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PubMed1987

The toxicity and mutagenicity of the anti-tumour drug 5-aziridino-2,4-dinitrobenzamide (CB1954) is greatly reduced in a nitroreductase-deficient strain of E. coli.

In the 1970s it was shown that the monofunctional alkylating agent CB1954 (5-aziridino-2,4-dinitrobenzamide) kills the Walker rat carcinoma 256 in vivo and in vitro, but is inactive against several other tumours. In studies with bacteria, the large differences in survival in DNA-repair-proficient and deficient strains of Escherichia coli B treated with CB1954 were characteristic of a difunctional cross-linking agent. It was concluded that DNA was the only target large enough to receive significantly more than one lethal hit per molecule and that mono-alkylation alone could not account for the lethal effects of CB1954. In 1986 it was shown that CB1954 induced DNA interstrand cross-links in CB1954-sensitive cultured Walker 256 cells, but not in resistant Chinese hamster V79 cells, suggesting that the sensitivity of Walker cells results mainly from their activation of the drug to a difunctional agent by nitroreduction. To test this, we assayed the toxicity and mutagenicity of CB1954 in nitroreductase-plus and -minus strains of E. coli WP2uvrA. Agar-overlay assays showed that CB1954 was mutagenic to several strains of E. coli WP2, in a dose range 1-100 micrograms per plate, with slopes (mutants/nmol) of 7.1, 1.05 and 0.16 for WP2uvrA pKM101, WP2uvrA and WP2. Assays with nitrofurazone showed that these strains possessed nitroreductase activity. However, E. coli NFR-343, a nitrofurazone-resistant mutant of WP2uvrA which lacks nitroreductase activity was markedly less sensitive to the mutagenicity of CB1954, giving a mean slope of 0.12 compared with 1.15 for WP2uvrA. Aroclor-induced rat-liver S9 did not change these responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1988

Some effects of furazolidone on the testis and plasma levels of testosterone, luteinizing hormone and prolactin in mature male turkeys.

Adult male turkeys were treated orally with furazolidone at doses of 1, 2.5, 5 or 20 mg/kg for 14 days and their plasma analysed for luteinizing hormone (LH), testosterone and prolactin (PRL) concentrations before, during and after treatment. At 20 mg/kg the drug produced a significant decrease in the plasma levels of LH and testosterone at the end of treatment, whereas at 5 mg/kg the drug had no significant effect. Prolactin concentrations were unaffected by any of the drug doses used. Intramuscular injection of luteinizing hormone releasing hormone (LHRH) at a dose of 5 micrograms/kg produced after 30 min a significant rise in plasma levels of LH, an effect that was decreased significantly by treatment with 20 mg/kg furazolidone. Incubation of normal turkey semen with graded doses of furazolidone or nitrofurazone for up to 30 min resulted in a dose- and time-dependent decrease in sperm motility. At a concentration of 20 mg/ml a complete absence of sperm motility was observed after incubation with either drug, although, on the whole, nitrofurazone seemed more potent than furazolidone as a sperm-immobilizing agent. Histological changes occurred in the 20 mg/kg group and consisted of a decrease in spermatocyte production, corrugation of sperm cell nuclear envelopes and distention of the endoplasmic reticulum of elongate spermatids. It is concluded that furazolidone depresses pituitary LH output but may, in addition, directly affect spermatogenesis and sperm motility.

Animals↗
PubMed1984

Studies on cis-trans isomerization of nitrofuran derivatives by bacterial nitroreductases.

cis-trans Isomerization of 3-(5-nitro-2-furyl)-2-(2-furyl)-acrylamide(AF-2) using Escherichia coli B/r and its two 5-nitro-2-furaldehyde semicarbazone (nitrofurazone)-resistant mutants was investigated. The isomerizing activity was detected in all three strains and markedly increased with acquiring resistance to nitro-furazone in intact cells and cell free extracts. Two distinct isomerases, nicotinamide adenine dinucleotide phosphate(NADPH)-dependent one with high activity and NAD(P)H-dependent with low activity were separated by Sephadex G-100 and Sepharose 4B columns. Both enzyme activities agreed with the nitrofurazone-reducing activity due to O2-sensitive nitroreductase as reported previously. Another nitroreductase, O2-insensitive one, was unable to isomerize cis AF-2 to trans form. These results suggest that bacterial cis-trans isomerases are not O2-insensitive nitroreductase, but O2-sensitive ones.

Bacteria↗
PubMed1990

Generation of radical anions of nifurtimox and related nitrofuran compounds by ascorbate.

Nifurtimox analogues bearing triazol-4-yl, benzimidazol-1-yl, triazin-4-yl or related groups as counterpart of the (5-nitro-2-furfurylidene) amino group were reduced to their nitro anion radicals by ascorbate in anaerobic solutions at high pH. The ESR spectra of the radical anions showed hyperfine spin couplings restricted to the nitrofuran moiety. With these compounds, the spin density at the nitro group was greater than with nifurtimox, nitrofurazone and nitrofurantoin. At neutral pH, solutions containing ascorbate and nitrofuran derivatives consumed oxygen, the compounds bearing unsaturated nitrogen heterocycles being the most effective. Superoxide dismutase and catalase decreased the rate of oxygen consumption, thus demonstrating the production of superoxide and hydrogen peroxide, respectively. NMR spectra of the triazol-4-yl and triazin-4-yl nitrofuran derivatives showed a deshielding effect for the azomethine proton, which was undetectable with nifurtimox and nitrofurazone.

Ascorbic Acid↗
PubMedDate not supplied

Liquid chromatographic determination of multiple sulfonamides, nitrofurans, and chloramphenicol residues in pasteurized milk.

A rapid and selective liquid chromatographic method was developed to detect 6 sulfonamides, 3 nitrofurans, and chloramphenicol residues in pasteurized milk. The 10 drugs were extracted with chloroform-acetone and the organic phase was evaporated; the residues were dissolved in an aqueous sodium acetate buffer solution 0.02M (pH = 4.8), and the fat was removed by washing with hexane. The aqueous layer was collected, filtered, and injected. The 6 sulfonamides and chloramphenicol were detected at 275 nm ultraviolet (UV) using a gradient system starting with sodium acetate buffer solution-acetonitrile (95 + 5) and finishing with sodium acetate buffer solution-acetonitrile (80 + 20). Nitrofurans were detected at 375 nm (UV) isocratically with sodium acetate buffer solution-acetonitrile (80 + 20). For 50 ppb fortified milk, the average recoveries were (sulfathiazole) 65.52%; (sulfamerazine) 75.36%; (sulfamethazine) 93.94%; (sulfachlorpyridazine) 75.94%; (sulfamethoxazole) 85.18%; (sulfamonomethoxine) 83.45%; (chloramphenicol) 104.17%; (nitrofurazone) 91.81%; (furazolidone) 100.76%; and (furaltadone) 72.38%. Method detection limits ranged from 4 ppb (nitrofurazone) to 16 ppb (sulfamethazine). Some matrix interferences (3-7 ppb) were observed only with sulfonamides.

Animals↗
PubMedDate not supplied

Liquid chromatographic-electrochemical detection screening procedure for six nitro-containing drugs in chicken tissues at low ppb level.

A screening procedure is described for the detection of furazolidone, nitrofurazone, aklomide, zoalene, nitromide, and sulfanitran residues in a single extract of chicken liver, breast, or thigh muscle at the low ppb level. The method includes extraction of tissue with chloroformethyl acetate-dimethyl sulfoxide (50 + 50 + 0.8), adsorption on neutral alumina, and subsequent elution of the residues with pH 6.0 phosphate buffer-methanol (1 + 1). Eluants are separated on a 25 cm, 5 microns C18 column with pH 6.0 phosphate buffer-methanol (57.5 + 42.5) as mobile phase. The drugs are detected with an electrochemical detector in the reductive mode at -0.8 V. Mean recoveries from all tissues ranged from 76.5% for nitrofurazone to 97.1% for zoalene.

Animals↗
PubMedDate not supplied

Determination of nitrofuran residues in poultry muscle tissues and eggs by liquid chromatography.

A liquid chromatographic (LC) method was developed and statistically validated for the determination of nitrofurazone, furazolidone, and furaltadone residues in poultry and porcine muscle tissues. The antimicrobial residues were extracted with a mixture of dichloromethane and ethyl acetate by using ultrasonication followed by solid-phase extraction cleanup and LC analysis with UV detection. A modification of the method incorporating acetonitrile extraction and solvent partition cleanup was developed for analysis of poultry eggs. The limits of detection were 1 microgram/kg ofr nitrofurazone and furazolidone and 2 micrograms/kg for furaltadone in both muscle tissues and eggs. Average recoveries for spike levels of 1, 2, and 5 micrograms/kg ranged from 84 to 128%, and coefficients of variation were between 1.1 and 12.1%. A field trial with these methods was conducted in conjunction with the Western Australian Department of Agriculture to determine the stability of furaltadone in both poultry tissue and eggs. Results of this study show that the concentration of furaltadone in muscle tissue diminished rapidly even when stored at -18 degrees C. Furaltadone was considerably more stable in eggs.

Acetonitriles↗
PubMed1996

Investigation of alternative prodrugs for use with E. coli nitroreductase in 'suicide gene' approaches to cancer therapy.

The most commonly employed 'suicide' gene/prodrug system used in cancer gene therapy is the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir system. We have examined the efficacy of an alternative approach utilising the E. coli nitroreductase B enzyme with CB1954 and a variety of other prodrugs. V79 cells transfected with a nitroreductase expression vector were up to 770-fold more sensitive to CB1954 than control non-expressing cells. In general other prodrugs which were found by HPLC to act as substrates for purified E. coli nitroreductase also exhibited increased cytotoxicity against the nitroreductase-expressing cells, although this correlation was not absolute. In particular nitrofurazone (97-fold) and additional aromatic nitro-compounds (nine- to 50-fold) showed a large differential whereas the quinones and the antimetabolite, B-FU, were less effective (< three-fold). The results support the possibility of using nitroreductase and CB1954 for 'suicide gene' therapy and in addition suggest that alternative prodrugs, such as nitrofurazone, warrant further investigation in this novel approach.

Animals↗
PubMed1965

EFFECT OF HEAT AND PLATING MEDIUM ON SURVIVAL OF ESCHERICHIA COLI AFTER TREATMENT WITH RADIOMIMETIC CHEMICALS.

Zampieri, Antonio (Palo Alto Medical Research Foundation, Palo Alto, Calif.), and Joseph Greenberg. Effect of heat and plating medium on survival of Escherichia coli after treatment with radiomimetic chemicals. J. Bacteriol. 89:931-936. 1965.-Survival of Escherichia coli strain S and its radioresistant mutant R(4) after treatment with mitomycin C, azaserine, nitrogen mustard, 1-methyl-3-nitro-1-nitrosoguanidine, nitrofurazone, and proflavine was studied. With all agents except proflavine, R(4) was more resistant than was S. Survival of strain S was greater on minimal glucose-salts medium than on Penassay (Difco), and greater on the latter than on Tryptone (Difco) agar; survival of S was greater when posttreatment incubation temperature was 45 C than when it was 37 C. Post-treatment plating medium or temperature had no effect on survival of R(4). Visible light did not affect survival of S or R(4). The survival curves of R(4) were exponential; those of S exhibited decreasing sensitivity with time of exposure. With proflavine, photoactivation by visible light was demonstrable, but there was no difference in survival between S and R(4). Survival of either strain was not affected by post-treatment plating medium or incubation temperature.

Acridines↗
PubMed1986

Thermodynamic proton-ligand and metal-ligand stability constants of some drugs.

The thermodynamic proton-ligand (pKa) and metal-ligand stability constants of clioquinol, clofibrate, nitrofurazone, and tetracycline with Cu2+, Zn2+, Mn2+, Mg2+, and Ca2+ have been determined at 35 degrees C in 50% ethanol-water media. An empirical pH correction for mixed-aqueous media has been applied. The metal-ligand stability constants were determined by following the Bjerrum Calvin titration technique as applied by Agrawal to mixed-aqueous solvents. The effect of the basicity of the ligand and the order of stability constants is discussed. The stability constants of the divalent metals follow the order: Cu2+ greater than Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+ with all the drugs.

Buffers↗
PubMed2003

Evaluation of wound healing activity of some herbal formulations.

The wound healing activity of two herbal formulations (Himax ointment and lotion) containing Indradaru extract, i.e. Arjuna bark (Terminalia arjuna, Family-Combretaceae), extract was evaluated for its wound healing potential in two types of wound models in rats (i) excision wound model and (ii) incision wound model. Both the formulations responded significantly in both the wound models tested. The results were also comparable to that of the standard drug nitrofurazone used as a standard drug for comparison in this present investigation. The results were also comparable in terms of wound contracting ability, epithelization period, tensile strength and regeneration of tissues at the wound area. Thus, this investigation con fi rms the use of the Himax ointment and lotion containing Terminalia arjuna extract as a wound-healing agent as known from folklore medicine.

Administration, Cutaneous↗
PubMed2005

Biochemical characterization of trinitrotoluene transforming oxygen-insensitive nitroreductases from Clostridium acetobutylicum ATCC 824.

The genes that encode oxygen-insensitive nitroreductases from Clostridium acetobutylicum possessing 2,4,6-Trinitrotoluene (TNT) transformation activity were cloned, sequenced and characterized. The gene products NitA (MW 31 kDa) and NitB (MW 23 kDa) were purified to homogeneity. The NitA and NitB are oxygen-insensitive nitroreductases comprised of a single nitroreductase domain. NitA and NitB enzymes show spectral characteristics similar to flavoproteins. The biochemical characteristics of NitA and NitB are highly similar to those of NfsA, the major nitroreductase from E. coli. NitA exhibited broad specificity similar to that of E. coli NfsA and displayed no flavin reductase activity. NitB showed broad substrate specificity toward nitrocompounds in a pattern similar to NfsA and NfsB of Escherichia coli. NitB has high sequence similarity to NAD(P)H nitroreductase from Archaeoglobus fulgidus. NitA could utilize only NADH as an electron donor, whereas NitB utilized both NADH and NADPH as electron donors with a preference for NADH. The activity of both nitroreductases was high toward 2,4-Dinitrotoluene (2,4-DNT) as a substrate. Both the nitroreductases were inhibited by dicoumarol and salicyl hydroxamate. The nitroreductases showed higher relative expression on induction with TNT, nitrofurazone and nitrofurantoin compared to the uninduced control.

Amino Acid Sequence↗
PubMed1984

Aerobic reduction of 5-nitro-2-furaldehyde semicarbazone by rat liver xanthine dehydrogenase.

Previous work in several laboratories has shown that enzymatic reduction of nitroheterocyclic compounds to reactive but uncharacterized metabolites that damage DNA constitutes an important "activation" step in both bacteria and hypoxic mammalian cells. However, since the known mammalian enzymes having nitroreductase activity are reported to be strongly inhibited by molecular oxygen, the relation of reductive activation to the toxic and mutagenic effects of nitroheterocyclic compounds in intact animals or aerobic cultured cells is unclear. We report here that the process of net nitroreduction of 5-nitro-2-furaldehyde semicarbazone (nitrofurazone) by rat liver xanthine dehydrogenase was considerably less sensitive to inhibition by oxygen than was nitroreduction catalyzed by rat liver or milk xanthine oxidase. The dehydrogenase is the native form of xanthine oxidoreductase and is known to change to the oxidase form as liver extracts are aged or treated with various agents. Incubation at 65 degrees rapidly converted the dehydrogenase form to the oxidase form with concomitant loss of aerobic nitroreductase activity. Similarly, much of the aerobic nitroreductase activity was lost when the preparation was treated with p-hydroxymercuribenzoate but was regained upon subsequent treatment with dithiothreitol. Intermediates generated in the aerobic nitroreduction process bound tightly and probably covalently to protein. Thus, it is possible that aerobic reduction of nitrofurans and other nitroheterocyclic and nitroaromatic components by xanthine dehydrogenase may constitute a significant "activation" process which contributes to the toxic action of such agents.

Aerobiosis↗
PubMed1995

The interaction of nitroaromatic drugs with aminothiols.

The effect of cysteamine and glutathione addition on the redox behaviour of metronidazole, chloramphenicol, M&B 4998, nitrofurazone, and nifuroxime has been studied by electrochemical techniques. The presence of thiol influences the redox behaviour of the nitro compound in a number of ways. In aqueous media, the single-step nitro/hydroxylamine reduction shows a decrease in current and a shift to more positive potentials, which is assigned to the thiol acting as the reducing agent, but only after the formation of the nitro radical anion. In addition, the reversible RNO/RNHOH couple is greatly diminished or removed. In a dimethylformamide/H2O solvent, the nitro radical anion can be selectively generated. The effect of thiol addition on the stability of the radical anion is strongly dependent on the drug, the identity of the thiol, and the concentration of the supporting electrolyte. The presence of thiol can result in an increase or a decrease in the lifetime of the radical with no apparent correlation with the redox couple of the nitro compound, or can act as an oxidizing agent and regenerate the original nitro compound. These disparate routes by which thiol can modify the redox characteristics of nitro compounds suggest that the traditional role of thiol as a radical scavenger needs to be extended.

Buffers↗
PubMed1984

No detectable reaction of the anion radical metabolite of nitrofurans with reduced glutathione or macro-molecules.

The initial metabolite formed by most mammalian nitroreductases is the nitro anion free radical. We, as well as others, have proposed that nitroheterocyclic anion radicals covalently bind to protein, DNA, or thiol compounds such as reduced glutathione (GSH). Our results indicate that even at 100 mM GSH does not affect the steady-state concentration of the nitro anion free radical of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) in rat hepatic microsomal or xanthine oxidase incubations. The steady-state ESR amplitude of the anion radical is also unchanged by the addition of BSA or DNA. Similar results are obtained with nitrofurazone and nitrofurantoin. The reactive chemical species which binds to tissue macromolecules and GSH upon the reduction of nitrofurans remains unknown, but the anion free radical metabolite can be excluded from consideration.

Anions↗
PubMed1977

Use of fresh amnion as a burn dressing.

Thirty-seven children with second and third degree burns dressed with amnion were compared to seventy-three children treated with Furacin (Eaton Labs, Norwich, N.Y.) dressing. Amnion was found to be as easy to use as Furacin. Fewer split thickness skin grafts were needed in amnion treated children and these patients required fewer days of hospitalization. Bacterial culture data suggests that amnion is as good as and possibly superior to nitrofurazone in decreasing the number of organisms on the burn wound. No adverse reactions to amnion were noted. The use of amnion is supported by this preliminary study and is deserving of further investigation and clinical use.

Amnion↗
PubMed1990

Studies on Tn10 transposition and excision in DNA-repair mutants of Salmonella typhimurium.

Transposition of Tn10 in polA, recA, uvrB, mutH and uvrD mutants of Salmonella typhimurium was studied by a mating-out assay mediated by R plasmid pKM101. A decrease in transposition frequency was observed with polA, recA and uvrD mutants; uvrB and mutH mutants showed frequencies somewhat higher than control values. No effect of dimethyl sulfoxide, sodium acetate or nitrofurazone on Tn10 transposition was observed with this assay. Precise excision of Tn10 from srl202::Tn10 in these DNA-repair mutants was also studied. An increase in excision frequency of about 20 or 150 times in 2 different polA mutants, and a smaller increase, of about 2 or 15 times over control values, was detected in mutH and uvrD mutants, respectively.

Acetates↗
PubMed1984

Cellular metabolism of fluorescent nitroheterocycles.

Since nitroheterocycles are preferentially metabolized and bound in hypoxic cells, we have examined more than 2 dozen nitroheterocycles as potential fluorescent probes for hypoxia. Using flow cytometry, several patterns of cellular fluorescence (CF) have been observed; for most nitroheterocycles, CF was several fold higher for anoxic than for aerobic cells (which was not predicted based on comparison of the fluorescence spectra of parent drug and reduced products). CF gradually increased when cells were exposed to 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2) or to 4-nitroquinoline-1-oxide (4-NQO), and cells remained fluorescent when the drug was washed off. In contrast, cells exposed to trans-5-amino-3-[5-nitro-2-furyl)vinyl-1,2,4-oxadiazole (NFVO) lost fluorescence with a half-time of 60 minutes. Cells exposed to nitrofurazone (NF-7) reached maximum fluorescence within 30 minutes and then lost fluorescence, even in the presence of the drug. Finally, cells exposed to 3-nitropyrene (NP-3) were initially more fluorescent when incubated under aerobic conditions than anoxic conditions; however, after 2 hours in the presence of NP-3, anoxic cells continued to increase in fluorescence while aerobic cells lost fluorescence. Differences in the patterns of cellular accumulation of fluorescent nitroheterocycles were accompanied by differences in the toxicity and metabolism of these drugs. Therefore, chemical studies alone do not allow us to predict the potential of a compound as a hypoxic probe; studies at the cellular level are also essential.

4-Nitroquinoline-1-oxide↗