Showing papers in "Mutation Research\/genetic Toxicology in 1979"
TL;DR: Over 70 naturally occurring and synthetic flavonoids were screened for mutagenicity with 5 tester strains in the Salmonella/mammalian microsome assay and 3 flavonol glycosides, namely, quercetrin, rutin and robinin, were found to be nonmutagenic.
Abstract: Over 70 naturally occurring and synthetic flavonoids were screened for mutagenicity with 5 tester strains in the Salmonella/mammalian microsome assay: TA1535, TA100, TA1537, TA1538 and TA98. Frameshift mutagenicity was confined to the flavonols (flavon-3-ols) in strains TA98, TA1537 and TA100. The two most mutagenic flavonols, namely, quercetin (3,3′,4′5,7-pentahydroxyflavone) and kaempferol (3,4′,5,7-tetrahydroxyflavone), exhibiting 12 and 7 revertants/nmol in TA98 respectively, are also the most common flavonols occuring in plants. Other flavonols exhibited less activity (revertants/nmol): galangin (2.0), rhamnetin (0.45), kaempferide (0.24), fisetin (0.14), myricetin (0.12), robinetin (0.06) and morin (0.05). All of these flavonols apparently exhibited significant activation by Aroclor 1254 induced rat-liver microsome preparations (S9). However, subsequent study revealed that only those flavonols either lacking or possessing one B ring hydroxyl group had an absolute requirement for microsomal activation. Alternatively, quercetin with two Bring OH groups is not activated by microsomal enzymes, but by soluble (S100) enzymes from liver which are apparently constitutive and not subject to the usual chemical induction. 3 flavonol glycosides, namely, quercetrin (quercetin-3- O -rhamnoside), rutin (quercetin-3- O -rutinoside) and robinin (kaempferol-3- O -galactosido-rhamnoside-7- O -rhamnoside), were found to be nonmutagenic. They could, however, be activated by a variety of mixed glycosidases incorporated in the usual pour plate procedure. The most effective enzyme mixtures were obtained from rat Cecal bacteria and from the snail Helixpomatia .
236 citations
TL;DR: A metabolic activation system with rat-liver microsome fraction plus cofactors (S9 mix) was applied to chromosomal aberration tests in vitro for the screening of chemical mutagens or carcinogens in the environment.
Abstract: A metabolic activation system with rat-liver microsome fraction plus cofactors (S9 mix) was applied to chromosomal aberration tests in vitro for the screening of chemical mutagens or carcinogens in the environment.
Dialkylnitrosamines only induced chromosomal aberrations in Chinese hamsters cells (CHL) when treated with S9 mix. The incidence of chromosomal aberrations in CHL varied with experimental conditions, e.g. incubation time, recovery time, components of S9 mix and inducers used for preparation of S9, For dimethylnitrosamine (DMN), the maximal incidence was obtained when the cells were incubated with S9 mix for 3 h and harvested 24 h after treatment. Therefore, this system (3 h incubation and 24 h recovery) was routinely applied to further screening of other chemicals with S9 prepared from PCB-pretreated rats. 10 carcinogens (e.g. 7, 12-dimethylbenz [a] anthracene, benzo-[a] pyrene, quinoline, etc.) out of 16 induced aberrations when they were treated with S9 mix, whereas the remaining 6 carcinogens (e.g., 3-methylcholanthrene, 4-o-tolylazo-o-toluidine, etc.) induced few or no aberrations even after activation. Two insecticides, allethrin and diazinon, were strongly positive at relatively low doses only when they were activated with the S9 mix. Medical drugs, such as ethenzamide, methyl p-hydroxybenzoate and nitrofurazone, and a food additive, sodium hypchlorite, were positive on activation. Chemicals used for industry, such as styrene monomer and tris-dichloropropylphosphate, were also positive in our activation system.
181 citations
TL;DR: Black tea, green tea and Japanese roasted tea were also mutagenic to TA100 without S9 mix and one cup of these teas prepared in the ordinary way produced 1.7-3.8 X 10(4) revertants of TA100.
Abstract: Coffee prepared in the usual way for drinking contains a substance(s) that is mutagenic to Salmonella typhimurium TA100 without mammalian microsomal enzymes. One cup of coffee (200 ml) contains mutagen(s) inducing 1.4-4.6 x 10 5 revertants under standard conditions. Instant coffee too is mutagenic to TA100 and one cup of instant coffee prepared from 1g of coffee powder and 200 ml of water induced 5.6-5.8 x 10 4 revertants of TA100. Caffeine-free instant coffee also has similar mutagenicity. Addition of microsomal enzymes abolished the mutagenicity. Black tea, green tea and Japanese roasted tea were also mutagenic to TA100 without S9 mix and one cup of these teas prepared in the ordinary way produced 1.7-3.8 x 10 4 revertants of TA100. Black tea and green tea were also mutagenic to TA98 in the presence of S9 mix after treatment with a glycosidase from Aspergillus niger , hesperidinase. This type of mutagen in one cup of black tea induced 2.4 x 10 5 revertants of TA98.
147 citations
TL;DR: The mutagenic activities of a series of 1,2-dicarbonyl compounds examined in the Salmonella/microsome assay exhibit antiviral and carcinostatic properties and are of particular toxicological interest because they occur in various foods.
Abstract: Our continued interest in naturally occurring mutagens has led us to examine the mutagenic activity of a series of 1,2-dicarbonyl compounds in the Salmonella/microsome assay. Several compounds in this class are of particular toxicological interest because they occur in various foods. Maltol, a product of carbohydrate dehydration, is found in coffee, chicory, soybeans, baked cereals, bread crusts and other products [4,5]. This compound and ethyl maltol, a synthetic homolog of maltol, are also used extensively as flavor-enhancing agents, particularly in carbohydrate-rich foods [10]. Kojic acid was originally isolated from mold-fermented rice. It is a metabolite of many microorganisms including several fungi used in food production [10]. Diacetyl is an aroma component of butter, beer, coffee and other foods [3,12,16,18]. In addition, glyoxal and some related 1,2-dicarbonyl compounds exhibit antiviral and carcinostatic properties [2,19]. We wish to report on the mutagenic activities of these and several other related compounds.
143 citations
TL;DR: The rate of chromosomal aberrations induced by metal compounds increased with an increase in treatment time from 24 to 48 h, indicating a time-dependent increase in the hereditable toxicity of metal compounds.
Abstract: Metal compounds were tested for their ability to induce chromosomal aberrations cultured mammalian cells. Chromosomal aberrations were induced by the application of some Cr, Mn and Ni compounds. Among 6-valent Cr compounds, K 2 Cr 2 O 7 and CrO 3 induced high levels of aberrations, at rates which were similar for Cr-equivalent doses. The perchromate compounds were more efficient in producing chromosomal aberrations than was a chromate compound, K 2 CrO 4 . A 3-valent Cr compound, Cr 2 (SO 4 ) 3 , was less toxic and failed to induce a demonstrable increase in chromosomal aberrations. KMnO 4 induced aberrations, but at a low rate. As to Ni compounds, NiCl 2 and (CH 3 COO) 2 Ni induced few aberrations. Administration of K 2 Ni(CN) 4 induced only gaps. NiS induced a low but definite increase in chromosomal aberrations. The rate of these aberrations increased with an increase in treatment time from 24 to 48 h, indicating a time-dependent increase in the hereditable toxicity of metal compounds. CdCl 2 and HgCl 2 were somewhat toxic, but failed to induce chromosomal aberrations in the present study.
133 citations
TL;DR: The antioxidants vitamin C, vitamin E, selenium and butylated hydroxytoluene (BHT) at 3 logarithmic concentrations markedly reduced mutagenesis in those strains which mutated by frameshift mechanism.
Abstract: Increasing concentrations of malonaldehyde and β-propiolactone were increasingly mutagenic with 7 mutants of Salmonella typhimurium , 5 of which mutated by a frameshift mechanism and 2 of which mutated through base-pair substitution. The antioxidants vitamin C, vitamin E, selenium and butylated hydroxytoluene (BHT) at 3 logarithmic concentrations markedly reduced mutagenesis in those strains which mutated by frameshift mechanism.
117 citations
TL;DR: The mutagenicity and cytotoxicity of cis- and trans-Pt(II) diamminedichloride were examined in Chinese hamster lung cells and compared with effects on DNA measured by alkaline elution and the interstrand crosslink could be the cytotoxic lesion produced by these Pt compounds whereas neither of these DNA lesions are necessarily mutagenic.
Abstract: The mutagenicity and cytotoxicity of cis - and trans -Pt(II) diamminedichloride (PDD) were examined in V79 Chinese hamster lung cells and compared with effects on DNA measured by alkaline elution. DNA—protein crosslinks and DNA interstrand crosslinks were detected following doses of cis -PDD which reduced cell survival 80–90% and which produced a mutant frequency of 3 × 10 −4 at the HGPRT locus. Equitoxic doses of trans -PDD were much less mutagenic than cis -PDD. At equitoxic doses, trans -PDD produced more DNA-protein crosslinking than did cis -PDD, but interstrand crosslinking for the two isomers was comparable. Hence, the interstrand crosslink could be the cytotoxic lesion produced by these Pt compounds whereas neither of these DNA lesions are necessarily mutagenic. The mutagenesis produced by cis -PDD could be due to crosslinks of a different type than those produced by trans -PDD or it may be due to monofunctional damage.
111 citations
107 citations
TL;DR: Over one-third of the benzanthrones tested were frameshift mutagens for Salmonella; the most potent response of 64 revertants/nmol was obtained with 3-p-toluidinobenzanthrone and microsomal activation in strain TA98.
Abstract: Approximately 70 anthraquinones and 20 benzanthrones were assayed for mutagenicity in the Salmonella/microsome test, employing 5 tester strains and Aroclor 1254 induced rat-liver microsomes. About one-third of the anthraquinones were frameshift mutagens, particularly phenolic and nitro anthraquinones. The most potent mutagens detected were of plant origin. Lucidin (1,3-dihydroxy-2-hydroxymethylanthraquinone) and its 2-ethyl ether gave values of 70 and 82 revertants per nmol, respectively, with strain TA100 (and microsomes in the case of the ether). A number of glycosides of mutagenic hydroxyanthraquinones were found to be nonmutagenic in the standard assay procedure, but could be activated by incorporation of cell-free sonic extracts of rat cecal bacteria, e.g., alizarin -2-O-β- d -glycoside , emodin-1 (8)-monoglucoside and lucidin-3-O-primveroside. Over one-third of the benzanthrones tested were frameshift mutagens for Salmonella; the most potent response of 64 revertants/nmol was obtained with 3-p-toluidinobenzanthrone and microsomal activation in strain TA98.
106 citations
TL;DR: In this paper, the mutagenic action of 51 imidazoles was investigated and no direct relationship between antimicrobial action, growth inhibition, and mutagenicity was established.
Abstract: The mutagenic action of 51 imidazoles was investigated. The fluctuation test of Luria and Delbruick was used, with Klebsiella pneurnoniae as test organism. 8 compounds, including 5 with a weak mutagenic action in the fluctuation test, were also investigated by the Ames test in which Salmonella typhimurium TA100 was used.
Of the 51 imidazoles examined, 33 were nitroimidazoles. 31 of the latter appeared to be mutagenic, whereas out of the 18 other imidazoles without a nitro group only 2 were mutagenic. Several of the substances tested for mutagenicity showed an antimicrobial activity. No direct relationship between antimicrobial action, growth inhibition and mutagenicity was established.
With methyl-nitroimidazoles a relationship was found between the chemical structure and mutagenic action. However, when the nitroirnidazoles had a more complex chemical structure, a relationship between this structure and mutagenicity could not be established.
100 citations
TL;DR: The mutagenicities of 7 pyrrolizidine alkaloids to Salmonella typhimurium TA100 were demonstrated by a modified Ames's method by pre-incubation of these alkal steroids with S9 mix and bacteria in a liquid medium.
Abstract: The mutagenicities of 7 pyrrolizidine alkaloids to Salmonella typhimurium TA100 were demonstrated by a modified Ames's method. The pyrrolizidine alkaloids found to be mutagenic were clivorine, fukinotoxin, heliotrine, lasiocarpine, ligularidine, LX201 and senkirkine. Pre-incubation of these alkaloids with S9 mix and bacteria in a liquid medium was essential for demonstration of their mutagenicities.
TL;DR: The frequency of structural chromosomal rearrangements and sister-chromatid exchanges (SCEs) was investigated in short-term phytohemagglutininstimulated lymphocyte cultures by means of bromodeoxyuridine substitution and fluorescence plus Giemsa (FPG) staining technique.
Abstract: The frequency of structural chromosomal rearrangements and sister-chromatid exchanges (SCEs) was investigated in short-term phytohemagglutinin-stimulated lymphocyte cultures by means of bromodeoxyuridine substitution and fluorescence plus Giemsa (FPG) staining technique. Both these parameters were significantly increased in patients treated with comparatively low doses of cyclophosphamide, busulphan and adriamycin. The increased SCE rate was proportional to the number of chromosome breaks, the ratio of SCE to breaks being about 100:1. The increase in the SCE number was maintained for several months after the termination of cytostatic therapy, when the conventional analysis of chromosome breaks yielded normal results. Normal SCE values were obtained in two patients treated with low doses of fluorouracil.
TL;DR: The mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) locus in Chinese hamster V79 cells induced by metal cations were examined by the development of resistance to 8-azaguanine (8AG).
Abstract: The mutations at the hypoxanthine—guanine phosphoribosyl transferase (HGPRTase) locus in Chinese hamster V79 cells induced by metal cations were examined by the development of resistance to 8-azaguanine (8AG). The spontaneous frequency of 8AG resistance was 5.8 per 10 6 cells, and the frequency was enhanced to 2–6 times that of the control by treatment of cells with the chlorides of beryllium and manganese. About 75% of 8AG-resistant colonies were sensitive to amethopterin, and 86% of the resistant colonies showed less than 3% of the HGPRTase activity of the wild-type cells. The mutant frequency in cultures treated with cobalt and nickel chlorides were slightly increased, and mutation induction was only detectable at very low rates of cell survival.
TL;DR: The effects of 4 Ni compounds, nickel chloride, nickel acetate, potassium cyanonickelate, and nickel sulfide were studied in a line of mammary carcinoma cells from the C3H mouse and showed that the syntheses of protein and DNA were more sensitive than RNA.
Abstract: The effects of 4 Ni compounds, nickel chloride, nickel acetate, potassium cyanonickelate, and nickel sulfide were studied in a line of mammary carcinoma cells from the C3H mouse. All 4 were easily taken up by the cells and reacted with protein, RNA, and possibly DNA. Measurements of leucine, uridine, and thymidine uptake during exposure showed that the syntheses of protein and DNA were more sensitive than RNA. Chromosomal aberrations were observed during the recovery period following the end of the treament with Ni. The implications of these results were discussed with respect to the carcinogenicity of the compounds and to the recommended protocols for mutagenicity testing by chromosomal aberrations.
TL;DR: Chinese hamster cells (CHO line) were treated in vitro for 30--39 h with hexavalent chromium compounds (K2Cr2O7 and Na2CrO7), at concentrations ranging from 0.1 to 1.0 microgram of Cr6+ per ml, in medium containing BUdr to study the responsiveness of the cell system to chromosomal damage.
Abstract: Chinese hamster cells (CHO line) were treated in vitro for 30–39 h with hexavalent chromium compounds (K 2 Cr 2 O 7 and Na 2 Cr 2 O 7 ), at concentrations ranging from 0.1 to 1.0 μg of Cr 6+ per ml, in medium containing BUdr. Chromosomal aberrations and sister-chromatid exchanges were scored on BUdr-labelled 2nd division metaphases, collected at the end of treatment and stained with Giemsa. Treatment with mitomycin C (0.009–0.030 μg/ml) was carried out as a control for the responsiveness of the cell system to chromosomal damage. Both chromium compounds induced marked mitotic delays. Chromosomal aberrations were increased about 10-fold by exposure to Cr 6+ (1.0 μg/ml). The principal aberrations observed were single chromatid gaps, breaks and interchanges, whose frequencies increased proportionally to the concentration of chromium. Dicentric chromosomes, isochromatid breaks, chromosome and chromatid rings were also induced. The frequency of sister-chromatid exchanges was hardly doubled 30 h after exposure to Cr 6+ at 0.3 μg/ml, whereas it was trebled 39 h after treatment, in the cells whose division cycle had been slowed down by chromium.
TL;DR: The results of this study reinforce current views regarding the genotoxic properties of chromates and illustrate the value of using mammalian cells in culture for screening chemicals for biological activity.
Abstract: Examples of chromic and chromate salts have been examined for their effects on a cultured Chinese hamster cell line. The responses studied were cytotoxicity, mutagenesis and clastogenesis. Chromate (hexavalent chromium) salts of both high and medium water solubility were active in producing all three classes of response, whereas an insoluble chromate salt and a soluble chromic (trivalent chromium) salt were inactive. In addition to illustrating the value of using mammalian cells in culture for screening chemicals for biological activity, the results of this study reinforce current views regarding the genotoxic properties of chromates.
TL;DR: From the results obtained, it is apparent that catalase exerted a greater effect in reducing the levels of SCEs and toxicity induced by treatment with DMH or ISH, in the presence of Mn 2+, than by each agent alone.
Abstract: Cysteine, cysteamine and glutathione all induce sister-chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells when applied to cell cultures at concentrations between 10 −4 and 10 −2 M. Acute exposure of cells to thiol compound for a period of 2–3 h resulted in a unique dose-response relationship in each instance. This consisted of two peak SCE frequencies, one at either extreme of the concentration range. Each peak corresponded to a 2–3-fold increase over the spontaneous level. A chronic exposure of 24 h, in contrast, resulted in a dose—response relationship consisting of a single peak SCE frequency (representing a 4–5-fold increase over the spontaneous level) at a concentration of approx. 4 × 10 −4 M. The effect of Cu 2+ ions included in the medium at a concentration of 10 −5 M was to increase the toxicity and, at some concentrations, the SCE levels occurring after either acute or chronic exposure to thiols. Hydrazine and its derivatives, dimethylhydrazine and isonicotinic acid hydrazide (isoniazid), as well as hydrogen peroxide, also induce SCEs in CHO cells. A 2–3-fold increase over the spontaneous level was observed, depending upon the particular treatment protocol applied. SCE yields after 3 h treatment with dimethylhydrazine and isoniazid were increased if Mn 2+ , but not Cu 2+ , was included in the tissue culture medium at a concentration of 10 −5 M. SCE yields after a 24-h treatment with dimethylhydrazine in which Mn 2+ was present in, and absent from, the medium were similar. Catalase was observed to out. From the results obtained, it is apparent that catalase exerted a greater effect in reducing the levels of SCEs and toxicity induced by treatment with DMH or ISH, in the presence of Mn 2+ , than by each agent alone. As anticipated, the ability of H 2 O 2 to induce SCEs was inhibited by catalase.
TL;DR: Pure crystalline nonmutagenic cholestrol free from autoxidation products becomes mutagenic towards Salmonella typhimurium strains upon heating at 70 degrees in air or following exposure to 60 Co gamma-radiation.
Abstract: Naturally air-aged commercial samples of USP or reagent-grade cholesterol contain components which are mutagenic towards Salmonella typhimurium strains TA1537, TA1538 and TA98 These mutagenic components are associated with the polar cholesterol autoxidation products, but identity of the mutagenic components has not been achieved Pure crystalline nonmutagenic cholestrol free from autoxidation products becomes mutagenic towards these strains upon heating at 70 degrees in air or following exposure to 60 Co gamma-radiation
TL;DR: In this paper, Diethylstilbestrol was tested for mutagenicity with his − S. typhimurium strains under 10 different metabolic situations (no exogenous metabolizing system; S 9 mix from liver homogenate of rats induced with Aroclor 1254, with or without inhibition of epoxide hydratase; liver and/or kidney S9 mix from control or hamsters treated with A roclor1254; horse-radish peroxidase + H 2 O 2 ).
Abstract: Diethylstilbestrol was tested for mutagenicity with his − S. typhimurium strains under 10 different metabolic situations (no exogenous metabolizing system; S9 mix from liver homogenate of rats induced with Aroclor 1254, with or without inhibition of epoxide hydratase; liver and/or kidney S9 mix from control or hamsters treated with Aroclor 1254; horse-radish peroxidase + H 2 O 2 ). Under none of these conditions did diethylstilbestrol give any indication of a mutagenic effect. Furthermore, 11 metabolites and other derivatives of diethylstilbestrol, 2 of them potent inducers of sister-chromatid exchange in cultured fibroblasts, were not mutagenic with any of the 4 tester strains ( S. typhimurium TA100, TA98, TA1537, TA1535) in the presence or absence of S9 mix from liver homogenate of rats induced with Aroclor 1254. Thus, One of the few known human carcinogens is very resistant to detection by the mammalian enzyme-mediated Salmonella typhimurium mutagenicity test (Ames test). This is especially remarkable since the metabolizing systems used included: (1) some of very high metabolic activity (S9 mix from liver homogenate of rats and hamsters induced with Aroclor 1254); (2) metabolizing systems from organs susceptible to the carcinogenic activity of diethylstilbestrol (hamster kidney); as well as (3) a mixture of (1) and (2) in case both activities are required for the carinogenic effect in the whole animal.
TL;DR: The mutagenicities of selenate and selenite were determined by two bacterial assay systems: Kada's rec-assay and Ames's Salmonella test, and in both assays these compounds were found to be weak mutagens.
Abstract: The mutagenicities of selenate (SeO 4 2− ) and selenite (SeO 3 2− ) were determined by two bacterial assay systems: Kada's rec -assay and Ames's Salmonella test. In both assays, these compounds were found to be weak mutagens. In the Salmonella test, selenate (0.05 revertants/nmole) and selenite (0.2 revertants/nmole) gave rise to base-pair substitution.
TL;DR: 3-CPs is the most effective inducer on the cytoplasmic "petite" mutation in stationary phase cells per unit irradiation dose or per viable cell, suggesting a certain specificity of genetic alterations produced by the bi-functional agents.
Abstract: The genetic effects of two mono-functional photosensitizing furocoumarins, 3-carbethoxypsoralen (3-CPs) and angelicin, were compared with those of two bi-functional furocoumarins, 8-methoxypsoralen and psoralen in Saccharomyces cerevisiae A drug concentration of 5 × 10−5 M plus various doses of 365-nm irradiation at a dose rate of 12 kJ m−2 min−1 were used Per dose of 365-nm irradiation, the frequency of induced nuclear events such as gene mutation and mitotic recombination (conversion and crossing-over) is higher for the bi-functional than for the mono-functional compounds The higher efficiency of the bi-functional furocoumarins is also evident when the frequency of mutants is expressed as a function of survival However, the photoaddition of the 4 furocoumarins studied leads to the same response for the induction of recombinational events per viable cell Amongst genetically altered colonies induced in the diploid strains D5 and D7, the colonies corresponding to the induction of crossing-over are effectively produced by bi-functional furocoumarins, but are rare (D7) or even absent (D5) after treatment with monofunctional furocoumarins This suggests a certain specificity of genetic alterations produced by the bi-functional agents 3-CPs is the most effective inducer on the cytoplasmic “petite” mutation in stationary phase cells per unit irradiation dose or per viable cell
TL;DR: Chromosome analysis of metaphase-II oocytes seems to be a useful method for the screening of mutagenicity of environmental contaminants in mammalian germ cells in vivo.
Abstract: When female golden hamsters were treated with cadmium chloride at the oogenesis stages of diakinesis/metaphase I to metaphase II, oocytes with the chromosomal complements of hyperhaploidy and diploidy, as well as oocytes at the anaphase-I stage, were observed Oocytes of this species were especially sensitive to cadmium Chromosome analysis of metaphase-II oocytes seems to be a useful method for the screening of mutagenicity of environmental contaminants in mammalian germ cells in vivo
TL;DR: Phenanthrene and 9 K-region derivatives, most of them potential metabolites of phenanthrene, were tested for mutagenicity by the reversion of histidine-dependent Salmonella typhimurium TA1535, TA1537, TA 1538, TA98 and TA100 and the rec assay with Bacillus subtilis H17 and M45 as discussed by the authors.
Abstract: Phenanthrene and 9 K-region derivatives, most of them potential metabolites of phenanthrene, were tested for mutagenicity by the reversion of histidine-dependent Salmonella typhimurium TA1535, TA1537, TA1538, TA98 and TA100 and the rec assay with Bacillus subtilis H17 and M45. The strongest mutagenic effects in the reversion assay were observed with phenanthrene 9,10-oxide, 9-hydroxyphenanthrene and N-benzyl-phenanthrene-9,10-imine. Interestingly, the mutagenic potency of the arene imine was similar to that of the corresponding arene oxide. This is the first report on the mutagenicity of an arene imine. The mutagenic effects of all these phenanthrene derivatives were much weaker than that of the positive control benzo[a]pyrene 4,5-oxide. Even weaker mutagenicity was found with cis-9,10-dihydroxy-9,10-dihydrophenanthrene and with trans-9,10-dihydroxy-9,10-dihydrophenanthrene. The other derivatives were inactive in this test. However, 9,10-dihydroxyphenanthrene and 9,10-phenanthrenequinone were more toxic to the rec− B. subtilis M45 strain than to the rec+ H17 strain. This was also true for phenanthrene 9,10-oxide and 9-hydroxyphenanthrene, but not with the other test compounds that reverted (9,10-dihydroxy-9,10-dihydrophenanthrenes; N-benzyl-phenanthrene 9,10-imine; benzo[a]pyrene 4,5-oxide) or did not revert (phenanthrene, 9,10-bis-(p-chlorophenyl)-phenanthrene 9,10-oxide, 9,10-diacetoxyphenanthrene) the Salmonella tester strains. Although the K region is a main site of metabolism and although all potential K-region metabolites were mutagenic, phenanthrene did not show a mutagenic effect in the presence of mouse-liver microsomes and an NADPH-generating system under standard conditions. However, when epoxide hydratase was inhibited, phenanthrene was activated to a mutagen that reverted his− S. typhimurium. This shows that demonstration of the mutagenic activity of metabolites together with the knowlegde that a major metabolic route proceeds via these metabolites does not automatically imply a mutagenic hazard of the mother compound, because the metabolites in question may not accumulate in sufficient quantities and therefore the presence and relative activities of enzymes that control the mutagenically active metabolites are crucial. N-Benzyl-phenanthrene 9,10-imine was mutagenic for the episome-containing S. typhimurium TA98 and TA100 but not for the precursor strains TA1538 and TA1535. This arene imine would therefore be useful as a positive control during routine testing to monitor in the former strains the presence of the episome which is rather easily lost.
TL;DR: There was no evidence of increased frequency of chromosomal aberration in bone marrow or testis cells of mice with either 50 ppm fluoride intake over several generations or 100 ppm intake for 6 weeks compared to animals drinking distilled water.
Abstract: We have examined the possible effect of fluoride intake on chromosome damage There was no evidence of increased frequency of chromosomal aberration in bone marrow or testis cells of mice with either 50 ppm fluoride intake over several generations or 100 ppm intake for 6 weeks compared to animals drinking distilled water Fluoride was not found to be mutagenic in a widely used bacterial mutagenesis assay over a range of 01 to as high as 2000 μg fluoride per plate
TL;DR: Strain of mouse, type of tissue and test substance are important variables in assessing the potential effect of microsomal enzyme-inducing agents on the metabolism of mutagenic substances.
Abstract: Homogenates of liver, lung, kidney, stomach, small intestine and colon from 8 strains of mice were compared for their ability to metabolize benzo[ a ] rmpyrene (BP) and dimethylnitrosamine (DMN) to mutagens. Females of strains CF1, AKR/J, AU/SsJ, DBA/2J, SWR/J, A/J, C3H/HeJ, and C57BL/6J were either untreated or received phenobarbital (PB), 3-methylcholanthrene (MC) or polychlorinated biphenyls (AR) to induce drug-metabolizing enzymes. The effects of these drugs on organ weight and on the amounts of DNA, S-10 protein, and microsomal protein per unit weight of tissue are reported. Salmonella typhimurium TA92 and TA98 were used as indicators of the formation of mutagens. For each organ there was an optimal balance between amount of tissue homogenate and concentration of test compound for maximal yield of revertants. A sensitive radiometric assay of DMN demethylase (DMND) is described which permits measurement of the enzyme in liver, lung and kidney. DMN at 1 mM is used as substrate. Aryl hydrocarbon hydroxylase (AHH) was measured in all tissue using BP as substrate. AR and MC are very good inducers of AHH activity in livers of mice classified as aromatic hydrocarbon responsive, but not in those classified as hydrocarbon nonresponsive. Responsiveness is strain-specific and genetically regulated. Metabolism of BP to mutagens by liver homogenates was correlated with extent of AHH induction. This dimorphism of response of AHH to inducers was present, but less pronounced, in non-hepatic tissues. Basal activities of AHH and DMND were correlated in livers and lungs from untreated mice. DMND activities were increased less than 2-fold by PB, MC or AR treatments. Metabolism of DMN to mutagens was not closely correlated with DMND activities. Strain of mouse, type of tissue and test substance are important variables in assessing the potential effect of microsomal enzyme-inducing agents on the metabolism of mutagenic substances.
TL;DR: The ability of propylene oxide to induce gene mutations and primary DNA damage in bacteria and chromosomal damage in mammalian cells is investigated, with contrasting findings in vitro and in vivo.
Abstract: Propylene oxide is used extensively in the chemical and food manufacturing industries, but relatively little is known of its ability to interact with genetic material. Studies were undertaken to investigate its ability to induce gene mutations and primary DNA damage in bacteria and chromosomal damage in mammalian cells. The induction of base-substitution mutations was demonstrated in spot tests with strains of Salmonella typhimurium and Escherichia coli at 700 μg/plate of propylene oxide; inclusion of a preparation of rat-liver microsomes and cofactors (S9 mix) was without significant effect on this response. A linear dose—response relationship was recorded in plate tests with S. typhimurium strains TA100 and TA1535 over the range 100–750 μg/plate. After addition to dividing lymphocytes in cultures established from human peripheral blood, propylene oxide caused dose-related chromosomal damage, detected at 1.85 and 9.25 μg/ml. Oral administration of propylene oxide at 2 X 100, 2 X 250 or 2 X 500 mg/kg to male mice produced no detectable increases in the incidence of micronucleated, polychromatic erythrocytes in bone marrow. A male mouse dominant lethal test employing oral doses of 50 or 250 mg/kg/day for 14 days gave no evidence of mutagenic action on sperm. Intraperitoneal injections of propylene oxide at 2 X 300 mg/kg induced increased numbers of micronucleated erythrocytes in mice, but lower doses given by this route had no such effect. Possible reasons for the contrasting findings in vitro and in vivo are discussed.
TL;DR: The findings suggest that not all classes of clatogenic chemicals which induce SCEs in proliferative cells substituted with BUdR are capable of inducing long-lived lesions in the DNA of Go lymphocytes that can lead to SCE formation.
Abstract: Human lymphocytes were treated prior to mitogenic stimulation with varying concentrations of 6 cytostatic drugs representing 4 classes of DNA-damaging chemicals Afterwards the cells were washed to remove residual chemical and cultured in the presence of bromodeoxyuridine for analysis of sister-chromatid exchanges (SCEs) A dose-related increase in SCEs was observed in cells exposed during G 0 to the alkylating chemicals mitomycin C, chlorambucil, and thiotepa, while significant increases in SCEs were not noted in cultures exposed to methotrexate, cytarabine, or bleomycin These findings suggest that not all classes of clastogenic chemicals which induce SCEs in proliferative cells substituted with BUdR are capable of inducing long-lived lesions in the DNA of G 0 lymphocytes that can lead to SCE formation
TL;DR: Oral contraceptive users showed significantly higher mean SCE per cell compared with both normal and pregnant women, which obviously means an increased mutagenic environment in these cells--due either to the pill itself or to a metabolite(s).
Abstract: The effect of the use of an oral contraceptive on the frequency of sister-chromatid exchanges (SCEs) was investigated. Oral contraceptive users showed significantly higher mean SCE per cell compared with both normal and pregnant women. This result obviously means an increased mutagenic environment in these cells — due either to the pill itself or to a metabolite(s).
TL;DR: The metabolic activation pathway via haloalkanols to mutagens must not be in common with all tris-BP-like phosphates, as such relations did not necessarily apply to the halogenated alkanols.
Abstract: 9 halogenated alkanols, 9 corresponding tris (haloalkyl)phosphates, and 2 bis-(2,3-dibromopropyl)phosphate salts were evaluated for mutagenicity against Salmonella typhimurium TA98, TA100, TA1535, TA1537 and TA1538, with and without rat liver in vitro metabolic activation system (S9 mix). Most of the test samples showed mutagenic activity in the strains TA100 and TA1535, but not in the strains TA98, TA1537 and TA1538. In general, the mutagenic activities of the phosphates obtained with S9 mix were greater than the activities obtained without S9 mix. Among the phosphates, several structure--activity relationships were found; i.e., (i) the bromoalkyl derivatives were more mutagenic than the corresponding chloroalkyl derivatives, (ii) the beta-haloethyl derivatives were more mutagenic than the gamma-halopropyl derivatives, (iii) the phosphates having adjacent beta and gamma halogen atoms in the alkyl moiety, e.g., tris-(2,3-dibromopropyl)phosphate, were particularly potent mutagens, (iv) the branched carbon chain reduced the mutagenic activities in spite of the presence of beta-halogen atoms, e.g., tris(1-bromomethyl-2-bromoethyl)phosphate. However, such relations did not necessarily apply to the halogenated alkanols. It is concluded that the metabolic activation pathway via haloalkanols to mutagens must not be in common with all tris-BP-like phosphates.