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Biomedical subjects

U Rannug

Publications and source records attributed to U Rannug.

52 records · Page 3Linked to original sources
PubMed1981

The metabolism of drugs and carcinogens in isolated subcellular fractions of Drosophila melanogaster. I. Activation of vinyl chloride, 2-aminoanthracene and benzo[a]pyrene as measured by mutagenic effects in Salmonella typhimurium.

The capacity of microsomal fractions from different Drosophila strains to activate three premutagens, 2-aminoanthracene (2-AA), vinyl chloride (VCM) and benzo[a]pyrene (BP) was investigated, using Salmonella typhimurium as the indicator organism. A significant increase in the mutation response in the Salmonella test system was obtained with all three substances in the presence of a metabolizing system (S9) from Drosophila larvae. 2-AA was converted to highly mutagenic metabolite(s) by the Drosophila S9 and the mutagenic effect was further increased after pretreatment with Aroclor 1254 (PCB) or beta-naphthoflavone (BNF). BP had only marginal mutagenic effects, causing less than a 2-fold increase in the number of mutants over the control. The data indicate that the metabolic conversion of BP is different in the Drosophila as compared to the rat liver microsomal fraction. In accordance with mutagenic data on Drosophila in vivo, vinyl chloride was a fairly weak mutagen in this Drosophila/Salmonella in vitro system.

Animals↗
PubMed1981

Mutagenic effects of effluents from chlorine bleaching of pulp.

Effluents from the bleaching of kraft pulp were tested for mutagenicity. Samples from different mills in which softwood kraft pulp is bleached in a conventional sequence of stages were spot-tested with the Escherichia coli pol A-/pol A+ system. All samples were nontoxic and therefore no difference could be noted between the repair-proficient and the repair-deficient strain. Also no toxic mutagenic effects were seen in spot tests with Salmonella. In a quantitative test with Salmonella, using the plate incorporation assay, effluents from the chlorination (C) stage induced point mutations of the base-substitution type. No frameshift mutations were noted. In the presence of a metabolizing system the direct mutagenic effect was reduced. This reduction was essentially NADPH-independent. Tests on effluents concentrated by freeze-drying indicated, in addition to the base-substitution effect of the C-stage effluent, the presence of frameshift mutagen(s) in this effluent and a base-substitution effect of the hypochlorite stage effluent. Fractionation of the C-stage effluent showed that the mutagenic components are of low molecular weight, extractable with diethyl ether, and sensitive to alkali treatment. Most of the mutagenicity is found in the neutral ether fraction. Induction of 6-thioguanine-resistant mutants in Chinese hamster V79 cells confirmed the mutagenic properties of the C-stage effluent.

Animals↗
PubMed1980

Measurement of drug-metabolizing systems in Salmonella typhimurium strains G46, TA15135, TA100, TA1538 and TA98.

Salmonella typhimurium strains which are commonly used in the Ames test for screening potential carcinogens were examined for a number of drug-metabolizing systems. Neither cytochrome P-450 itself nor two activities catalyzed by the cytochrome P-450 system in mammalian cells, i.e., benzpyrene monooxygenase and ethoxycoumarin O-deethylation, could be detected. Nor do these bacterial strains demonstrate any ability to detoxify epoxides by hydrating them or to conjugate p-nitrophenol with glucuronic acid. On the other hand, S. tryphimurium strains G46, TA1535, TA100, TA1538 and TA98 contain considerable amounts of acid-soluble thiols, approx. 5--10% of which is glutathione. These bacteria can also enzymatically conjugate glutathione with 1-chloro-2,4-dinitrobenzene (CDNB) and can reduce oxidized glutathione using NADPH as cofactor. Thus, enzymatic and non-enzymatic reaction of immediate carcinogens with thiol groups in s. typhimurium may have a significant effect on the outcome of the Ames test in certain cases.

Bacterial Proteins↗
PubMed1979

The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. II. Activation by the isolated perfused rat liver.

In this investigation Salmonella typhimurium strain TA 1530 and TA 1535 were combined with isolated perfused rat liver. Samples of perfusate and bile produced were tested for mutagenicity after treatment with 1,2-dichloroethane (DCE), 1,2-dibromoethane (DBE) or 2-chloroethanol. The results are in good agreement with our previous experiments which indicate that both DEC and DBE are activated through conjugation with glutathione (GSH). Most GSH conjugates are normally excreted in bile. Following liver perfusion the bile was highly mutagenic after DCE and DBE treatments, while 2-chloroethanol did not have this effect. The highest mutagenic effect was seen 15--30 min after the addition of DCE or DBE. The production of mutagenic bile also occurred in mice treated in vivo with DCE. One possible metabolic endproduct of a GSH conjugate is the corresponding mercapturic acid. Thus synthetic N-acetyl-S-(2-chloroethyl)-L-cysteine was tested on TA 1535 and found to be as mutagenic as S-(2-chloroethyl)-L-cysteine in the concentration range 0.2--0.6 mumol/plate. Differences and similarities in the metabolism of DCE and vinyl chloride are discussed on the basis of these results.

Animals↗
PubMed1979

Mutagenicity and metabolism studies on 12 thiuram and dithiocarbamate compounds used as accelerators in the Swedish rubber industry.

12 thiuram and dithiocarbamate compounds used in the rubber industry as accelerators, and to some extent as sources of sulfur, were tested, as well as carbon disulfide, a metabolite found in vivo after dithiocarbamate treatment, for mutagenicity in Salmonella typhimurium. A mutagenic effect on the base-substitution-sensitive strains TA1535 and TA100 was found for 7 compounds. The most potent directly acting mutagens were: tetramethylthiuram disulfide (TMTD), zinc dimethyldithiocarbamate (ziram), cadmium diethyldithiocarbamate and zinc diethyldithiocarbamate. Tetraethylthiuram disulfide (TETD), also known as Antabus, and carbon disulfide were non-mutagenic. The relatively low direct mutagenic effect of tetramethylthiuram monosulfide (TMTM) was enhanced in the presence of a metabolizing system (S9 mix). A hypothesis is given regarding the activation process of the monosulfide TMTM.

Animals↗
PubMed1978

The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium I. Activation through conjugation with glutathion in vitro.

One of the main components in the waste products from vinyl chloride industries (EDC-tar), is ethylene dichloride (1,2-dichloroethane). This compound has been tested for mutagenicity on Salmonella typhimurium TA 1535. It is concluded that 1,2-dichloroethane gives a weak direct mutagenic effect, which is enhanced by addition of the postmitochondrial liver fraction (S-9). This activation is NADPH-independent and non microsomal. It is caused by a factor in the soluble fraction (115 000 g supernatant). This activation was further enhanced by the addition of glutathione but not by the addition of L-cysteine, N-acetyl-L-cysteine or 2-mercaptoethanol. No activation was observed when glutathione was added in the presence of a totally denaturated S-9 fraction or in the absence of this fraction. Activation of 1,2-dichloroethane was also found in the presence of glutathione and glutathione S-transferase A and C but not with glutathione S-tranferase B. A synthetic conjugate S-(2-chloroethyl)-L-cysteine gave a strong direct mutagenic effect at concentrations where no effects were seen with 1,2-dichloroethane. It is thus concluded that 1,2-dichloroethane is activated by conjugation to glutathione. Another main component in EDC-tar, 1,1,2-trichloroethane, was not mutagenic under any of our experimental conditions. For comparison 1,2-dibromoethane was also tested and gave a stronger direct mutagenic effect than 1,2-dichloroethane. Like the latter 1,2-dibromoethane was also activated by a NADPH-independent process.

Animals↗
PubMed1977

Mutagenicity of waste products from vinyl chloride industries.

The by-product from vinyl chloride production, EDC-tar, is a complex mixture of mainly short-chained chlorinated aliphatic hydrocarbons. This mixture has been tested for mutagenicity by means of Ames' Salmonella/mammalian microsome method. Since most of the components in the tar are poorly soluble in water, three agents were used as solvents or emulsifier: ethanol, DMSO, and Tween 80. The results with all these agents showed that EDC-tar contains direct as well as indirect mutagenic constitutents. It could be concluded that the mutagenic effect observed in the test could not be due to any significant extent to one of the main components, ethylene dichloride (1,2-dichloroethane). This substance showed a weak mutagenic effect, but only at higher concentrations than could be available in the highest concentration tested of the tar. Although the microsomal system enhanced the mutagenicity both of the EDC-tar and of 1,2-dichloroethane, this enhancement was dependent on NADPH in the case of EDC-tar but independent of NADPH with 1,2-dichloroethane. The Salmonella/mammalian microsome method seems to be a suitable tool for both mutagenicity screening of complex chemical mixtures and identification of mutagenic constituents in such mixtures.

Animals↗
PubMed1977

Mutagenicity of fume particles from stainless steel welding.

Welding fume particles collected from different welding procedures were tested for mutagenicity in Escherichia coli, with the inhibition zone in pol A- as compared to pol A+, and in Salmonella typhimurium, TA 100 strain. While no mutagenicity was found with mild steel welding, a mutagenic effect was established with samples from stainless steel welding. This mutagenicity was particularly associated with manual metal arc (MMA) welding, and less so with metal inert-gas welding. A decrease in or an elimination of the effect occurred with a liver microsomal metabolizing system (S-9 mix). The MMA samples produced the strongest mutagenic effect. More-detailed investigations on these samples showed that the mutagenic agent(s) is water soluble. An increased mutagenicity, which also revealed the induction of frame shift mutations, was found with TA 98. The same welding fume sample was used for a mutagenicity test (resistance to 6-thioguanine) with V 79 hamster cells. Because of the high toxicity of these welding fume particles on the cells, only very low concentrations could be tested, but the increase of mutations, when compared to the negative control, was significant. It is suggested that hexavalent chromium may be involved in the mutagenic effect of the welding fumes.

Air Pollutants↗
PubMed1976

The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride.

Previous investigations have shown that the carcinogen vinyl chloride causes base-pair substitution in the bacterium Salmonella typhimurium. The ability of four conceivable metabolites-chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid-to cause base-pair substitution directly in Salmonella typhimurium TA1535 has been compared. The main comparison was performed at initial concentrations from 0.1 to 1.5 mM. In this region, however, a mutagenic effect was observed only with chloroethylene oxide and chloroacetaldehyde, the former being approximately 20 times more effective than the aldehyde when compared on a molar basis.2-Chloroethanol and chloroacetic acid were studied also at higher concentration (1 mM-1 M), and a weak mutagenic response was found with 1 M 2-chloroethanol solution. With chloroacetic acid no enhancement of the mutation frequency could be detected. Chloroethylene oxide was found to be approximately 450 times more effective as a mutagen than chloroacetaldehyde when the comparison is based on exposure doses, defined as the time-dependent concentrations of the compounds in the treatment solutions, integrated between the times of onset and termination of treatment. Similarly, chloroethylene oxide was 10,000-15,000 times more effective as a mutagen than ethylene oxide, used as a positive control.

Acetaldehyde↗
PubMedDate not supplied

Genotoxic effects of ethylene oxide and propylene oxide: a comparative study.

The two alkylating agents ethylene oxide (EO) and propylene oxide (PO) were compared for genotoxic effectiveness in various test systems. The study was undertaken partly to shed light on the difference between the compounds found after chronic exposure of monkeys (Lynch et al., 1984) where EO but not PO was able to induce SCE and chromosomal aberrations. In the present study EO was found to be 5-10 times more effective than PO with respect to gene conversion and reverse mutation in Saccharomyces cerevisiae D7 and sister-chromatid conversion in S. cerevisiae RS112. In contrast, the abilities of the two compounds to induce point mutation in S. typhimurium strains and SCE in human lymphocytes were approximately equal. One possible cause of EO being more effective than PO in certain respects, discussed on the basis of inference from earlier studies, is an expected difference in ability to cause strand breaks via alkylation of DNA-phosphate groups.

Cell Survival↗
PubMedDate not supplied

The mutagenicity on Salmonella typhimurium of nitrobenzoic acids and other wastewater components generated in the production of nitrobenzoic acids and nitrotoluenes.

The wastewater contained mutagens which induced mutations in Salmonella typhimurium TA1535, TA1538, TA98 and TA100. By the use of nitroreductase-proficient and -deficient tester strains, it was possible to demonstrate that the mutagens were to a great extent aromatic nitro compounds. 30-40% of the mutagenicity could be related to the 16 identified nitroaromatic compounds. Although 13 of these induced mutations, one single compound, 3,5-dinitrobenzoic acid, was responsible for more than 80% of their total mutagenicity. p-Nitrobenzoic acid was used for further studies of the enzymatic nitroreduction leading to the formation of reactive intermediates. The bacterial enzymes and the active metabolites did not seem to be oxygen-sensitive, as the mutagenicity was decreased when anaerobic incubation was applied. The addition of dicoumarol resulted in a decreased effect, indicating that bacterial DT diaphorase or an enzyme with similar properties is responsible at least in part for the activation of this compound. Under our experimental conditions rat-liver enzymes were not able to produce any detectable amounts of mutagenic metabolites of p-nitrobenzoic acid when the nitroreductase-deficient strain TA100NR was used.

Animals↗
PubMedDate not supplied

Protection from toxic and mutagenic effects of H2O2 by catalase induction in Salmonella typhimurium.

Demple and Halbrook (1983) have reported that pretreatment of E. coli with H2O2 induces protection against the toxic effects of subsequent treatment with H2O2, which cannot be attributable to catalase induction, but rather to inducible repair of oxidative DNA damage. Here we report that pretreatment of Salmonella typhimurium with small doses of H2O2 also renders them resistant to subsequent higher doses of H2O2. However, this induced protection against H2O2, both concerning survival and mutations, is proportional to the amount of induced catalase activity of the bacteria, which accelerates the breakdown of H2O2 in the medium, thus lowering the effective dose.

Catalase↗
PubMedDate not supplied

Influence of physical and chemical characteristics of diesel fuels and exhaust emissions on biological effects of particle extracts: a multivariate statistical analysis of ten diesel fuels.

The emission of diesel exhaust particulates is associated with potentially severe biological effects, e.g., cancer. The aim of the present study was to apply multivariate statistical methods to identify factors that affect the biological potency of these exhausts. Ten diesel fuels were analyzed regarding physical and chemical characteristics. Particulate exhaust emissions were sampled after combustion of these fuels on two makes of heavy duty diesel engines. Particle extracts were chemically analyzed and tested for mutagenicity in the Ames test. Also, the potency of the extracts to competitively inhibit the binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor was assessed. Relationships between fuel characteristics and biological effects of the extracts were studied, using partial least squares regression (PLS). The most influential chemical fuel parameters included the contents of sulfur, certain polycyclic aromatic compounds (PAC), and naphthenes. Density and flash point were positively correlated with genotoxic potency. Cetane number and upper distillation curve points were negatively correlated with both mutagenicity and Ah receptor affinity. Between 61% and 70% of the biological response data could be explained by the measured chemical and physical factors of the fuels. By PLS modeling of extract data versus the biological response data, 66% of the genotoxicity could be explained, by 41% of the chemical variation. The most important variables, associated with both mutagenicity and Ah receptor affinity, included 1-nitropyrene, particle bound nitrate, indeno[1,2,3-cd]pyrene, and emitted mass of particles. S9-requiring mutagenicity was highly correlated with certain PAC, whereas S9-independent mutagenicity was better correlated with nitrates and 1-nitropyrene. The emission of sulfates also showed a correlation both with the emission of particles and with the biological effects. The results indicate that fuels with biologically less hazardous potentials should have high cetane number and contain less PAC and sulfur. The results also indicate that engine factors affect the formation and emission of nitrated PAC.

Automobiles↗
PubMedDate not supplied

Short-term mutagenicity tests.

The universality of the genetic system in living organisms and the high experimental correlation between mutagenicity and carcinogenicity provide the rational basis for the use of mutagenicity in screening of possible carcinogens. The present genetic methodologies using microorganisms, cell cultures, Drosophila, and rodents are evaluated. No mutagenicity test can cover all aspects of tumor formation in the whole animal or human body, because each species and tissue has its own capacity for repair as well as balance of activation and deactivation mechanisms. The strategy of testing must vary, depending on the nature and use of the chemicals.

Animals↗