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Nitrous acid (NA) induced mutations efficiently in mitDNA, conferring resistance to erythromycin and weakly induces mit- mutations. In some strains of yeast it also enhanced rho- mutations. The frequencies of nuclear and mitochondrial mutations induced with NA are compared.
The pH dependence of the formation and decomposition of the N-nitroso derivative, which is produced by the reaction of cyclohexylsulphamic acid with nitrous acid, was investigated by means of continuous photometric measurement of the changes in absorbance. Reaction at pH 2.45 resulted in an optimal yield of the N-nitroso derivative. The half-life of the decomposition reaction (the reactants cyclohexylsulphamic acid/sodium nitrite being in a molar ratio of 1:1.11) at pH 2.61 was 13.6 min. The N-nitroso derivative showed a relatively high stability at pH 4.5. The reaction in isolated human gastric juice and urine showed the same pH dependency as in aqueous HCl solution.
Induction of antiviral activity and interferon by human placenta ribonucleic acid deaminated with sodium nitrite (NO2-RNA) was studied in vitro and in vitro. (1) Viral multiplication in diploid cells from human kidney (HK cells) was depressed by pretreatment with NO2-RNA, but not by pre-treatment with the original placenta RNA. (2) NO2-RNA showed an interferon-inducing activity in rabbits and mice. (3) NO2-RNA sedimenting in 18 S and 28 S regions showed a higher antiviral activity than that sedimenting in 4 S region.
A number of mutant strains of Escherichia coli have been examined for their sensitivity to nitrous acid and in some instances to methylmethanesulfonate. All ung- mutants tested are abnormally sensitive to nitrous acid. Since the ung mutation is phenotypically expressed as a defect in uracil DNA glycosidase, this observation supports the contention that treatment of cells with nitrous acid causes deamination of cytosine to uracil. In addition the observed sentitivity indicates that the ung gene is involved in the repair of uracil in DNA. Studies with other mutants suggest that both exonuclease III and DNA polymerase I of E. coli are involved in the repair of nitrous acid damage in vivo.
Six strains with an increased nitrous acid sensitivity were isolated (Fig. 1). The putative HNO2-sensitive mutants, as well as the parental strain 55R5 behaved abnormally in crosses, so that studies on the segregation of the sensitivity were difficult and unreliable. During 1.5 years the oversensitivity of the mutants gradually decreased to disappear completely (Tab. V). The differences in HNO2 sensitivity between respiratory-sufficient and cytoplasmic respiratory-deficient strains (Tab. I), as well as between different respiratory-sufficient strains (Tab. II-IV) are analysed.
The effect of nitrous acid (NA) on viability, integrity of cellular DNA and on membrane transport were studied in 5 strains of Escherichia coli. Stationary phase cells, grown on mineral salts medium, were exposed to NA. The viability of strains decreased in thefollowing order: W3110 wild-type greater than WP2 wild-type, WP2 uvrA greater than NG30 recA greater than P3478 polA. Alterations were found in the DNA sedimentation profile in alkaline sucrose gradient. Disturbance of DNA synthesis was measured by 3H-labelled thymidine ([3H]Thd) incorporation. No degradation of DNA was found after NA treatment. Low doses of NA caused significant inhibition of leucine and glucose transport into whole cells. The results are interpreted in terms of the multi-target action of NA causing the death of cells.
Ultraviolet radiation is more effective than either ethyl methanesulfonate or nitrous acid in inducing reverse mutation from auxotrophy to prototrophy in C. albicans. The killing effect of each of the mutagens is greater for cells grown at 37 C than at 25 C after treatment; mutation frequencies are unaffected by post-treatment growth temperatures. Though caffeine depresses survival of mutagen treated cells at both 25 C or 37 C, its effect is more pronounced at 37 C. Caffeine has no effect on mutagenesis by nitrous acid or ethyl methanesulfonate; it depresses UV mutagenesis, but only at 37 C and at high UV dosages. These findings indicate that UV mutagenesis in C. albicans is mediated by a caffeine-sensitive, recombinational system for DNA repair analogous to those known to occur in other species of yeasts. The repair system of C. albicans is unique in being susceptible to caffeine only at high temperature and when the number of DNA lesions to be repaired is large. The caffeine-sensitive steps in repair critical to UV mutagenesis are not involved in fixing mutations induced by the chemical mutagens tested.
Exponentially growing yeast cultures separated into discrete periods of the cell cycle by zonal rotor centrifugation show cyclic variation in both UV and nitrous acid induced cell lethality, mitotic gene conversion and mitotic crossing-over. Maximum cell survival after UV treatment was observed in the S and G2 phases of the cell cycle at a time when UV induction of both types of mitotic recombination was at a minimum. In contrast, cell inactivation by the chemical mutagen nitrous acid showed a single discrete period of sensitivity which occurred in S phase cells which are undergoing DNA synthesis. Mitotic gene conversion and mitotic crossing-over were induced by nitrous acid in cells at all stages of the cell cycle with a peak of induction of both events occurring at the time of maximum cell lethality. The lack of correlation observed between maximum cell and the maximum induction of mitotic intragenic recombination suggest that other DNA-repair mechanisms besides DNA-recombination repair are involved in the recovery of inactivated yeast cells during the cell cycle.
The effects of genome ploidy and posttreatment incubation on inactivation by nitrous acid (NA) were studied in normal, radio- and nitrous acid-sensitive strains of yeast. In normal yeast cells the increase of ploidy (haploid to triploid) resulted in "the protective effect", i.e. haploid cells were the most sensitive, triploid -- the most resistant. This "protective effect" is absent in polyploid yeast homozygous for the xrs1-5 (rad 54) mutation; in this case the NA-sensitivity rises with the increase of ploidy, i.e. haploid cells are the most resistant ones. The effect of liquid holding (LH) after the NA treatment depends on the genetic background and ploidy of treated cells. Posttreatment incubation in buffer has practically no effect on the survival of wild-type Berkeley's yeast strains (1n, 2n, 3n). The highly homozygous haploid strains from Zakharov' collection, both wild type and xrs1-5 mutant, exhibit no LH-recovery too. However the death of wild-type cells drastically rises in LH-condition as the ploidy increases. 24 hours incubation in buffer results in at least a ten-fold decrease in survival of wild type 2n, 3n, 4n cells. The loss of viability is proportional to the time of incubation, but the cell titer being constant. The strains (2n, 3n, 4n) homozygous for the xrs1-5 mutation (rad 54) show considerable LH-recovery. It is supposed that the xrs1-5 mutation results in the derepression of the prereplicative pathway of LH-recovery which eliminates the NA-INDUCED DAMAGE OF DNA.
3,4-Dihydrophthalazin-1(2H)-one (I) was oxidized to phthalazin-1(2H)-one (III) with nitrous acid or with ferric chloride . Phthalazino [2,3-b] phthalazine-5,12(7H, 14H)-diones (IV) did not react with ferric chloride but they were oxidized with nitrous acid to 2-[1(2H)-oxo-2-phthalazinyl] methylbenzoic acids (V) and (VI). The formation of (V) or (VI) depends upon the substituents of compounds (IV). Strucutres (V) and (VI) were established by pKa measurements in methylcellosolve and by mass and N.M.R. spectra.
A simple and speedy procedure is described for the preparation and application of nitrous acid in mutagenic experiments. The conventional incubation mixture of sodium nitrite solution with acetate buffer is replaced by an aqueous solution of nitrous acid prepared by running a solution of sodium nitrite through a column of ion exchange. The procedure eliminates also the interference of other substances. Experimental appraisal of the technique was done during the mutagenic improval of the fungus Claviceps purpurea.
Biogenic hydrogen sulfide produced in sewer systems causes odor nuisance and concrete corrosion, necessitating effective biocidal control. Free nitrous acid (FNA) has emerged as a promising biocide, but its unclear mechanisms complicate dosage optimization and risk assessment. Here, using Desulfovibrio vulgaris as a model lysogenic bacterium, we demonstrate that low-dose FNA (0.2-4.0 mg N/L) induces bacterial inactivation via prophage activation-associated lysis in addition to chemical oxidation. Reactive nitrogen species (RNS) scavenging tests revealed that RNS-mediated oxidative stress was closely associated with prophage activation. Activated phages further infected new hosts, reducing the viability of freshly cultured D. vulgaris cells by 25.7% and increasing total phage production 15.2-fold. The phenomenon was further validated in real sewage biofilms, where increased phage production and decreased bacterial viability were observed at a low FNA dose of 0.2 mg N/L, below the dose required for cell destruction by chemical oxidation. Furthermore, metagenomic analysis of 896 sewage samples worldwide revealed that 71.9% of recovered sewage-derived microbial genomes harbor prophages, indicating a widespread genomic basis for prophage activation-mediated bacterial inactivation. Overall, this study expands current understanding of the biocidal mechanisms of FNA and contributes to the development of environmentally sustainable biocidal strategies.
Purified native Hemophilus influenzae DNA is relatively insusceptible to nitrous acid (NA) mutagenesis in vitro, but is readily mutated following denaturation. NA mutagenicity for duplex DNA is significantly increased in the presence of various alcohols, glycols, phenols or primary amines. Phenol-extracted DNA contains dissociable contaminants of low molecular weight that enhance NA mutagenesis. Enhancement of NA mutagenesis by phenol and by spermine is due to the formation of unstable molecular species. We propose that reactive organic nitroso compounds are formed which then serve as delivery vehicles to promote mutagenicity of native DNA, perhaps via transnitrosation reactions. Similar reactions probably occur in vivo to promote NA-induced base substitution (but not frameshift) mutations in Salmonella typhimurium and in Escherichia coli. The possible significance of these observations to carcinogenesis is discussed.
The effects of rho-fluorophenyalanine (PFPA), an analogue of phenylalanine (PHE), on the potency and the specificity of nitrous acid (NA) mutagenesis in the gamma system of bacteriophage T4 were measured. (a) Forward mutation. THE frequencies of NA-induced gamma mutants were approximately doubled when mutagenized phage infected E. coli B in the presence of the analogue compared to controls where PHE was substituted for PFPA, or where no amino acid was added. The spontaneous forward mutation frequency was not affected by the analogue, nor was the specificity of the NA mutagenesis. (b) Reverse mutation. The frequency of spontaneous and NA-induced reversion of an gammaII transition mutant was unaffected by PFPA if the phage were plated direct on the restrictive growth in the presence of PFPA the induced reversion frequency was increased about 3-fold compared to the control.
Fifty-two cultures grown under standard conditions from separate subclones of haploid Saccharomyces strain X2180-1A were exposed to standard treatment with nitrous acid (NA). When the duration of NA-treatment was the same:a) cell survival varied markedly and the frequency distribution of its values differed significantly from the normal one; b) the overall frequency of induced ade1- and ade2-mutants (OMF) and the proportion of complete mutants among them (PCM) also displayed significant subclonal variation, apparently co-ordinated with the variation in survival. In the same experiments several different types of dependence of the OMF and PCM on the duration of NA-treatment were found. Thus the characteristics of the action of NA on yeast cells appeared to be unstable. Subclones with pronounced and reproducible differences in sensitivity to the lethal action of NA were isolated from X2180-1A without any induction or enrichment technique. This fact proves the genetic nature of the instability discovered, i.e. this instability appears to reflect the behavior of unstable genetic factors playing, along with the stable ones, a role in the control of NA-sensitivity of X2180-1A cells.
Cultured fibroblasts from normal persons or persons afflicted by xeroderma pigmentosum were used as hosts for adenovirus 2 infection. With xeroderma cells as hosts, nitrous acid-treated virus showed less plaque-forming ability than when normal cells were used, indicating that DNA damaged by nitrous acid is at least partly repaired by normal human cells.
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A procedure is reported for the isolation of cross-linked nucleosides from nitrous acid-treated calf thymus DNA. Cross-linked DNA was hydrolyzed enzymatically with deoxyribonuclease I and snake venom phosphodiesterase and fractionated on a DEAE-Sephadex column. After desalting, the fractions were characterized by ultraviolet spectroscopy, anion exchange high pressure liquid chromatography, gel filtration, and two dimensional thin layer chromatography. A cross-linked dinucleotide, and a series of oligonucleotides were isolated. The oligomers, which had resisted digestion by the above enzyme system, were digested to the nucleoside level by a spleen phosphodiesterase-alkaline phosphatase combination. A second cross-linked product was isolated from this mixture. The cross-linked nucleosides were less than 0.17% of the total nucleotides of the DNA. The methods developed here are recommended for the isolation of products from DNA treated with other cross-linking agents.