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At least 127 records · Page 7Linked to original sources
PubMed1988

Mutagenicity of furoquinoline alkaloids in the Salmonella/microsome assay. Mutagenicity of dictamnine is modified by various enzyme inducers and inhibitors.

Furoquinoline alkaloids are activated to mutagens by microsomal preparations of rat liver. The mutagenic effects decrease with the increasing number of methoxyl-substituents on the furoquinoline skeleton. After metabolic activation dictamnine, gamma-fagarine and skimmianine exhibit strong mutagenicity in Salmonella typhimurium strains TA98 and TA100 and have comparatively little or no activity in the corresponding non-R-factor strains TA1538 and TA1535. This indicates that these compounds primarily act as frameshift mutagens. The activation capacity of the metabolizing mixture depends on the amount of microsomal protein. Pretreatment of male Wistar rats with phenobarbital (Pb) or 3-methylcholanthrene results in an increase in the metabolic capacity of the corresponding liver microsome preparations, Pb induction showing the greater effect. Various enzyme inhibitors, such as carbon monoxide, metyrapone, SKF-525A, 7,8-benzoflavone and methimazole, decrease the activation capacities of rat liver preparations, whereas 1,1,1-trichloropropene-2,3-oxide has no effect. These results suggest that furoquinolines are activated to mutagenic metabolites by cytochrome-P-450 and cytochrome-P-448, and possibly by the flavin-containing monooxygenase.

Alkaloids↗
PubMed1983

Advantages of and problems with short-term mutagenicity tests for the assessment of mutagenic and carcinogenic risk.

The Salmonella microsomal assay has become an indispensible tool for the screening of mutagens and carcinogens, particularly when a large number of samples have to be tested, as in the present context for the screening of air pollution. However, for a more definite identification of potential carcinogens, a verification of the results from bacterial tests has to be performed with a battery of other tests, including point mutations and chromosomal aberrations in eukoaryotic systems. While there is a close qualitative correlation between the mutagenic and carcinogenic property of chemicals, a corresponding quantitative correlation between the mutagenic and carcinogenic potency is not always found. One reason for this lack of quantitative correlation presumably depends on the fact that cancer is induced in two steps, of which only the initiating, but not the promoting, step constitutes a mutational event, which is reflected by mutagenicity tests. Present mutagenicity tests have concentrated on discrete major mutations, while mutations of polygenes, acting on quantitative characters, have largely been omitted. Mutational data from Drosophila indicate, however, that polygenes mutate at a considerably higher rate than major genes and that they have a comparatively strong effect in heterozygous condition. It seems of great importance to develop appropriate methods to study induced mutations of polygenic systems and to get a better understanding of the properties of these genetic systems and an evaluation of the risk connected with induced mutations in polygenes.

Air Pollutants↗
PubMed1988

Dinitrochlorobenzene is inherently mutagenic in the presence of trace mutagenic contaminants.

2,4-Dinitrochlorobenzene (DNCB) is used for immunotherapy of alopecia areata and verruca vulgaris. We initially postulated that the presence of mutagenic contaminants in commercially available DNCB might account for part of its mutagenicity. We have now characterized changes in the dose-mutagenic response curve of 99% DNCB modified by adding 1% concentrations of known contaminants: 1-chloro-2-nitrobenzene; 1,3-dinitrobenzene; and 2,4-dichloronitrobenzene. Dose-response curves were generated using Salmonella typhimurium tester strains TA-98 and TA-100 at concentrations of 0, 1, 5, 10, 25, 50, and 100 micrograms per plate in a modified Ames assay. We observed a linear dose-response relationship with a slight, but nonsignificant, shift to the right when contaminants were added. We conclude that DNCB is itself mutagenic, and that contaminants play a minor role in its observed mutagenicity.

Dinitrobenzenes↗
PubMed1983

Biological monitoring of occupational exposure to mutagenic chemicals in the rubber industry. Use of the bacterial urinary mutagenicity assay.

The assay of mutagenicity in the urine with the bacterial fluctuation test was used as an approach to monitor the exposure to mutagenic chemicals among 129 rubber workers. Especially those workers exposed to chemical dusts or fumes showed high mutagenicity in their urine. Smoking was also found to increase mutagenicity in the urine, but this effect could be detected only with the frame-shift detector strain Salmonella typhimurium TA 98. Escherichia coli WP 2 uvrA could thus be used to monitor the occupational exposure to base-pair substitution mutagens, without the interfering effect of smoking.

Animals↗
PubMed1979

Metabolic and mutagenicity studies on DDT and 15 derivatives. Detection of 1,1-bis(p-chlorophenyl)-2,2-dichloroethane and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (kelthane acetate) as mutagens in Salmonella typhimurium and of 1,1-bis(p-chlorophenyl) ethylene oxide, a likely metabolite, as an alkylating agent.

Using a novel in vitro technique, whereby microsomal enzymes were embedded in an agar layer to prolong their viability, 1,1-bis(p-chlorophenyl) ethylene(DDNU), a mammalian metabolite of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), was converted by microsomal mono-oxygenases of mouse liver into 1,1-bis(p-chlorophenyl)-1,2-ethanediol (DDNU-diol). The putative epoxide intermediate, 1,1-bis(p-chlorophenyl)ethylene oxide (DDNU-oxide), a new compound, was synthesized; it showed weak alkylating activity with 4-(4-nitrobenzyl)pyridine but was not mutagenic in Salmonella typhimurium strains TA100 and TA98. DDT and 13 of its metabolites or putative synthetic derivatives, including 1,1-bis(p-chlorophenyl)-2,2-dichloroethylene (DDE), 1 1,1-bis(p-chlorophenyl)-2-chloroethylene (DDMU), 1,1-bis(p-chlorophenyl)-2-chloroethane (DDMS)-DDNU, 2,2-bis(p-chlorophenyl)ethanol (DDOH), bis(p-chlorophenyl)acetic acid (DDA) and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethanol (Kethane), caused no mutagenic effects in S. typhimurium strains TA100 or TA98, either in the presence or absence of a mouse-liver microsomal fraction. 1,1-Bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (Kelthane acetate) was a direct-acting mutagen in strain TA100, whereas 1,1-bis(p-chlorophenyl)-2,2-dichloroethane (DDD) was mutagenic in TA98, only in the presence of a mouse-liver microsomal system. The results are discussed in relation to possible pathways whereby DDT is activated to mutagenic and/or carcinogenic metabolites.

Alkylation↗
PubMed1991

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC publication No. 18. Review of the genotoxicity and carcinogenicity of antischistosomal drugs; is there a case for a study of mutation epidemiology? Report of a task group on mutagenic antischistosomals.

One of the interests of ICPEMC is to identify situations in which the possible induction of inherited defects in man by mutagen exposure could actually be studied. The large-scale use of mutagenic drugs in field programmes against schistosomiasis, mainly during the 1970's, was considered a possible case. An ICPEMC task group approached the problem by (1) updating the genetic toxicology data base for antischistosomal drugs, and (2) reviewing possible study areas. Expertise was combined from genetic toxicology, mutation epidemiology and tropical medicine. It was considered that: (a) if any, hycanthone would be the most appropriate candidate drug for study; (b) it would be virtually impossible to meet the basic requirements of an appropriate mutation epidemiology study, in endemic countries; (c) as more defined genetic endpoints would be selected (e.g. sentinel phenotypes) the required large sample sizes would seem prohibitive, since documentation on past programmes is limited and local demography would render the reliable tracking of substantial numbers of offspring of treated persons an almost impossible task; (d) in most endemic countries proper diagnosis and registration of inherited defects is largely lacking; (e) the problems encountered in demonstrating inherited effects in humans after heavy or chronic exposure to established animal mutagens such as ionizing radiation and cancer chemotherapy, in combination with the ambiguous nature of the animal germ cell data with hycanthone, do not particularly warrant large expectations; (f) since non-mutagenic antischistosomal drugs are now in use, the problem is academic and of low priority in the endemic countries whose medical and research resources are often limited. Thus, studying offspring of hycanthone-treated people to demonstrate the mutagenic potential of the drug in man is not a viable enterprise.

Animals↗
PubMed1988

Influence of glutathione on the mutagenicity of 2-chloroethylnitrosoureas. Mutagenic potential of glutathione derivatives formed from 2-chloroethylnitrosoureas and glutathione.

2-Chloroethylnitrosoureas (CNU) are antineoplastic agents whose therapeutic dose is limited by toxic and carcinogenic side effect. The clinically used drugs, bis-(2-chloroethyl)nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HECNU) and their analogue N-(2-chloroethyl)-N-nitrosocarbamoyl-glycinamide (CNC-GA) were tested for mutagenicity and toxicity in the Salmonella typhimurium tester strain TA1535 in the presence and absence of glutathione (GSH). All 3 compounds proved to be potent mutagens. The cytotoxicity of these CNUs, however, varied depending on their carbamoylating activity. These cytotoxic effects were decreased considerably by the addition of GSH. It has been shown that the isocyanate decomposition product of the 2-chloroethylnitrosoureas reacts with GSH yielding S-carbamoylated GSH derivatives. The adducts resulting from coincubation of BCNU or HECNU with GSH, 2-chloroethyl-S-carbamoyl-GSH and 2-hydroxy-S-carbamoyl-GSH, were also tested for their mutagenic activity. While the hydroxyethylated compound exhibited no effects, 2-chloroethyl-S-carbamoyl-GSH and its cysteine analogue, 2-chloroethyl-S-carbamoyl-GSH, were strong mutagens. Further experiments with 3-chloropropyl-S-carbamoyl-GSH and t-butyl-S-carbamoyl-GSH indicate that a chlorine substituent in the beta position is necessary for the induction of a potent mutagenic response.

Carmustine↗
PubMed1995

Cell proliferation as a determining factor for the carcinogenicity of chemicals: studies with mutagenic carcinogens and mutagenic noncarcinogens.

Recent work in our laboratory has examined mechanisms whereby chemicals produce mutagenicity in short-term in vitro assays yet fail to produce carcinogenesis in 2-year rodent bioassays. These studies have used mutagenic structural analogs of carcinogenic and noncarcinogenic chemicals for comparison. Our previous studies have determined that differences in the metabolism and disposition of these chemicals were not responsible for their observed carcinogenic differences, but that carcinogenicity correlated with the ability of the respective isomer to induce cell proliferation in the target organ. Mutagenic noncarcinogens such as 2,6-diaminotoluene (DAT), 1-nitropropane (NP), dimethoate, dioxathion, and dichlorvos failed to induce an increase in cell turnover in the target organs. An increase in cell proliferation was observed following exposure to the mutagenic carcinogen analogs 2,4-DAT (liver), 2-NP (liver), and tris(2,3-dibromopropyl)phosphate (kidney). Our recent studies have used transgenic (Big Blue) mice to detect in vivo mutagenesis induced by DAT isomers. Results of these studies demonstrate that administration of the carcinogenic isomer, 2,4-DAT, resulted in an increase in in vivo mutation frequency, whereas administration of the noncarcinogenic isomer, 2,6-DAT, failed to do so. These results indicate that cell proliferation may be requisite for expression of chemical-induced mutagenicity in vivo and thereby accommodate expression of carcinogenicity.

Animals↗
PubMed2004

Molecular complexes of IQ and 4-hydroxy-coumarin: a mutagen-anti-mutagen system.

Molecular complexes formed between a cooked food mutagen-carcinogen (2-amino-3-methylimidazo[4,5-f] quinoline, IQ) and a potent anti-mutagen (4-hydroxy-coumarin, 4HC) were synthesized and crystallized from a solution. The active functional groups in IQ and in 4HC that may involve in the formation of these complexes are investigated by UV-visible, infrared, and NMR spectroscopy. The geometrical conformations and heat of formation of IQ:4HC complexes were optimized by semi-empirical molecular orbital calculations. The experimental and theoretical results indicate that the complexes exist in multiple conformations. The energetically favorable ones are formed via hydrogen-bonding type of interactions between amino group in IQ and carbonyl group in 4HC, and also between quinoline-nitrogen (and imidazole-nitrogen) in IQ and hydroxyl group in 4HC. The observed complex formation could serve as a model for understanding the active molecular sites responsible for the initial mutagenic activity in cooked-food mutagens as well as the anti-mutagenic activity in coumarins.

4-Hydroxycoumarins↗
PubMed1996

A 3 milliTesla 60 Hz magnetic field is neither mutagenic nor co-mutagenic in the presence of menadione and MNU in a transgenic rat cell line.

The mechanisms by which an electromagnetic field (EMF) influences biological material are poorly understood. One potentially important model suggests that a magnetic field can stabilize free radicals in such a way as to permit their dispersement rather than their return to the ground state (Okazaki et al., 1988; Scaiano, 1995). We have tested this hypothesis by examining mutagenesis in the E. coli lacI gene target carried in the Big Blue rat embryo fibroblast cell line, R2 lambda LIZ. Mutant frequencies were determined in cells exposed to a magnetic field, cells pretreated with the mutagens N-methylnitrosourea (MNU) or 2-methyl-1,4-naphthoquinone (menadione), prior to being held in a 60 Hz 3 milliTesla (mT) magnetic field and cells concurrently exposed to the mutagens and the magnetic field. Menadione was selected because its mutagenic mechanism involves the formation of free radicals, while MNU is an alkylating agent not thought to act through radical formation. According to the radical stabilization hypothesis the application of a magnetic field to menadione treated cells would accentuate the mutagenic effects. Our results failed to indicate that the magnetic field affects mutagenesis by the oxygen-radical mediated mutagen, menadione.

Alkylating Agents↗
PubMed1994

Inhibitory effect of dairy products on the mutagenicities of chemicals and dietary mutagens.

The antimutagenic effects of uninoculated milk and milks cultured with Bifidobacterium or Lactobacillus strains towards the mutagenicity induced by two direct mutagens, 4-nitroquinoline N-oxide and 2-nitrofluorene, and three dietary indirect mutagens, aflatoxin B1, benzo(a)pyrene and quercetin, were investigated using the in vitro Salmonella typhimurium test. Each cultured milk sample and control milk had a significant antimutagenic effect, to an extent varying with the mutagen used. Uninoculated milk had a greater inhibitory effect than cultured milks towards dietary indirect mutagens.

4-Nitroquinoline-1-oxide↗
PubMed2003

Inhibitory effect of dibenzoylmethane on mutagenicity of food-derived heterocyclic amine mutagens.

Dibenzoylmethane (DBM), a structural analogue of curcumin (a bioactive phytochemical present in a widely used spice turmeric) was screened for its inhibitory effect against seven cooked food mutagens (heterocyclic amines): 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), in both TA98 and TA100 strains of Salmonella typhimurium using Ames Salmonella/reversion assay in the presence of Aroclor1254-induced rat liver S9 homogenate. DBM has been reported to antagonize the mutagenicity of several chemical carcinogens in vitro and has recently been shown to be even more effective than curcumin in suppressing the 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats. But there are no reports regarding its antimutagenic properties against cooked food mutagens. Results of the present investigations clearly indicate that dibenzoylmethane is a very potent antimutagenic agent, that could effectively inhibit mutagenicity induced by all the tested cooked food mutagens in both the frame shift (TA98) as well as the base pair mutation sensitive (TA100) strains of S. typhimurium. These highly potent inhibitory effects of dibenzoylmethane against heterocyclic amines observed in our preliminary investigations strongly warrant further studies of its efficacy as a cancer chemopreventive agent.

Amines↗
PubMed2004

Mode of mutagenic action for the biocide Bioban CS-1246 in mouse lymphoma cells and implications for its in vivo mutagenic potential.

The biocidal agent, BIOBAN CS-1246 (7-ethyl bicyclooxazolidine, CAS# 7747-35-5, CS-1246) induced a concentration-dependent mutagenic response in mouse lymphoma (L5178Y TK+/-) cells both with and without the addition of S9 metabolic activation. Previous data indicating the ability of CS-1246 to hydrolyze in aqueous media to generate formaldehyde (FA), led us to investigate the potential role of FA in the CS-1246-induced mutagenic response in the mouse lymphoma assay (MLA). To accomplish this, the MLA on CS-1246 was repeated in the presence of a metabolizing system (formaldehyde dehydrogenase/NAD+), which was shown to successfully inhibit the mutagenic response of formaldehyde in this assay system. Significantly, the observed mutagenicity of CS-1246 was completely abrogated when the cultures were supplemented with formaldehyde dehydrogenase/NAD+, suggesting that the positive MLA response was attributable to the generation of FA in situ. These results demonstrate that in vitro mutagenicity of CS-1246 in the MLA is most likely associated with FA. Negative results from two in vivo assays for genotoxicity were consistent with the known activity of FA in these assays. In the mouse bone marrow micronucleus (MNT), there were no significant increases in micronucleated polychromatic erythrocytes (with evaluation of 2000/animal), after treatment with 0.5, 1, and 2 g/kg/day CS-1246 (6/dose group) for 2 consecutive days and sacrifice 24 h later. Furthermore, in the unscheduled DNA synthesis (UDS) study, male F344 rats (5 /dose group), given a single oral gavage (0, 1, and 2 g/kg) and evaluated at two time points (2-4 and 14-15 h post dosing), did not elicit an UDS response, indicating a lack of DNA reactivity in vivo. Based on the negative in vivo findings, it can be inferred that the FA detoxification mechanisms that exist in intact organisms prevent the likelihood of generating FA at levels capable of causing genotoxicity following exposure to CS-1246 at low, environmentally relevant concentrations. The extensive literature on FA would therefore be of value in assessing the carcinogenic risk to humans and animals from CS-1246 exposure.

Aldehyde Oxidoreductases↗
PubMed1978

Mutagenicity of diallate, sulfallate, and triallate and relationship between structure and mutagenic effects of carbamates used widely in agriculture.

In an investigation of the mutagenic properties of 20 carbamate herbicides and fungicides by use of the Salmonella/microsome mutagenicity test as developed by Ames et al. (Mutation Res., 31: 347-364, 1975), we have found that three thiocarbamate compounds, diallate, sulfallate and triallate, are mutagenic in the presence of a liver microsomal fraction on strains TA1535 and TA100. This indicates that the metabolic products of these thiocarbamates are causing base-pair substitutions. Since the 2-chloro-allyl group is common to the three mutagenic compounds but is not common to the 17 nonmutagenic compounds, a metabolic derivative of this group is probably responsible for the mutagenic activity.

Animals↗
PubMed1984

Exposure to low concentrations of mutagens alters the mutagenic and lethal effects of 4-nitroquinoline-N-oxide and mitomycin C in Escherichia coli.

Mitomycin C and 4-nitroquinoline-N-oxide are two mutagens which can induce the SOS DNA repair system in Escherichia coli. Growth of E. coli B/r strain WP2, or its uvrA- derivative, in very low concentrations of either mutagen led to the increased sensitization to the lethal and/or mutagenic effects of a subsequent challenge with the same mutagen. These phenomena were not observed in either the recA- or lexA- derivatives of the parent strain. Induction of the adaptive response repair pathway by prior cultivation in low concentrations of N-methyl-N'-nitro-N-nitrosoguanidine reduced both the mutagenic and lethal effects of a subsequent challenge with mitomycin C but not 4-nitroquinoline-N-oxide.

4-Nitroquinoline-1-oxide↗
PubMedDate not supplied

Anthraflavic acid inhibits the mutagenicity of the food mutagen IQ: mechanism of action.

The ability of anthraflavic acid to inhibit the mutagenicity of IQ was investigated using the Ames test and employing hepatic activation systems from Aroclor 1254-pretreated rats. Incorporation of anthraflavic acid into the S9 mix caused a concentration-dependent decrease in the mutagenicity of IQ. A similar effect was seen when microsomes only were employed as activation systems. Cytosol, as we have previously demonstrated, potentiated the microsome-mediated mutagenicity of IQ and this potentiation was also inhibited by anthraflavic acid. In contrast, anthraflavic acid had no effect on the mutagenicity of the direct-acting microsome-generated metabolites of IQ. It is concluded that anthraflavic acid is a potent inhibitor of IQ mutagenicity by virtue of its ability to inhibit both its microsomal and cytosolic activation pathways.

Animals↗
PubMed1992

Quantitative structure-activity relationship investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 2. Mutagenicity of aromatic and heteroaromatic nitro compounds in Salmonella Typhimurium TA100.

A quantitative structure-activity relationship (QSAR) has been derived for the mutagenic activity of 117 aromatic and heteroaromatic nitro compounds acting on Salmonella typhimurium TA100. Relative mutagenic activity is bilin-early dependent on hydrophobicity, with an optimal log P of 5.44, and is linearly dependent on the energy of the lowest unoccupied molecular orbital of the nitro compound. The dependence of mutagenic activity on hydrophobicity and electronic effects is very similar for TA98 and TA100. Mutagenic activity in TA100 does not depend on the size of the aromatic ring system, as its does in TA9. The effect of the choice of assay organism, TA98 versus TA100, on nitroarene QSAR is seen to be similar to the effect previously found for aminoarenes. Lateral verification of QSARs is presented as a tool for establishing the significance of a new QSAR.

Amines↗
PubMed1980

Mutagenicity of trialkyltriazenes: mutagenic potency of alkyldiazonium ions, the putative ultimate carcinogens from dialkylnitrosamines.

Although aryldialkyltriazenes have been known for many years and their mutagenic, carcinogenic and carcinostatic properties have been investigated, almost nothing is known of the related trialkyltriazenes. Our recently developed general preparative route to these substances has allowed the examination of the mutagenic properties of several representative examples of this class of compounds. This, 1-benzyl-3,3-dimethyl-, 3-benzyl-1,3-dimethyl, 3-benzyl-3-methyl-1-n-butyl- and 1,3-di-n-butyl-3-methyltriazenes are direct acting mutagens in the TA1535 strain of Salmonella typhimurium. The respective mutagenic potencies of these substances can be accounted for by the in situ generation of alkyldiazonium ions. These ions are considered to be strong candidates for the ultimate mutagens/carcinogens derived from some dialkylnitrosamines.

Mutagenicity Tests↗