weakly. We concluded that trapping by complex formation plays a role in the antimutagenic actions of chlorophyllin against many mutagens, particularly notable being the actions against ICR-170, quinacrine, aflatoxin B1, Trp-P-1 and Trp-P-2. An unusual behavior of Trp-P-2 in the adsorption process, i.e., a very tight complex formation at an extremely low Trp-P-2 concentration, was found; the implication of this phenomenon in relation to the real environmental setting is discussed.

Adsorption↗

PubMed1975

Microsomal activation to mutagens of antischistosomal methyl thioxanthenones and initial tests on a possibly non-mutagenic analogue.

Five methylthioxanthenone and methylbenzothiopyranoindazole analogues, including lucanthone (Miracil D), are non-mutagenic for Salmonella typhimurium but are activated to mutagens by a rat liver microsome preparation. Hydroxymethyl analogues, including hycathone (Etrenol), are mutagenic in the absence of microsomes. It seems reasonable to assume that the hydroxymethyl derivatives are the more proximal mutagens and that Salmonella is unable to carry out the hydroxylation necessary for mutagen activation. During the pase 24 years, several million patients with schistosomiasis have been treated with lucanthone, and in recent years about 700 000 persons with hycanthone. The possible long-term deleterious effects of these agents for man even now remain to be determined. Our studies indicate that particular modifications in the structure of thioxanthenones drastically alter their mutagenicity. One apparently non-mutagenic thioxanthenone has been found. A number of the less mutagenic compounds also exhibit decreased acute toxicity in the mouse while retaining appreciable antischistosomal activity, suggesting that genetic and schistosomicidal activities may be dissociated from each other.

Animals↗

PubMed1979

The mutagenic action of nitroimidazoles. IV. A comparison of the mutagenic action of several nitroimidazoles and some imidazoles.

The mutagenic action of 51 imidazoles was investigated. The fluctuation test of Luria and Delbrück was used, with Klebsiella pneumoniae as test organism. 8 compounds, including 5 with a weak mutagenic action in the fluctuation test, were also investigated by the Ames test in which Salmonella typhimurium TA100 was used. Of the 51 imidazoles examined, 33 were nitroimidazoles. 31 of the latter appeared to be mutagenic, whereas out of the 18 other imidazoles without a nitro group only 2 were mutagenic. Several of the substances tested for mutagenicity showed an antimicrobial activity. No direct relationship between antimicrobial action, growth inhibition and mutagenicity was established. With methyl-nitroimidazoles a relationship was found between the chemical structure and mutagenic action. However, when the nitroimidazoles had a more complex chemical structure, a relationship between this structure and mutagenicity could not be established.

Drug Evaluation, Preclinical↗

PubMed1991

Mutagenicity of Maillard reaction products from D-glucose-amino acid mixtures and possible roles of active oxygens in the mutagenicity.

The mutagenicity for Salmonella typhimurium TA100 without S9 mix of Maillard reaction products (MRP) obtained from equimolar amounts of glucose and amino acids under different pHs was investigated. MRP derived from arginine and lysine exhibited the strongest mutagenicity, and weaker mutagenicity was shown by the mixtures with alanine, serine, threonine and monosodium glutamate. MRP from proline and cysteine had no detectable mutagenicity. Furthermore, glucose-arginine and glucose-lysine reaction mixtures, which presented a marked mutagenicity, showed pH- and browning intensity-dependent expression of their mutagenic activities. The mutagenicity of MRP, especially glucose-arginine and glucose-lysine mixtures, was significantly suppressed by active oxygen scavengers such as cysteine, mannitol, alpha-tocopherol, catalase and superoxide dismutase (SOD) and reducing agents such as sodium bisulfite and glutathione. Among these desmutagenic factors tested, cysteine, catalase, sodium bisulfite and glutathione had higher desmutagenic activities than the others. Accordingly, it is assumed that the mutagenicity of MRP is due to the direct action of low-molecular-weight compounds such as carbonyls and heterocyclics produced by the Maillard reaction and is enhanced by active oxygens, especially singlet oxygen and hydrogen peroxide derived from their autoxidation.

Amino Acids↗

PubMed1975

Hair dyes are mutagenic: identification of a variety of mutagenic ingredients.

We have previously described a sensitive bacterial test for dectecting carcinogens as mutagens. We have previously described a sensitive bacterial test for detecting carcinogens as mutagens. We show here that 89% (150/169) of commercial oxidative-type (hydrogen peroxide) hair dye formulations are mutagenic in this test. Of the 18 components of these hair dyes, nine show various degrees of mutagenicity:2,4-diaminoanisole, 4-nitro-o-phenylenediamine, 2-nitro-p-phenylenediamine, 2,5-diaminoanisole, 2-amino-5-nitrophenol, m-phenylenediamine, o-phenylenediamine, 2-amino-4-nitrophenol, and 2,5-diaminotoluene. Three hair dye components (p-phenylenediamine, 2,5-diaminotuluene, and 2,5-diaminoanisole) become strongly mutagenic after oxidation by H2O2: the mutagenic product of p-phenylenediamine is identified as the known trimer, Bandrowski's base. 2,4-Diaminotoluene, a hair dye component until recently, is also shown to be mutagenic: this compound has been shown to be a carcinogen in rats and is used in large amounts in the polyurethane foam industry. About 20,000,000 people (mostly women) dye their hair in the U.S. and the hazard could be considerable if these chemicals are actually mutagenic and carcinogenic in humans.

Amines↗

PubMed1990

[Study on influence of cigarette smoking on the mutagenicity of urine. I. Influence of cigarette smoking on the mutagenicity of urine in healthy smokers and bladder cancer patients].

We studied the mutagenicity of urine of healthy smokers and smokers with bladder tumors by the Ames test. The 41 healthy smokers studied showed a significant increase in urinary mutagenic activity compared to the 24 passive smokers and the 22 non-smokers, but there was no significant difference between the passive smokers and non-smokers. In the 5 healthy subjects, the urinary mutagenic activity increased in accordance with the increase of tobacco consumption. In the 32 healthy subjects and 22 smokers with bladder tumors, the time-course changes of the mutagenicity of urine after smoking were investigated by testing the urine every 2 hours. In the healthy subjects, urinary mutagenic activity was increased up to 4 hours after cigarette smoking and decreased to the level noted before smoking after the 6th hour. By contrast, in the 22 smokers with bladder tumors, the urinary mutagenic activity remained high even after the 6th hour, and only decreased to the level seen before smoking after the 8th hour. The influence of smoking on the mutagenicity of urine tended to protract in smokers with bladder tumors in comparison to healthy smokers. There was no correlation between urinary mutagenic activity and tumor status and recurrence rate of the bladder tumors.

Adult↗