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PubMed1996

A comparison of the genotoxic effects of carboplatin and cisplatin in Escherichia coli.

cis-Diammine(1,1,-cyclobutanedicarboxylato)platinum(II) (carboplatin) is a second generation platinum anticancer agent with antineoplastic properties like that of its parent compound, cis-diamminedichloroplatinum(II) (cisplatin) but with substantially less deleterious side effects in treated patients with cisplatin. We compared their genotoxic effects in Escherichia coli and found carboplatin to be less cytotoxic (measured as loss of colony forming ability) that cisplatin in that equitoxic doses required greater than 60 time more carboplatin. However, solutions of carboplatin containing chloride ion became more cytotoxic to E. coli after a 24 h incubation period than similar freshly made solutions. Two platinum conversion products which were neither present in freshly made solutions nor in solutions lacking chloride were resolved by thin-layer chromatography (TLC). One of the conversion products migrated like cisplatin and its occurrence in carboplatin solutions was associated with cisplatin-like properties, enhanced cytotoxicity and ability to induce the SOS responses in E. coli. The SOS-inducing abilities were determined by induction of a sulA::lacZ fusion. Likewise, adducts formed in end-labeled oligonucleotides treated with carboplatin appeared identical to those caused by cisplatin when carboplatin was preincubated in chloride-containing solutions but not by carboplatin in freshly made solutions. It is likely that responses evoked by carboplatin in biological systems are partly due to activation of carboplatin by its conversion of cisplatin.

Antineoplastic Agents↗
PubMed2006

In vitro induction of micronuclei by monofunctional methanesulphonic acid esters: possible role of alkylation mechanisms.

Six monofunctional alkylating methanesulphonates of widely varying structures were investigated in the in vitro micronucleus assay with Syrian hamster embryo fibroblast cells. The results were compared with the alkylating activities measured in the 4-(nitrobenzyl)pyridine test (NBP-test) and the N-methyl mercaptoimidazole (MMI-test) as measures for S(N)2 reactivity as well as in the triflouoroacetic acid (TFA) solvolysis and the hydrolysis reaction as measures for S(N)1 reactivity in order to provide insights into the role of alkylation mechanisms on induction of micronuclei. Moreover we compared the results of micronucleus assay with those of the Ames tests in strain TA 100 and TA1535 and with those of the SOS chromotest with the strains PQ37, PQ243, PM21 and GC 4798. The potency of methanesulphonates to induce micronuclei depended only to a certain degree, on the total alkylating activity (S(N)1 and S(N)2 reactivity). An inverse, significant correlation between the Ames test and the micronucleus assay was observed and an inverse correlation between the micronucleus assay and the SOS chromotest with the different strains. The results indicate that the primary mechanism leading to induction of micronuclei is not O-alkylation in DNA as it is the case in the Ames test with the hisG46 strains TA1535 and TA100 and not N-alkylation as with the SOS chromotest. There is evidence that protein alkylation, e.g. in the spindle apparatus in mitosis is decisive for induction of micronuclei by alkylating compounds. The structurally voluminous methanesulphonates 2-phenyl ethyl methanesulphonate and 1-phenyl-2-propyl methanesulphonate show a clear higher micronuclei inducing potency than the other tested though the bulky methanesulphonates possess a lower total alkylating activity than the others. This effect can be explained by a higher disturbance during mitosis after alkylation of the spindle apparatus with the structurally more bulky methanesulphonates.

Alkylating Agents↗
PubMed2006

Soil screening for identifying ecological risk stressors using a battery of in vitro cell bioassays.

Soil screening could be a process of identifying and defining areas, contaminants, and condition at the sites that warrant further attention for developing ecological risk assessments. In present work, a total of 41 surface soil samples from Tianjin, China were sampled and the soil organic extracts were evaluated using a battery of in vitro cell bioassays. The battery included ethoxyresorfin O-deethylase (EROD) with H4IIE rat hepatoma cells bioassay for Aryl hydrocarbon (Ah) receptor (Ah-agonists) effects, the SOS/umu bioassay for genotoxic effects, and human estrogen receptor recombinant yeast bioassay for estrogenic effects. The results have showed that total estrogenic effects in these soil samples was measured to be between 0.1 and 14.2ng EEQkg(-1) soil (d.w.); Ah-agonists effects assayed by EROD bioassay varied from 2.8ng TEQkg(-1) soil (d.w.) to 42.6ng TEQkg(-1) soil (d.w.), and the amounts of soil weight required for the extracts to lead positive result (IR 2.0) in the SOS/umu bioassay were between 3.9 and 31.3mg (d.w.) per well. In addition, the geographic distributions of Ah-agonists effects and genotoxic effects in Tianjin area exhibited a strong positive correlation with each other. However, the distribution of estrogenic effects with high levels in northwest Tianjin was markedly different from that of Ah-agonists effects, where the high levels were distributed in the urban of Tianjin, as well as coastal towns. It has been concluded that the toxicity assessment of surface soil using a battery of in vitro cell bioassays could provided meaningful information regarding characterization procedure in ecological risk assessment.

Animals↗
PubMed2006

Making bio-sense of toxicity: new developments in whole-cell biosensors.

Bacterial whole-cell biosensors are very useful for toxicity measurements of various samples. Semi-specific biosensors, containing fusions of stress-regulated promoters and reporter genes, have several advantages over the traditional, general biosensors that are based on constitutively expressed reporter genes. Furthermore, semi-specific biosensors are constantly being refined to lower their sensitivity and, in combination, are able to detect a wide range of toxic agents. However, the requirement for a positive response of these biosensors to toxicants can result in false-negative responses. The application of in situ inoculation and single-cell detection, combined with the introduction of new reporter genes and refined detection equipment, could lead to the extensive use of semi-specific, stress-responsive biosensors for toxicity estimations in the future.

Bacteria↗
PubMed2005

Error-prone DNA repair and translesion synthesis: focus on the replication fork.

Dean Rupp and Paul Howard-Flanders showed that, following exposure to ultraviolet light, bacteria deficient in nucleotide excision repair synthesised DNA with minimal delay and in pieces roughly the size of the distances between pyrimidine dimmers. The discontinuities or gaps between these pieces were subsequently sealed. This led directly to the hypothesis of translesion synthesis.

Bacteriophage lambda↗
PubMed2005

Error-prone DNA repair and translesion DNA synthesis. II: The inducible SOS hypothesis.

Evelyn Witkin hypothesized in 1967 that bacterial cell division is controlled by a repressor which, like the lambda repressor, is inactivated by a complex process that starts with the presence of replication-blocking lesions in the DNA. She further suggested that this might not be the only cellular function to show induction by DNA damage. Three years later, Miroslav Radman, in a privately circulated note, proposed that one such function might be an inaccurate (mutation-prone) DNA polymerase under the control of the recA and lexA genes. Thus was born the SOS hypothesis.

DNA Repair↗
PubMed2005

Roles of replicative and specialized DNA polymerases in frameshift mutagenesis: mutability of Salmonella typhimurium strains lacking one or all of SOS-inducible DNA polymerases to 26 chemicals.

Progression of DNA replication is occasionally blocked by endogenous and exogenous DNA damage. To circumvent the stalling of DNA replication, cells possess a variety of specialized DNA polymerases that replicate through DNA damage. Salmonella typhimurium strain TA1538 has six DNA polymerases and four of them are encoded by damage-inducible SOS genes, i.e. polB(ST) (pol II), dinB(ST) (pol IV), umuDC(ST) (pol V) and samAB. The strain has been used for the detection of a variety of chemical mutagens because of the high sensitivity to -2 frameshift occurring in CGCGCGCG sequence. To assign the role of each DNA polymerase in the frameshift mutagenesis, we have constructed the derivatives lacking one or all of SOS-inducible DNA polymerases and examined the mutability to 26 chemical mutagens. Interestingly, the chemicals could be categorized into four classes: class I whose mutagenicity was reduced by the deletion of dinB(ST) (1-aminoanthracene and other four chemicals); class II whose mutagenicity was reduced by the deletion of either dinB(ST) or umuDC(ST) plus samAB (7,12-dimethylbenz[a]anthracene and other three chemicals); class III whose mutagenicity largely depended on the presence of umuDC(ST) plus samAB (1-N-6-azabenzo[a]pyrene and other three chemicals) and class IV whose mutagenicity was not reduced by deletion of any of the genes encoding SOS-inducible DNA polymerases (Glu-P-1 and other 12 chemicals). Deletion of polB(ST) reduced by 30-60% the mutagenicity of six chemicals of classes II and III. These results suggest that multiple DNA polymerases including the replicative DNA polymerase, i.e. DNA polymerase III holoenzyme, play important roles in chemically induced -2 frameshift and also that different sets of DNA polymerases are engaged in the translesion bypass of different DNA lesions.

Alcohol Oxidoreductases↗
PubMed2005

Stimulation of mutagenesis by proportional deoxyribonucleoside triphosphate accumulation in Escherichia coli.

Intracellular pool sizes of deoxyribonucleoside triphosphates (dNTPs) are highly regulated. Unbalanced dNTP pools, created by abnormal accumulation or deficiency of one nucleotide, are known to be mutagenic and to have other genotoxic consequences. Recent studies in our laboratory on DNA replication in vitro suggested that balanced accumulation of dNTPs, in which all four pools increase proportionately, also stimulates mutagenesis. In this paper, we ask whether proportional dNTP pool increases are mutagenic also in living cells. Escherichia coli was transformed with recombinant plasmids that overexpress E. coli genes nrdA and nrdB, which encode the two protein subunits of aerobic ribonucleotide reductase. Roughly proportional dNTP pool expansion, by factors of 2- to 6-fold in different experiments, was accompanied by increases in spontaneous mutation frequency of up to 40-fold. Expression of a catalytically inactive ribonucleotide reductase had no effect on either dNTP pools or mutagenesis, suggesting that accumulation of dNTPs is responsible for the increased mutagenesis. Preliminary experiments with strains defective in SOS regulon induction suggest a requirement for one or more SOS functions in the dNTP-enhanced mutagenesis. Because a replisome extending from correctly matched 3'-terminal nucleotides is almost certainly saturated with dNTP substrates in vivo, whereas chain extension from mismatched nucleotides almost certainly proceeds at sub-saturating rates, we propose that the mutagenic effect of proportional dNTP pool expansion is preferential stimulation of chain extension from mismatches as a result of increases in intracellular dNTP concentrations.

Bacterial Proteins↗
PubMed2006

Specificity of replicative and SOS-inducible DNA polymerases in frameshift mutagenesis: mutability of Salmonella typhimurium strains overexpressing SOS-inducible DNA polymerases to 30 chemical mutagens.

DNA replication is frequently hindered because of the presence of DNA lesions induced by endogenous and exogenous genotoxic agents. To circumvent the replication block, cells are endowed with multiple specialized DNA polymerases that can bypass a variety of DNA damage. To better understand the specificity of specialized DNA polymerases to bypass lesions, we have constructed a set of derivatives of Salmonella typhimurium TA1538 harboring plasmids carrying the polB, dinB or mucAB genes encoding Escherichia coli DNA polymerase II, DNA polymerase IV or DNA polymerase RI, respectively, and examined the mutability to 30 chemicals. The parent strain TA1538 possesses CGCGCGCG hotspot sequence for -2 frameshift. Interestingly, the chemicals could be classified into four groups based on the mutagenicity to the derivatives: group I whose mutagenicity was highest in strain YG5161 harboring plasmid carrying dinB; group II whose mutagenicity was almost equally high in strain YG5161 and strain TA98 harboring plasmid carrying mucAB; group III whose mutagenicity was highest in strain TA98; group IV whose mutagenicity was not affected by the introduction of any of the plasmids. Introduction of plasmid carrying polB did not enhance the mutagenicity except for benz[a]anthracene. We also introduced a plasmid carrying polA encoding E. coli DNA polymerase I to strain TA1538. Strikingly, the introduction of the plasmid reduced the mutagenicity of chemicals belonging to groups I, II and III, but not the chemicals of group IV, to the levels observed in the derivative whose SOS-inducible DNA polymerases were all deleted. These results suggest that (i) DNA polymerase IV and DNA polymerase RI possess distinct but partly overlapping specificity to bypass lesions leading to -2 frameshift, (ii) the replicative DNA polymerase, i.e., DNA polymerase III, participates in the mutagenesis and (iii) the enhanced expression of E. coli polA may suppress the access of Y-family DNA polymerases to the replication complex.

Benzo(a)pyrene↗
PubMed2005

Assessment of genotoxic activity of petroleum hydrocarbon-bioremediated soil.

The relationship between toxicity and soil contamination must be understood to develop reliable indicators of environmental restoration for bioremediation. Two bacterial rapid bioassays, SOS chromotest and the umu test with and without metabolic activation (S-9 mixture), were used to evaluate the genotoxicity of petroleum hydrocarbon-contaminated soil following bioremediation treatment. The soil was taken from an engineered biopile at the Czechowice-Dziedzice Polish oil refinery (CZOR). The bioremediation process in the biopile lasted 4 years, and the toxicity measurements were done after this treatment. Carcinogens detected in the soil, polyaromatic hydrocarbons (PAHs), were reduced to low concentrations (2mg/kg dry wt) by the bioremediation process. Genotoxicity was not observed for soils tested with and without metabolic activation by a liver homogenate (S-9 mixture). However, the umu test was more sensitive than the SOS chromotest in the analysis of petroleum hydrocarbon-bioremediated soil. Analytical results of soil used in the bioassays confirmed that the bioremediation process reduced 81% of the petroleum hydrocarbons including PAHs. We conclude that the combined test systems employed in this study are useful tools for the genotoxic examination of remediated petroleum hydrocarbon-contaminated soil.

Biodegradation, Environmental↗
PubMed2005

A dam mutant of Yersinia pestis is attenuated and induces protection against plague.

We have constructed a dam mutant of Yersinia pestis GB. In BALB/c mice inoculated subcutaneously, the median lethal dose of the mutant was at least 2000-fold higher than the wild type. Mice inoculated with sub-lethal doses of the mutant were protected against a subsequent challenge with virulent Y. pestis. The effect of dam inactivation on gene expression was examined using a DNA microarray, which revealed increased expression of a number of genes associated with the SOS response. These results confirm the key role of Dam in the regulation of virulence, and its potential role as a target for the generation of attenuated strains of pathogenic bacteria.

Animals↗
PubMed2007

Investigations into the in vitro antimicrobial activity and mode of action of the phenazine antibiotic D-alanylgriseoluteic acid.

D-Alanylgriseoluteic acid (AGA) is a potent antimicrobial phenazine compound produced by Pantoea agglomerans (Erwinia herbicola) Eh1087. Susceptibility tests against a range of microbes indicated that AGA had a broad spectrum of antimicrobial activity and was particularly active against Gram-positive pathogens. Comparison of the in vitro efficacy of AGA with eight other antibiotics against 119 clinical isolates of Streptococcus pneumoniae demonstrated that all were inhibited by low concentrations of AGA (minimal inhibitory concentration range <or=0.06-0.75 microg/mL), regardless of their susceptibility to other antimicrobials. Investigations into the mode of action of AGA revealed that it induced the SOS response in Escherichia coli and slightly increased the frequency of GC-AT transition mutations. In cell-free assays, both AGA and griseoluteic acid reduced cytochrome c in the presence of a redox recycler (ferredoxin-NADP(+) reductase), but AGA was six to seven times more readily reduced than griseoluteic acid in the absence of the reductase. The potency and broad spectrum of AGA activity suggest that AGA may warrant further investigation.

Alanine↗
PubMed2005

Screening of potential lactobacilli antigenotoxicity by microbial and mammalian cell-based tests.

Antigenotoxicity is considered an important property for probiotic lactobacilli. The ability of non probiotic lactobacilli from dairy products and starters to inhibit two reference genotoxins: 4-nitroquinoline-1-oxide and N-methyl-N'-nitro-N-nitrosoguanidine was evaluated. The study was carried out using short-term assays with different targets, such as procaryotic cells (SOS-Chromotest for genotoxicity in Escherichia coli and Ames test for mutagenicity in Salmonella typhimurium) and eucaryotic cells (Comet assay for genotoxicity in Caco-2 enterocytes). A high proportion of strains inhibiting 4-nitroquinoline-1-oxide activity was found in Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus plantarum. Inhibition of N-methyl-N'-nitro-N-nitrosoguanidine activity occurred in only one L. acidophilus strain. All the strains with antigenotoxic properties also demonstrated antimutagenic activity and produced modifications in genotoxin spectroscopic profiles. Strain viability during and after genotoxin exposure was confirmed. Concordance of the results obtained with microbial and mammalian cell-based tests is underlined.

4-Nitroquinoline-1-oxide↗
PubMed2005

The effect of probiotics on the genotoxicity of furazolidone.

Antigenotoxic activity of probiotic bacteria against furazolidone was studied using the short-term bacterial assay SOS chromotest, with Escherichia coli PQ37 as the test organism. The supernatants from probiotic and furazolidone co-incubation exhibited rather strong suppression on SOS induction produced by furazolidone on E. coli PQ 37 (sfiA: lacZ). Genotoxicity inhibition was found for all strains of the examined bacteria belonging to three genera. The highest genotoxicity inhibition was detected for Bifidobacterium lactis Bb-12 (92.0%) and for Lactobacillus acidophilus T20 (81.9%).

Anti-Infective Agents, Local↗
PubMed2006

Tetramerization of the LexA repressor in solution: implications for gene regulation of the E.coli SOS system at acidic pH.

Structural changes on LexA repressor promoted by acidic pH have been investigated. Intense protein aggregation occurred around pH 4.0 but was not detected at pH values lower than pH 3.5. The center of spectral mass of the Trp increased 400 cm(-1) at pH 2.5 relatively to pH 7.2, an indication that LexA has undergone structural reorganization but not denaturation. The Trp fluorescence polarization of LexA at pH 2.5 indicated that its hydrodynamic volume was larger than its dimer at pH 7.2. 4,4'-Dianilino-1,1'-binaphthyl-5,5'- disulfonic acid (bis-ANS) experiments suggested that the residues in the hydrophobic clefts already present at the LexA structure at neutral pH had higher affinity to it at pH 2.5. A 100 kDa band corresponding to a tetramer was obtained when LexA was subject to pore-limiting native polyacrylamide gel electrophoresis at this pH. The existence of this tetrameric state was also confirmed by small angle X-ray scattering (SAXS) analysis at pH 2.5. 1D 1H NMR experiments suggested that it was composed of a mixture of folded and unfolded regions. Although 14,000-fold less stable than the dimeric LexA, it showed a tetramer-monomer dissociation at pH 2.5 from the hydrostatic pressure and urea curves. Albeit with half of the affinity obtained at pH 7.2 (Kaff of 170 nM), tetrameric LexA remained capable of binding recA operator sequence at pH 2.5. Moreover, different from the absence of binding to the negative control polyGC at neutral pH, LexA bound to this sequence with a Kaff value of 1415 nM at pH 2.5. A binding stoichiometry experiment at both pH 7.2 and pH 2.5 showed a [monomeric LexA]/[recA operator] ratio of 2:1. These results are discussed in relation to the activation of the Escherichia coli SOS regulon in response to environmental conditions resulting in acidic intracellular pH. Furthermore, oligomerization of LexA is proposed to be a possible regulation mechanism of this regulon.

Anilino Naphthalenesulfonates↗
PubMed2006

Proteomic profiling of ClpXP substrates after DNA damage reveals extensive instability within SOS regulon.

ClpXP, a bacterial AAA+ protease, controls intracellular levels of many stress-response proteins. To investigate substrate profile changes caused by a specific environmental stress, quantitative mass spectrometry (SILAC) was used to analyze proteins trapped by ClpXP(trap) before and after DNA damage. The abundance of half of the trapped proteins changed more than 3-fold after damage. Overrepresented substrates included the DNA-repair proteins RecN and UvrA. Among SOS-response proteins, 25% were ClpXP substrates and, importantly, nearly all of the highly induced regulon members were rapidly degraded. Other proteins, including the stress regulator sigma(S), were underrepresented in ClpXP(trap) after DNA damage; overproduction experiments suggest that simple substrate competition does not account for this reduced recognition. We conclude that damage-response proteins are an unusually rapidly degraded family and that ClpXP has substantial capacity to process the influx of newly synthesized substrates while maintaining the ability to degrade its other substrates in an environmentally responsive manner.

Adenosine Triphosphatases↗
PubMed2004

Inhibitory effects of water-soluble cationic manganese porphyrins on peroxynitrite-induced SOS response in Salmonella typhimurium TA4107/pSK1002.

We have investigated the protective effects of water-soluble cationic Mn(III) porphyrins against peroxynitrite (ONOO-)-induced DNA damage in the cells of Salmonella typhimurium TA4107/pSK1002 and lipid peroxidation of red blood cell membranes. Mn(III) tetrakis (N-methylpyridinium-4-yl) porphine (TMPyP) and the brominated form, Mn(III) octabromo-tetrakis (N-methylpyridinium-4-yl) porphine (OBTMPyP) effectively reduced the damage and peroxidation induced by N-morpholino sydnonimine (SIN-1), which gradually generates ONOO- from O2*- and *NO produced through hydrolysis. Mn(III)OBTMPyP became 10-fold more active than the non-brominated form. In the presence of authentic ONOO-, the Mn(III) porphyrins were ineffective against damage and strongly enhanced lipid peroxidation, while the coexistence of ascorbic acid inhibited peroxidation. Using a diode array spectrophotometry, the reactions of Mn(III)TMPyP with authentic ONOO- and SIN-1 were measured. Mn(III)TMPyP is known to be catalytic for ONOO- decomposition in the presence of antioxidants. OxoMn(IV)TMPyP with SIN-1 was rapidly reduced back to Mn(III) without adding any oxidants. Further, in the SIN-1 system, the concentration of NO2- and NO3- were colorimetrically determined by Griess reaction based on the two-step diazotization. NO2- increased by addition of Mn(III) porphyrin and the ratio of NO2- to NO3- was 4-7 times higher than that (1.05) of SIN-1 alone. This result suggests that O2*- from SIN-1 acts as a reductant and *NO cogenerated is oxidized to NO2-, a primarily decomposition product of *NO. Under the pathological conditions where biological antioxidants are depleted and ONOO- and O2*- are extensively generated, the Mn(III) porphyrins will effectively cycle ONOO- decomposition using O2*-.

Cations↗