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PubMed1993

Influence of S9 mix composition on the SOS response in Escherichia coli PQ37 by polycyclic aromatic hydrocarbons.

To investigate the variability in test results obtained with the SOS chromotest (Escherichia coli PQ37 genotoxicity assay) when varying the composition of the exogenous metabolizing system (S9 mix), we examined the influence of different S9 and NADP concentrations, of buffer pH value, of SDS concentrations, the effects of E. coli PQ37 density and centrifugation steps on the expression of beta-galactosidase (beta g) and alkaline phosphatase (ap) activity, the calculated induction factors (IFs) and SOS-inducing potencies (SOSIPs). Additionally we examined the metabolic potency (stability) of S9 mix when stored at 37 degrees C before use. Initially, we used 0-5000 ng (= 0-20 nmole) benzo[a]pyrene (B[a]P) as a reference compound for the test procedure in the presence of standard S9 mix. Subsequently, to evaluate the results of S9 mix variations we examined several polycyclic aromatic hydrocarbons (PAHs) using both the standard and a modified S9 mix composition and test protocol. We observed the highest beta g and ap activities and/or IFs using only 11-27 microliters 9000 x g liver supernatant (S9) from Aroclor 1254-induced rats per assay (20-50% of standard amount) and calibrating the S9 mix Tris buffer to pH 7.8-8.0. 60-300 micrograms NADP/assay (10-50% of standard) was sufficient for optimum activation of PAHs. In contrast to previous investigations about the variability of the SOS chromotest in the absence of a metabolizing system, higher induction factors were obtained when using higher bacterial densities (12-18 x 10(6) cfu/assay). Centrifugation steps as recommended by other investigators were not necessary when using optimum S9 amounts. The metabolic activity of S9 mix remained nearly constant approximately 20 min after preparation, but decreased to 80% of its activity in about 1 h.

Animals↗
PubMed1994

Isolation and prevalidation of an Escherichia coli tester strain for the use in mechanistic and metabolic studies of genotoxins.

We have isolated an Escherichia coli tester strain for the use in mechanistic and metabolic studies of genotoxins. We started with one of the more used and better characterized E. coli K-12 laboratory strains, AB1157. We isolated a lipopolysaccharide defective mutant of strain AB1886 which is an excision repair deficient derivative of AB1157 and introduced a newly constructed plasmid pKR11, encoding mucAB, resulting in strain MR2101/pKR11. A genotoxicity assay was designed, monitoring the reversion to arginine prototrophy and a preliminary validation was carried out against Ames tester strain TA100 with a set of diagnostic compounds. The results seem to indicate that strain MR2101/pKR11 is an adequate tester strain which can be a useful tool in mechanistic studies. Moreover, this strain can serve as mother strain to isolate improved and more specialized tester strains.

Dose-Response Relationship, Drug↗
PubMed1995

Development of high sensitive umu test system: rapid detection of genotoxicity of promutagenic aromatic amines by Salmonella typhimurium strain NM2009 possessing high O-acetyltransferase activity.

A highly sensitive umu test system for the detection of carcinogenic/mutagenic aromatic amines has been developed utilizing a new tester strain, Salmonella typhimurium NM2009, possessing an elevated O-acetyltransferase (O-AT) level. NM2009 was constructed by subcloning the bacterial O-AT gene into a plasmid vector pACYC184 and introducing the plasmid into the original strain S. typhimurium TA1535/pSK1002 harboring an umuC'-'lacZ fusion gene. The system is based on the ability of DNA-damaging agents (genotoxins) to induce umuC gene expression and monitored by measuring the cellular beta-galactosidase activity evoked by the fusion gene. Twenty-two aromatic amine compounds including arylamines, aminoazo dyes, and heterocyclic aromatic amines were tested for inducibility of DNA damage after metabolic activation by rat liver S9 in strain NM2009 and the sensitivity was compared with those of the parent strain TA1535/pSK1002 and the O-AT-defective strain NM2000. NM2009 had about 400 times higher O-AT activity than the parent strain. It was found that NM2009 was much more sensitive to aromatic amines than other strains to induce umuC gene expression after metabolic activation; the chemicals which were extremely sensitive in strain NM2009 include 2-aminoanthracene, 2-aminofluorene, 2-acetylaminofluorene, benzidine, 6-aminochrysene, 2,4-diaminotoluene, 2,6-diaminotoluene, 1-naphthylamine, o-tolidine, 3-MeO-AAB, o-aminoazotoluene, Glu-P-1, Trp-P-1, MeA alpha C, A alpha C, MeIQ, MeIQx, and IQ. In contrast, Trp-P-2 and PhIP showed almost similar sensitivities in three tester strains used in this study. These results suggest that strain NM2009 with high O-acetyltransferase activity is very useful to detect the genotoxic activities of potential mutagenic aromatic amine compounds, which require metabolic activation via the cytochrome P-450/acetyltransferase system.

Acetyltransferases↗
PubMed1986

Genotoxic activity of two furan analogues of benzo[a]pyrene and their 2-nitro derivatives.

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS Chromotest (an assay for SOS induction in E. coli), of two pairs of isomeric furan analogues of benzo[a]pyrene: pyreno[1,2-b]furan (R7490) and pyreno[2,1-b]furan (R7692) and their 2-nitro derivatives, 8-nitro-pyreno[1,2-b]furan (R7489) and 8-nitro-pyreno[2,1-b]furan (R7691). We found that: For all 4 compounds, the responses were correlated in the two tests. For the 2-nitro derivatives, R7489 and R7691, the responses were extremely high, reaching SOS-inducing potencies of 5.2 X 10(3) and 10(5)/nmole in the SOS Chromotest and mutagenic potencies of 6.3 X 10(4) and 3.7 X 10(7) revertants/nmole in the Salmonella/histidine assay (strain TA98), respectively; the responses were only slightly decreased in nitroreductase-deficient strains. The responses to the two pyrenofurans were increased in the presence of an "activating mixture" but were still lower than that to benzo[a]pyrene. In contrast to benzo[a]pyrene and pyreno[2,1-b]furan (R7692), pyreno[1,2-b]furan (R7490) also gave a response in the absence of an "activating mixture". (5) Compounds with the oxygen heteroatom within the "bay region" gave lower responses than their isomers with the oxygen heteroatom outside the "bay region".

Animals↗
PubMed1986

Genotoxicity assessment of low-molecular weight interferon inducers by the SOS Chromotest.

Tilorone and its aza-analogs, as well as CMA and its butyric analog (CNPA) were investigated as potential genotoxic agents by the SOS Chromotest. The SOS-inducing potency values (SOSIP) were 0.0033 and 0.0009 for SAF and vivakorfen, respectively, after activation with S9 fraction of mouse liver only. In contrast, an SOSIP value for tilorone of 0.0011 was observed in a non-activated assay. The SOSIPs of investigated compounds were low and comparable to the lowest values determined for other genotoxins. CMA and CNPA were not SOS inducers in any test system.

Animals↗
PubMed1987

Study of the genotoxic potential of 48 inorganic derivatives with the SOS chromotest.

The genotoxic potential of 48 inorganic derivatives was studied using the bacterial colorimetric assay: the SOS Chromotest. Some of these compounds are known as carcinogens (As, CR(VI), Cd, Ni) or suspected carcinogens for human beings (Hg, Pb), others are known as non-carcinogens. Among these 48 derivatives, only the two Cr(VI) compounds and the Sn(II) compounds gave positive results.

Animals↗
PubMedDate not supplied

Statistical analysis of Salmonella test data and comparison to results of animal cancer tests.

A quantitative framework for the analysis of results of the Salmonella (Ames) test is presented, and the relationship between mutagenesis and carcinogenesis is examined. Color graphics are used for the Salmonella data to describe variability, and trends across multiple chemicals and test conditions. Positivity in the Salmonella test, using statistical criteria to classify results, is compared to positivity in carcinogenesis bioassays for 48 chemicals tested in NCI/NTP-sponsored programs. Sensitivity of the Salmonella test across 5 tester strains was 91% (21/23), while specificity was only 36% (9/25). Results were most concordant for TA100 Aroclor-induced rat S9: sensitivity was 87%, specificity 64%. The correlation of mutagenic potency and carcinogenic potency was 0.41 (p less than 0.001) for 80 chemicals, using results from both the general published literature and the NCI/NTP-sponsored programs. After removal of 3 extreme values, the correlation was 0.24 (p = 0.04).

Animals↗
PubMed1988

Screening for genotoxic activity of amitraz with short-term bacterial assays.

Genotoxic effects of both amitraz and its metabolites made by S9 fraction were reevaluated in short-term bacterial assays. Neither amitraz nor its metabolites induced frameshift mutation or caused base-pair substitution as detected by the Ames test. They also did not introduce any damages into DNA recognized by correndonuclease II as shown by the repair test. Metabolites of amitraz (but not amitraz itself) induced the SOS-repair system in E. coli strain PQ 243 tagA, alkA which was deficient in N-glycosylases. It is concluded that neither amitraz nor its metabolites have mutagenic activity. In contrast to amitraz, its metabolites alkylate DNA in the N3-position of adenine.

Alkylating Agents↗
PubMed1988

Evaluation of the genotoxic activity of 2-nitroanthrafurans.

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS chromotest (an assay for SOS induction in E. coli), of three 2-nitroanthrafurans: 2-nitroanthra[1,2-b]furan (R-7688), the isomeric compound 2-nitroanthra[2,1-b]furan (R-7686) and its 8-methoxylated derivative (R-7707). Their genotoxic activities were compared to that of 7-methoxy-2-nitronaphtho[2,1-b]furan (R-7000) which has been studied in previous works (Arnaise et al., 1986). We found that: (1) for all three 2-nitroanthrafurans, as generally observed for other 2-nitrofuran derivatives, the responses were correlated in the 2 tests and were decreased in the presence of an 'activating mixture' and in nitroreductase-deficient strains; (2) in contrast to what is usually observed with other 2-nitrofuran derivatives for which methoxylation increases genotoxic activity, the genotoxic activity of the methoxylated 2-nitroanthrafuran (R-7707) was comparable and may be even lower than that of the unsubstituted 2-nitroanthrafuran (R-7686); (3) the addition of a third ring that leads from 2-nitronaphthofurans to 2-nitroanthrafurans increased slightly the genotoxic activity of these compounds; (4) compounds with the oxygen heteroatom outside the 'bay region', R-7686 and R-7707, gave higher responses than their isomers with the oxygen heteroatom within the 'bay region', R-7688.

Animals↗
PubMed1988

Absence of genotoxic activity of refined smoke flavor (RSF) in two bacterial short-term tests.

The genotoxic activities of refined smoke flavor (RSF) produced in Poland and used in food processing were investigated in 2 bacterial short-term tests. Its mutagenic activity was examined in the Salmonella/histidine plate assay and its SOS-inducing capacity in the SOS Chromotest both without and with 'activation' by a rat liver homogenate. No genotoxic activity was detected using these 2 bacterial tests.

Animals↗
PubMed1989

SOS Chromotest study concerning some appreciation criteria of humic substances' genotoxic potency.

The genotoxicity of 5 compounds: 2 fulvic acids, a trade humic acid, a synthetic humic material (SHM), and 2,5-dihydroxybenzoic acid, was assessed after chlorination, by means of the SOS Chromotest for tester strain E. coli PQ 37 without metabolic activation. Chlorination was carried out for humic material concentration of 0.5 mg total organic carbon per liter, and chlorine concentrations in the range of 0.1-2.0 chlorine equivalents per mole of carbon. Among all the considered criteria that can account for potent toxicity: chemical degradation determined by the UV absorption decrease, chlorine consumption, average molecular weight, only the polymerization index (O.D. 665 nm/O.D. 465 nm) can be related to the genotoxicity of humic samples. This latter criterion appears a possible predictor of genotoxic potency, revealed subsequent to the aqueous chlorination of humic materials. Looking at the various genotoxic activities of the tested compounds, SHM can be considered a better model of natural humic materials than the trade humic acid.

Alkaline Phosphatase↗
PubMed1989

Genotoxicity and genotoxic enhancing effect of tetrandrine in Salmonella typhimurium.

Tetrandrine has been used for the treatment of silicosis in China. The potential genotoxic and carcinogenic hazards of this drug were studied using the Salmonella/histidine reversion assay and the SOS/Umu test. The results show that tetrandrine was weakly mutagenic to Salmonella typhimurium TA98 with metabolic activation and did not induce SOS response. However, tetrandrine increased the mutagenic activity of benzo[alpha]pyrene, trinitrofluorenone (TNF), 2-aminoanthracene (2AA), diesel emission particles, airborne particles, and cigarette smoke condensate by more than 100%; the activity of aflatoxin B1 and fried beef was increased by over 75%. It also increased the 2AA and TNF-induced SOS response by more than 300%. These results indicated that tetrandrine was a weak promutagen inducing frameshift mutations and was a potent genotoxic enhancer. The mechanism for the genotoxic enhancement is not known. However, the fact that the increase in mutagenicity was noted only in TA98 and not in TA1538 suggested that the enhancement of genotoxicity by tetrandrine may result from an increase in error-prone DNA repair.

Alkaloids↗
PubMed1990

Mutagenic and genotoxic effects of aqueous extracts of Achyrocline satureoides in prokaryotic organisms.

Aqueous extracts of Achyrocline satureoides (Marcela and/or Macela) were tested for the presence of genotoxic activity in microorganisms. This species belongs to the family Compositae and is used on a large scale by the population of South Brazil. The extracts showed genotoxic activity in the presence of S9 mix in the Ames test TA100, TA98 and TA102 strains, 'SOS' spot chromotest and Microscreen phage-induction assay. The positive results were related to the presence of quercetin and caffeic acid in the aqueous extracts.

Animals↗
PubMed1990

Genotoxic effects of various chlorinated butenoic acids identified in chlorinated drinking water.

The mutagenic activities of the chlorinated butenoic acids recently identified in chlorinated drinking waters were determined by the Salmonella microsome assay and by the SOS chromotest. The Salmonella typhimurium tester strains TA97, TA98 and TA100 were used without and with S9 mix. In the SOS chromotest Escherichia coli PQ37 was used as an indicator organism with and without metabolic activation. In addition, the extremely potent Ames test mutagen (Z)-2-chloro-3-(dichloromethyl)-4-oxobutenoic acid (MX, in the open form), was studied by the micronucleus test with mice using intraperitoneal treatment. The results of the Salmonella assay and the SOS chromotest showed that MX was by far the most potent mutagen of the compounds tested. Mutations were also induced by the reduced form of MX, (Z)-2-chloro-3-(dichloromethyl)-4-hydroxybut-2-enoic acid (red-MX), and by the geometric isomer of MX, (E)-2-chloro-3-(dichloromethyl)-4-oxobutenoic acid (EMX). However, since the solution of EMX contained approximately 5% MX, most of its activity might be attributable to MX. The oxidised form of EMX, (E)-2-chloro-3-(dichloromethyl)-butenedioic acid (ox-EMX), was marginally active in the SOS chromotest only. All these compounds were directly acting mutagens and in the presence of metabolic activation (S9 mix) they did not generate mutagenicity. The oxidised form of MX, (Z)-2-chloro-3-(dichloromethyl)-butenedioic acid (ox-MX), was not mutagenic at the dose levels tested. MX did not induce micronuclei in the bone marrow of mice.

Animals↗
PubMed1991

Quantitative assessment of the genotoxicity of fecapentaenes.

Fecapentaenes are a group of fecal mutagens of microbial origin isolated from human stools. Fecapentaene-12 (F-12) and fecapentaene-14 (F-14), differing only in two carbon atoms in the side chain, are glyceryl ethers with a highly reactive chromophoric aliphatic side chain incorporating a conjugated pentaene moiety. Although these compounds are known for their genotoxicity, no test systems have been developed to precisely assess their relative genotoxicity. In this study F-12 and F-14 were assayed for their genotoxicity using the SOS Chromotest in which the induction of beta-galactosidase in E. coli PQ37 was used as a quantitative measure of biological activity. The activity obtained with F-12 and F-14 was compared with that of 4-nitroquinoline oxide (4-NQO) as the reference standard of a direct acting mutagen. While F-14 was almost as active as 4-NQO, F-12 was only about 25% as active as F-14, the higher analog.

4-Nitroquinoline-1-oxide↗
PubMed1991

A comparison of the relative activities of 8 radiosensitizers in the SOS chromotest.

Misonidazole, and RSU 1069 and 6 of its analogues are all reported to show increased cytotoxicity towards hypoxic cells compared to oxic cells. DNA is considered to be the target through which these drugs exert their cytotoxic activity. Therefore we monitored induction of the SOS response in uvrABC excinuclease proficient and deficient strains of E. coli, under oxic and hypoxic conditions, as an indirect method of assessing the activity of these drugs towards DNA in a biological system. This was done using the SOS chromotest which utilizes E. coli strains which possess a sfiA::lacZ fusion allowing induction of the SOS response to be monitored by assaying beta-galactosidase activity. All of the drugs tested here show some induction of the SOS response in both uvrABC excinuclease proficient and deficient strains. Data shown here suggests that the uvrABC excinuclease is important in the production of a SOS induction signal from RSU 1069-induced DNA lesions and that RSU 1069 may act as a crosslinking agent. The data also shows that SOS induction activity and toxicity do not necessarily correlate and that production of a SOS induction signal may occur via a different pathway for RSU 1069 than for its analogues.

Cell Hypoxia↗
PubMed1992

Assessment of the genotoxic potential of riboflavin and lumiflavin. A. Effect of metabolic enzymes.

The mutagenic potential of riboflavin and its photodegradation product lumiflavin was evaluated using the umu test, SOS chromotest and Ames Salmonella assay. Both riboflavin and lumiflavin by themselves were found to be non-mutagenic. On treatment with rat liver microsomal enzymes (S9) or caecal cell-free extract (CCE), lumiflavin acquired mutagenicity, while the status of riboflavin remained unaffected. Activation of lumiflavin by metabolic enzymes was found to result in an alteration of its spectral characteristics.

Alkaline Phosphatase↗