Genotoxicity studies with two antichagasic drugs.
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Drug Resistance, Microbial↗
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Enhancement and inhibition of benzo[a]pyrene-induced SOS function in E. coli by synthetic antioxidants.
8 antioxidants were tested in the SOS chromotest for induction of SOS function and for modulation of benzo[a]pyrene-induced SOS function. None of the antioxidants leads to increased beta-galactosidase activity by itself. Butylated hydroxytoluene at concentrations between 10(-5) M and 3 X 10(-4) M enhances benzo[a]pyrene-induced SOS function at benzo[a]pyrene concentrations between 10(-6) M and 3 X 10(-5) M. Butylated hydroxyanisole, ethoxyquin, propyl gallate and octyl gallate also slightly enhance benzo[a]pyrene-induced SOS function at concentrations up to 3 X 10(-4) M though to a lesser degree than butylated hydroxytoluene. Dodecyl gallate, vitamin C and alpha-tocopherol do not increase benzo[a]pyrene action. In concentrations exceeding 3 X 10(-4) M all synthetic antioxidants tested but not vitamin C and alpha-tocopherol decrease beta-galactosidase activity both in the absence and, more extensively, in the presence of benzo[a]pyrene. Preliminary data suggest that the apparent suppression of benzo[a]pyrene-induced SOS function is not due to an effect on the formation of benzo[a]pyrene metabolites by the metabolizing system used.
Antioxidants↗
Harman and norharman induce SOS responses and frameshift mutations in bacteria.
Norharman and harman, beta-carboline derivatives with comutagenic activity in Salmonella typhimurium, were examined for their activity to induce SOS responses in S. typhimurium using the umu-test and mutations in Escherichia coli. The inducibility of the umuC gene by norharman and harman was assayed by measuring the levels of beta-galactosidase activity in tester cells harbouring the umuC'-'lacZ fusion gene on a plasmid. In the umu-test, both norharman and harman weakly induced umuC gene expression at 25-100 and 50-150 micrograms/ml, respectively. In the mutation test using reversion from trpE9777 to Trp+, harman was relatively more potent than norharman in inducing the mutations. These results indicate that norharman and harman induce SOS responses as well as reversion of trpE9777 frameshift mutation in bacteria.
Alkaloids↗
Non-mutability by ultraviolet light in uvrD recB derivatives of Escherichia coli WP2 uvrA is due to inhibition of RecA protein activation.
The deficiency in UV mutagenesis in uvrD3 recB21 strains of E. coli is almost completely overcome by constitutive activation of RecA protein and expression of the SOS system (by recA730 or 43 degrees C treated recA441 lexA71). When SOS was expressed but RecA protein not self-activated (recA441 lexA71 at 30 degrees C), uvrD3 recB21 still reduced UV mutagenesis at low doses. The uvrD3 recB21 combination is therefore inhibiting activation of RecA protein. It is suggested that the DNA unwinding activity of the products of the uvrD and recB genes may be involved in generating single-stranded DNA needed to activate RecA protein both for the cleavage of LexA repressor and for a further role in UV mutagenesis.
DNA Repair↗
Mutagenesis by the anti-tumour drug nitracrine in Escherichia coli.
The antitumour drug nitracrine [1-nitro-9-(dimethylaminopropylamino)acridine], known to be a potent frameshift mutagen in strains of Salmonella typhimurium, also strongly reverts the lacZ19124 frameshift marker in Escherichia coli. The results in E. coli indicate that nitracrine causes DNA damage which can be excised by the UvrA,B,C excinuclease, can generate mutations by a recA-dependent mechanism, and gives enhanced yields of mutants when plasmid pKM101 is present. Despite these observations, mutagenesis by nitracrine appears to be independent of the UmuC gene product, and hence nitracrine differs from most (but not all) other chemicals which generate mutations via the SOS response. Given that umuC mutants are about as mutable by nitracine as the wild-type parent strain, it is somewhat surprising that plasmid pKM101 causes an enhancement of nitracrine mutagenesis. Nevertheless, we have found that the observed enhancement of mutagenesis by pKM101 is a function of the mucB gene, normally assumed to be essentially homologous to the umuC gene.
Aminoacridines↗
Induction of error-free DNA repair in Escherichia coli by thiamine deprivation.
Incubation of Escherichia coli AB1157 in a thiamine-deficient medium causes a large, time-dependent increase in resistance to UV-radiation (254 nm) and a fall in its UV-induced mutation frequency to histidine prototrophy which are abolished in its uvrA mutant, but only delayed in lon- and recA- cells. The response of the lexA3 mutant resembles that of the parental cells. These effects are very similar to those we have shown to be induced by heat shock and are clearly due to an error-free, DNA-excision repair-dependent process. They may represent a general response to non-mutagenic stress in these cells.
Bacterial Proteins↗
A comparative study of mutagenic and SOS-inducing activity of biphenyls, phenanthrenequinones and fluorenones.
A total of 23 chemicals--biphenyls, phenanthrenequinones and fluorenones--were tested for mutagenicity towards Salmonella typhimurium strains TA1538, TA1535 and TA98. SOS-inducing activity of the same chemicals was studied in terms of the SOS-inducing potency in Escherichia coli PQ37, using an automated instrument controlled by a dedicated computer program for the SOS Chromotest. Of the 23 chemicals studied 14 induced His+ revertants in S. typhimurium TA1538 hisD305 (-1 frameshift); none induced His+ reversions in TA1535 (base-pair substitution). The mutagenicity of the chemicals in S. typhimurium TA98 (pKM 101) was lower than in TA1538. There was a close correlation between mutagenicity and SOS-inducing activity of fluorenones and phenanthrenequinones. None of the biphenyls tested induced SOS response and this property does not depend upon the mutagenic activity of the chemicals. SOS Chromotest is particularly valid in detecting chemicals which give rise to base-pair substitutions through SOS induction. If positive results are obtained, the Salmonella assay may be omitted. However, this test cannot replace the Ames test especially for the primary screening of mutagenicity of chemicals with unknown structure.
Biphenyl Compounds↗
Expression of the recA gene is reduced in Escherichia coli topoisomerase I mutants.
We studied the influence of DNA topological changes on Escherichia coli recA gene expression. This was monitored by measuring beta-galactosidase activity in cells containing a recA-lacZ fusion. To modulate DNA supercoiling we used mutations in the genes encoding for topoisomerase I and DNA gyrase. After either UV irradiation or treatment with the gyrase inhibitor ciprofloxacin, induction of the recA gene was reduced in topA10 mutants, this reduction being alleviated when gyrA or gyrB mutations causing DNA relaxation were present. A reduced induction of recA was also observed after incubation of cells carrying the recA441 mutation at 42 degrees C in the presence of adenine. Using bacteria deficient in the LexA repressor, we have demonstrated that the topA10 mutation reduces the constitutive expression of the recA gene. We suggest that the increase in negative supercoiling resulting from topoisomerase I deficiency interferes with transcription from the recA promoter. The reduction in the expression of the recA gene in topA10 bacteria could determine their increased UV sensitivity as well as their partial defectiveness in SOS mutability.
Ciprofloxacin↗
Plasmid pSK1002-mediated mutator effect and SOS response and SOS mutagenesis of 2,5-dichloronitrobenzol in Salmonella typhimurium.
The plasmid pSK1002 (umuC'-'lacZ) could increase the number of revertants induced by methyl methanesulfonate (MMS) and 4-nitroquinoline-N-oxide (4NQO) in Salmonella typhimurium TA 1535 (his-). The values induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were not different irrespective of the presence or absence of plasmid. However, the plasmid pKM101-mediated mutagenesis-enhancing effect was much greater than that mediated by pSK1002 as induced by the 3 mutagens mentioned above. Moreover, the plasmid pSK1002 could induced umu-mediated SOS response in the presence of any of these 3 mutagens or of mitomycin C, and a dose-response relationship was evident. It shows that pSK1002 (umuC'-'lacZ) has a dual biological effect, namely a mutator effect and the effect of inducing the SOS response. Besides, this study has proved SOS mutagenesis of 2,5-dichloronitrobenzol (2,5-DCNB) because of the dual indicator nature of pSK1002. Therefore, it is probable that pSK1002 could be further developed and applied in studying the relation between the SOS response and mutagenesis and in identifying environmental SOS mutagens.
Mutagenesis↗
SOS system induction in Escherichia coli cells with distinct levels of ribonucleotide reductase activity.
The UV-mediated induction of recA and sfiA genes in Escherichia coli cells with distinct levels of dATP has been studied. Low levels of dATP were obtained by using either a temperature-sensitive ribonucleotide (RDP) reductase-deficient (nrdA) mutant or a wild-type strain treated with hydroxyurea. High pools of dATP were achieved by using a plasmid overproducing RDP reductase. The results obtained show that expression of the recA and sfiA genes was inhibited neither in the UV-irradiated nrdA mutant at 42 degrees C nor in the wild-type strain in the presence of hydroxyurea. Likewise, the increase of the dATP pool did not enhance recA and sfiA gene expression after UV irradiation. All these data suggest that the basal level of dATP is not a limiting factor in the process of induction of the SOS system in Escherichia coli.
Adenosine Triphosphate↗
Precise excision of transposons and point mutations induced by chemicals.
The ability of 23 chemicals (carcinogens and non-carcinogens) to induce precise excision of Tn10 and point mutations was studied in experiments with a single strain. The mutation assay was shown to detect a wider spectrum of genotoxic agents than the assay of Tn10 precise excision. The latter was induced only by potent SOS mutagens, which is in accordance with data on the SOS dependence of the induction of precise excision of Tn10. The precise excision assay as an additional test contributing to the knowledge of particular features of the action of a tested mutagen is discussed. The induction of precise excision of Tn10 by pyrene (and its failure to induce point mutations in this strain) demonstrates the value of using the transposon excision assay in cases of 'problem' mutagens.
Carcinogenicity Tests↗
UV resistance of E. coli K-12 deficient in cAMP/CRP regulation.
Deletion of genes for adenylate cyclase (delta cya) or cAMP receptor protein (delta crp) in E. coli K-12 confers a phenotype that includes resistance to UV radiation (254 nm). Such mutations lead to UV resistance of uvr+, uvrA, lexA and recA strains which could partly be abolished by the addition of cAMP to delta cya but not to delta crp strain culture medium. This effect was not related to either inducibility of major DNA repair genes or growth rate of the bacteria. Enhanced survival was also observed for UV-irradiated lambda bacteriophage indicating that a repair mechanism of UV lesions was involved in this phenomenon.
Bacteriophage lambda↗
Mutagenicity of 3-azido-1,2-propanediol and 9-(3-azido-2-hydroxypropyl)-adenine in repair deficient strains of Escherichia coli.
The mutagenicity of two non-aromatic organic azido compounds, 3-azido-1,2-propanediol (AG) and 9-(3-azido-2-hydroxypropyl)-adenine (AHPA), was studied in E. coli repair deficient strains uvrA6, uvrA6 + umuC36, uvrA6+ umuC122::Tn5, polA1, tagA1+ alkA1, ada and dam3. The mutagenicity of both agents was markedly enhanced by defects of UvrABC excinuclease (uvrA6) and was independent of umuC function of the SOS error-prone pathway. Neither azido compound promoted umuDC operon expression. The mutagenicity of AG in tag A1, alkA1 and ada mutants does not differ from that found in the wild-type strain. The expression of both ada and alkA genes was not elevated by AG. Experiments on polA1 and dam3 mutants suggest that DNA polymerase I as well as the mutHLS mismatch repair pathway does not contribute to the removal of putative DNA lesions induced by AG.
Adenine↗
The protective role of gallic acid esters in bacterial cytotoxicity and SOS responses induced by hydrogen peroxide.
The effects of gallic acid and its esters on H2O2-induced cytotoxicity, mutagenicity and SOS response were investigated in bacterial assay systems, i.e., the Ames test with Salmonella typhimurium TA104 and the SOS chromotest with E. coli PQ37. In the Ames test, gallic acid esters showed protective effects against H2O2-induced cytotoxicity and no effects on the number of revertant colonies. In the SOS chromotest, gallic acid esters lowered the SOS induction factor raised by H2O2. Throughout the study, the effects of gallic acid itself were weak or negligible, and lauryl gallate was most effective among the three gallic acid esters. This structure-activity relationship indicates the similarity of the protective effects of gallic acid esters on the H2O2-induced damages to both bacterial and mammalian cells.
Escherichia coli↗
The action of 4-hydroxyaminobiphenyl in Escherichia coli: cytotoxic and mutagenic effects in DNA repair deficient strains.
The cytotoxic and mutagenic effects of 4-hydroxyaminobiphenyl (N-OH-ABP) were studied using Escherichia coli strains with different repair capacities. N-OH-ABP was equally cytotoxic for uvrA and recA mutants as well as in wild-type cells while polA mutant strains proved particularly sensitive to its toxicity. In contrast, the mutation frequency in the uvrA strains tested was elevated to 30-400-fold the wild-type values. We suggest that aminobiphenyl-DNA adducts responsible for mutation are repaired by UVR endonuclease but different pathways exist for removal of DNA lesions responsible for bacterial killing. From the 32P-postlabeling analysis, it was concluded that ABP-DNA adducts can be relatively rapidly repaired in wild-type strains, while persisting in the uvrA strains.
4-Nitroquinoline-1-oxide↗
Spontaneous mutation in stationary-phase Escherichia coli WP2 carrying various DNA repair alleles.
Escherichia coli WP2 trpE65(ochre), when grown to stationary phase and plated on glucose salts medium, gave rise to slow growing tryptophan-independent mutants which formed increasing numbers of visible colonies from about day 6 onwards. These mutants were neither revertants at the ochre codon nor mutants at the tRNA suppressor loci normally found in this strain with logarithmic phase mutagenesis. The yield of mutants was not affected by the presence of the following alleles, umuC122, lexA102, polA1, recA1, recA56 or del(srlR-recA)306, except that in the three recA-defective strains, mutant colonies were initially slower to appear, possibly reflecting a lower viability in the inoculum. Stationary-phase spontaneous mutation in bacteria carrying on ochre mutation is thus a distinct and specific process that does not require the SOS system, or UvrA protein or DNA polymerase I. It may reflect the occurrence of a type of non-bulky DNA damage with altered base pairing specificity. In 3 out of 4 experiments with a strain carrying recA441 plus lexA51(Def) the rate of stationary-phase mutagenesis was elevated suggesting that there may be an additional component requiring an activated SOS system.
Adenosine Triphosphatases↗
Inhibitory effect of curcumin on SOS functions induced by UV irradiation.
The antigenotoxic effects of curcumin, including the inhibition of SOS induction and mutagenesis by UV light, were investigated in Salmonella typhimurium TA1535/pSK1002 and Escherichia coli K-12 strains. Induction of the SOS gene (umuC) expression was assayed by measuring accumulated beta-galactosidase activity. We found that curcumin blocked umuC induction promoted by UV irradiation in a dose-dependent manner. Also, with another SOS response, Weigle reactivation, we observed that curcumin effectively inhibited phage reactivation by UV irradiation. Furthermore, we tested the effect of curcumin on UV mutagenesis. We showed that mutagenesis induced by UV irradiation was suppressed by the addition of curcumin. Together these results indicate that curcumin acts as an inhibitor of SOS functions including UV mutagenesis.
Antimutagenic Agents↗
In vitro replication and mutagenesis of ColE1 plasmid DNA in extracts from repair deficient Escherichia coli mutants.
We have investigated conditions in vitro for the analysis of replication of ultraviolet-irradiated ColE1 DNA in cell extracts from Escherichia coli. In wild-type extracts substantial replication was obtained; however, this could be greatly reduced when the irradiated plasmid was incubated in extracts prepared from a uvrA recB strain. Modest stimulation of DNA replication was then obtained by addition of extracts from the same strain previously ultraviolet-irradiated. However, this stimulating activity proved to be highly unstable and has so far proved unsuitable as a basis for purification of specific factors involved in replication on irradiated templates. We also investigated the mutagenesis of pBR325 DNA replicated in cell extracts from a strain expressing the SOS response constitutively. Conditions for efficient recovery and transformation by plasmid DNA replicated in vitro were determined and, using this system, a more than 10-fold increase in reversion frequency of a mutation in the tet gene, compared to that with wild-type extracts, was obtained. This mutagenesis appeared to be independent of replication, indicating the presence of an error-prone repair system in the extract. This effect was not enhanced by the presence of the muc gene products in the extracts. This suggests that the observed mutagenesis is also independent of the lexA-controlled umuCD genes.
Bacteriocin Plasmids↗