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PubMed1976

Mutagenicities of nitrofuran derivatives on a bacterial tester strain with an R factor plasmid.

Many nitrofuran derivatives are known to be mutagenic on Escherichia coli WP2 but not on Salmonella typhimurium TA1535, TA1536, TA1537 or TA1538. Ames and coworkers recently obtained a new tester strain of S. typhimurium, TA100, by putting an R factor plasmid, pKM101, into TA1535. We found that all mutagenic nitrofuran derivatives previously found to be mutagenic on E. coli WP2 were mutagenic on this new strain (TA100).

Drug Resistance, Microbial↗

PubMed1980

Enhancement of sister-chromatid exchange in Chinese hamster ovary cells by nitrofurans.

The nitrofurans, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA), 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), 2-methyl-4-(5-nitro-2-furyl)thiazole (MNFT), 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2), nitrofurantoin, 5-nitro-2-furfurylidene diacetate and 5-nitro-2-furamidoxime were assayed for the enhancement of sister-chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells and for the mutagenic activity in Salmonella typhimurium strain TA100. All of the nitrofurans significantly increased the frequency of SCE in CHO cells, and they were mutagenic for Salmonella. The increases in the frequencies of SCE were well correlated with the mutagenic activities in Salmonella.

Animals↗

PubMed1984

Effect of liver enzymes on the mutagenicity of nitroheterocyclic compounds: activation of 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)- 1,2-benzisoxazole and deactivation of nitrofurans and nitroimidazoles in the Ames test.

The effect of liver enzymes (S9) on the mutagenic response of nitroimidazoles and nitrofurans in the Ames test was evaluated with strain TA100. A diminished response was observed with a 5-nitroimidazole and 5-nitrofurans when the S9 preparation was incorporated in the agar layer. Preincubation with S9 under anaerobic conditions prior to adding the bacteria resulted in a greater and sometimes complete loss of the mutagenic effect. The loss of mutagenic potency was dependent on both incubation time and quantity of the S9 preparation. These results suggest that metabolites formed after reductive metabolism are neither mutagenic (presumably due to the loss of the nitro group) nor capable of activation to mutagenic metabolites. One 5-nitroimidazole, 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro -1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436), gave an increased response in the presence of S9 in both the plate test and when preincubated under aerobic conditions. 7 metabolites were produced by the incubation. 4 monooxygenated metabolites were isolated and found to possess significant mutagenic activity. 2 synthetic dihydroxy analogs were more mutagenic than MK-0436. Similar results were obtained with S9 preparations from human liver and the livers of control, phenobarbital and Aroclor-1254 pretreated rats.

Animals↗

PubMed1981

Relative refractoriness of guinea pigs to carcinogenesis by 5-nitrofurans.

Guinea pigs were observed to be refractory to carcinogenesis by 3 different carcinogenic 5-nitrofurans administered at 0.1% of the diet for 50 weeks followed by 74 weeks of control diet. In view of the evidenced involvement of nitroreduction in the metabolic activation of 5-nitrofurans, it is of interest that guinea pig refractoriness is not due to a quantitative nitroreductase deficiency in guinea pig liver.

Animals↗

PubMed1992

Cytotoxicity of dual function nitrofurans in rodent and human tumor cells.

The efficacy and selective hypoxic cell cytotoxicity of four dual function nitrofurans and two nitroimidazole-aziridines was determined in human (A549, HT-29) and rodent (KHT/iv) tumor cells. All bioreductive compounds were found to be less effective at killing human than mouse tumor cells (approximately 2-6-fold). This reduced cytotoxicity in the human tumor cells occurred irrespective of the state of oxygenation. In addition, the degree of selective toxicity toward hypoxic cells or the cytotoxicity factor (CF), defined as the ratio of the surviving fraction in air to that under hypoxic conditions, was (a) greater for the nitroimidazole-aziridines than for the nitrofurans and (b) less in the human than the rodent tumor cell lines investigated. For example, CF values in A549 or HT-29 cells typically were 2-4-fold lower than those determined in KHT/iv cells. This reduction in the CF in the human cells resulted from a greater loss in the hypoxic toxicity than in the aerobic toxicity when compared with the rodent cells.

Animals↗

PubMed1990

On-line combination of dialysis and column-switching liquid chromatography as a fully automated sample preparation technique for biological samples. Determination of nitrofuran residues in edible products.

The potential of dialysis coupled on-line with trace enrichment by column-switching high-performance liquid chromatography as an automated sample treatment technique in drug residue analysis has been investigated. The nitrofuran veterinary drugs furazolidone, nitrofurazone, nitrofurantoin and furaltadone were used as model compounds. Critical parameters, i.e., dialyser dimensions, air segmentation, dialysis time, flow-rates and enrichment column breakthrough, were evaluated. Depending on the analytical purpose, the technique can be set up in either a highly sensitive or a high-speed mode. High dialysis efficiencies (greater than 85%) can be obtained in a stopped-flow dialysis of only 3 min. Aqueous biological sample volumes (eggs, meat, milk) of 100 microliters to 4 ml can be injected with only sample treatment. A routine monitoring method for residues of nitrofuran drugs in edible products was set up. A 4-ml sample was dialysed in a pulsed mode with an efficiency of about 30% and concentrated on a short C18 column. Recoveries compared with standards were 75-85% (coefficient of variation 2-7%). Limits of determination ranged from 1 to 10 micrograms/kg. At this concentration level, ca. 30 samples can be monitored per day.

Animals↗

PubMed2000

Mutagenic properties of a nitrofuran, 7-methoxy-2-nitronaphtho[2, 1-b]furan (R7000), in lacI transgenic mice.

The in vivo mutagenic properties of a 5-nitrofuran, the 7-methoxy-2-nitronaphtho[2,1-b]furan (R7000), already well known in bacteria, was evaluated in lacI transgenic mice (Big Blue). The mutation frequency was determined in various organs of i.p. - treated mice and the nature of induced mutations was determined for the target organs in which mutation induction was significant. It was found that R7000 is mutagenic in mice, although, on the basis of the number of induced mutants per unit mass in comparison with other known mutagenic chemicals, R7000 appears to be considerably less mutagenic in mice than in bacteria. The most affected organs, small intestine, caecum and colon organs belong to the digestive apparatus. The distribution of R7000-induced mutations in the lacI gene recovered from small intestine of transgenic mice was very similar to that which had been found in E. coli. The difference between mouse and E. coli in the R7000 induced mutational spectra are mainly in the proportion of single base frameshifts versus base substitutions. Since R7000 induced mutations seemed to arise in the population of stem cells and that the stem cells are important for carcinogenesis, our results are compatible with a possible carcinogenic effect of R7000 and other nitrofurans.

Animals↗

PubMed1990

Synthesis and evaluation of novel electrophilic nitrofuran carboxamides and carboxylates as radiosensitizers and bioreductively activated cytotoxins.

A series of 5-nitrofuran-2- and 3-carboxamides bearing alkylating side-chains has been synthesized and tested for their ability to radiosensitize selectively hypoxic Chinese hamster cells (V79) to the lethal effects of ionizing radiation and also for their ability to act directly and selectively as cytotoxic drugs on hypoxic V79 cells. The compounds were extremely efficient radiosensitizers of such cells in vitro and were more efficient than known nitroimidazoles of similar type. Their efficiencies as radiosensitizers correlated with their high electron affinity (E7(1] as measured by pulse-radiolysis. However the compounds showed little radiosensitizing activity towards KHT sarcomas in C3H mice. The compounds in this series of nitrofurans were generally more toxic towards hypoxic cells than towards oxic cells in vitro but were less effective upon the basis of a differential effect than were similar nitroimidazoles reported previously.

Amides↗

PubMed2001

Investigation of 5-nitrofuran derivatives: synthesis, antibacterial activity, and quantitative structure-activity relationships.

Three sets of antibacterial nitrofuran derivatives [set I, 5-R-substituted (Z)-2-(5-nitrofuran-2-ylmethylene)-3(2H)-benzofuranones (R = OCH(3), H, CH(3), C(2)H(5), nC(3)H(7), Cl, Br, CN, and NO(2)) and their 2-hydroxyphenyl and 2-acetoxyphenyl analogues; set II, 5-R-substituted (E)-1-(2-hydroxyphenyl)-3-(5-nitrofuryl)-2-propen-1-ones (R = H, CH(3), C(2)H(5), Cl, and NO(2)); and set III, 5-R-substituted (E)-1-(2-acetoxyphenyl)-3-(5-nitrofuryl)-2-propen-1-ones (R = H, CH(3); C(2)H(5), Cl, and NO(2))] were prepared and tested against a Gram-positive (Staphylococcus aureus, strain ATCC-25923) and a Gram-negative bacterium (Caulobacter crescentus, strain NA 1000). QSAR equations derived for the IC(50) values against both bacteria show negative contributions of two terms: an electronic one, expressed either by sigma, the Hammett substituent constant, or by E, the cyclic voltametric reduction potential. Another term described by an indicator variable, I(abs), is assigned the value of 0 for set I compounds and the value of 1 for sets II and III. No important contribution of the hydrophobic factor was found. For the three sets, the QSAR regressions suggest that the same structural features describe the activities for both bacteria and that, although reduction is a necessary step, it should not be the determining one. These results agree with those found for the QSAR of 5-nitroimidazole analogues.

Anti-Bacterial Agents↗

PubMed2004

Quantitative structure-activity relationships from optimised ab initio bond lengths: steroid binding affinity and antibacterial activity of nitrofuran derivatives.

The present day abundance of cheap computing power enables the use of quantum chemical ab initio data in Quantitative Structure-Activity Relationships (QSARs). Optimised bond lengths are a new such class of descriptors, which we have successfully used previously in representing electronic effects in medicinal and ecological QSARs (enzyme inhibitory activity, hydrolysis rate constants and pKas). Here we use AM1 and HF/3-21G* bond lengths in conjunction with Partial Least Squares (PLS) and a Genetic Algorithm (GA) to predict the Corticosteroid-Binding Globulin (CBG) binding activity of the classic steroid data set, and the antibacterial activity of nitrofuran derivatives. The current procedure, which does not require molecular alignment, produces good r2 and q2 values. Moreover, it highlights regions in the common steroid skeleton deemed relevant to the active regions of the steroids and nitrofuran derivatives.

Adrenal Cortex Hormones↗

PubMed1976

Nitrofurans, a group of synthetic antibiotics, with a new mode of action: discrimination of specific messenger RNA classes.

Nitrofurans, a class of antibacterial drugs in extensive use, interferes with gene expression in a highly specific manner. While in the low dose range (0.5-25 mug/ml), 5-nitro-2-furfurylidene-1-aminohydantoin has no effect on transcription, it inhibits specifically the expression of one class of genes in translation. The specific inhibition concerns the inducible genes. The inhibition of messenger RNA expression occurs at the initiation step. The action of nitrofurans, thus, indicates heterogeneity in the population of mRNA molecules and in the translational machinery and suggests the possibility of selective translational control.

Cyclic AMP↗

PubMed2004

Detection of 3-amino-2-oxazolidinone (AOZ), a tissue-bound metabolite of the nitrofuran furazolidone, in prawn tissue by enzyme immunoassay.

Furazolidone, a nitrofuran antibiotic, is banned from use in food animal production within the European Union. Increasingly, compliance with this ban is monitored by use of analytical methods to detect a stable tissue-bound metabolite, 3-amino-2-oxazolidinone (AOZ). Widespread use of furazolidone in poultry and prawns imported into Europe highlighted the urgent need for development of nitrofuran immunoassay screening tests. The first enzyme-linked immunoabsorbant assay for detection of AOZ residues in prawns (shrimps) is now described. Prawn samples were derivatized with o-nitrobenzaldehyde, extracted into ethyl acetate, washed with hexane and applied to a competitive enzyme immunoassay based on a rabbit polyclonal antiserum. Assay limit of detection (LOD) (mean + 3 s) calculated from the analysis of 20 known negative cold and warm water prawn samples was 0.1 microg kg(-1). Intra- and interassay relative standard deviations were determined as 18.8 and 38.2%, respectively, using a negative prawn fortified at 0.7 microg kg(-1). The detection capability (CCbeta), defined as the concentration of AOZ at which 20 different fortified samples yielded results above the LOD, was achieved at fortification between 0.4 and 0.7 microg kg(-1). Incurred prawn samples (n = 8) confirmed by liquid chromatography coupled with tandem mass spectrometry detection to contain AOZ concentrations between 0.4 and 12.7 microg kg(-1) were all screened positive by this enzyme-linked immunoabsorbant assay. Further data are presented and discussed with regard to calculating assay LOD based on accepting a 5% false-positive rate with representative negative prawn samples. Such an acceptance improves the sensitivity of an ELISA and in this case permitted an LOD of 0.05 microg kg(-1) and a CCbeta of below 0.4 microg kg(-1).

Animals↗

PubMed2000

Bactericidal activity of nitrofurans against growing and dormant Mycobacterium bovis BCG.

Depletion of oxygen triggers the shift-down of Mycobacterium bovis BCG to a state of dormancy. Bacilli in their dormant state are resistant to standard anti-mycobacterials. The nitroimidazole metronidazole was the first compound identified to show bactericidal activity against dormant tubercle bacilli. In contrast to metronidazole's selective toxicity for dormant bacilli, we report here that the nitrofurans nitrofurantoin, furaltadone and nitrofurazone showed bactericidal activity against dormant and growing bacteria. Importantly, the bactericidal effect of nitrofurans on dormant bacilli was 35- to 250-fold higher compared with metronidazole.

Anti-Bacterial Agents↗

PubMed1989

Genotoxicity testing of antiparasitic nitrofurans in the Drosophila wing somatic mutation and recombination test.

Nifurtimox and eight structurally related 5-nitrofuran compounds active against Trypanosoma cruzi were tested for genotoxicity in the wing somatic mutation and recombination test in Drosophila melanogaster. Nifurtimox, compound ada and compound 1B were clearly mutagenic and recombinogenic whereas the remaining six compounds were negative. In contrast to the situation in bacterial mutagenicity tests, nitroreductase activity is probably not decisive for the genotoxicity of these compounds in Drosophila. The three non-genotoxic nitrofurans with high antiparasitic activity are promising candidates for the replacement of nifurtimox. However, these compounds require further genotoxicity testing in eukaryotic assay systems for a final evaluation.

Animals↗

PubMed2006

Illegal use of nitrofurans in food animals: Contribution to human salmonellosis?

Recent observations in Portugal of a remarkable incidence (65%) of Salmonella isolates from several sources (predominantly human and poultry) with decreased susceptibility to nitrofurantoin (MIC > or =64 mg/L), mostly comprising serogroup D isolates of Salmonella Enteritidis belonging to different phage types, suggest that illegal use of nitrofurans, especially in the poultry industry, might have contributed to the selection and prevalence of S. Enteritidis in food animals, and consequently to human salmonellosis in Portugal. Indiscriminate use of nitrofurans might also be implicated in the emergence of two multiresistant Salmonella Typhimurium clones disseminated throughout the country.

Animal Husbandry↗

PubMed1975

Nitrofuran-reducing enzymes of Euglena.

Euglena gracilis strain Z, green, dark-brown, and "bleached" with N-methyl-N-nitro-N-nitrosoguanidine, was found to contain 2 soluble enzymes which reduce nitrofurans. A small amount of activity was demonstrated also in a particulate fraction of sonic extracts, but none in isolated chloroplasts. The reduction of 5 nitrofurans, having widely differing bleaching activities, by each of the 2 enzymes was examined.

Chloroplasts↗

PubMed1998

Oxygen-insensitive nitroreductases: analysis of the roles of nfsA and nfsB in development of resistance to 5-nitrofuran derivatives in Escherichia coli.

Nitroheterocyclic and nitroaromatic compounds constitute an enormous range of chemicals whose potent biological activity has significant human health and environmental implications. The biological activity of nitro-substituted compounds is derived from reductive metabolism of the nitro moiety, a process catalyzed by a variety of nitroreductase activities. Resistance of bacteria to nitro-substituted compounds is believed to result primarily from mutations in genes encoding oxygen-insensitive nitroreductases. We have characterized the nfsA and nfsB genes of a large number of nitrofuran-resistant mutants of Escherichia coli and have correlated mutation with cell extract nitroreductase activity. Our studies demonstrate that first-step resistance to furazolidone or nitrofurazone results from an nfsA mutation, while the increased resistance associated with second-step mutants is a consequence of an nfsB mutation. Inferences made from mutation about the structure-function relationships of NfsA and NfsB are discussed, especially with regard to the identification of flavin mononucleotide binding sites. We show that expression of plasmid-carried nfsA and nfsB genes in resistant mutants restores sensitivity to nitrofurans. Among the 20 first-step and 53 second-step mutants isolated in this study, 65 and 49%, respectively, contained insertion sequence elements in nfsA and nfsB. IS1 integrated in both genes, while IS30 and IS186 were found only in nfsA and IS2 and IS5 were observed only in nfsB. Insertion hot spots for IS30 and IS186 are indicated in nfsA, and a hot spot for IS5 insertion is evident in nfsB. We discuss potential regional and sequence-specific determinants for insertion sequence element integration in nfsA and nfsB.

Amino Acid Sequence↗

PubMed1977

Two new bioassay techniques for nitrofurans: Bacteroides fragilis and rec-Escherichia coli as indicator strains.

Techniques for the microbiological assay of nitrofurans are described. In one the indicator strain is Bacteroides fragilis; use of this system enables concentrations of nifuratel and furazolidone of down to 0.7 micrograms/ml to be estimated. The other system uses a recombination-deficient (recA-uvrA-) mutant of Escherichia coli; with this indicator, concentrations of 0.2 micrograms/ml, or less, of five nitrofurans can be assayed.

Bacteriological Techniques↗