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PubMed1976

[Individual variation in the frequency of chromosome aberrations under the influence of chemical mutagens. I. Inter-cultural and inter-individual variations in the effect of mutagens on human lymphocytes].

The study of the distribution law of human peripheral blood cultures for the sensitivity to thiophosphamide was performed. In the first experiment the blood from one person was used, in the second one the blood was used from different persons. "The percent of aberrant cells" and "the number of chromosome breaks per 100 cells" were scored. The distribution law of the cultures in all the experiments was found to be normal. Analysis of the variances on the percent of aberrant cells showed that the distribution law of the cultures received from one donor corresponded to the binomial one, and that of the cultures received from different donors--to the Poisson's one.

Alkylating Agents↗
PubMed1977

[Mutagenic process in bacteriophage T4B after long-term exposure to a mutagen].

Bacteriophage T4B was continuously passed on solid media in the presence of 5-bromodeoxyuridine in two simultaneous experiments. The subsitutions of amino acids were registered, and in one of the experiments biological changes were revealed in non-optimal conditions. Calculations has shown that the number of amino acid substitutions observed corresponds to at least 140--200 fixed mutations. The possibility of the mutation fixation via selection is discussed and their relative neutrality is suggested.

Amino Acids↗
PubMed1979

Some factors determining the concentration of liver proteins for optimal mutagenicity of chemicals in the Salmonella/microsome assay.

In plate assays in the presence of S. typhimurium TA100 and various amounts of liver 9000 X g supernatant (S9) from either untreated, phenobarbitone- (PB) or Aroclor-treated rats, the S9 concentration required for optimal mutagenicity of aflatoxin B1 (AFB) depended both on the source of S9 and on the concentration of the test compound. In these assays, the water-soluble procarcinogen, dimethylnitrosamine (DMN) was mutagenic in S. typhimurium TA1530 only in the presence of a 35-fold higher concentration of liver S9 from PB-treated rats than that required for AFB, a lipophilic compound. In liquid assays, a biphasic relationship was observed in the mutagenicities in S. typhimurium TA100 of benzo[a]pyrene (BP) and AFB and the concentration of liver S9. For optimal mutagenesis of BP, the concentration of liver S9 from rats treated with methylcholanthrene (MC) was 4.4% (v/v); for AFB it was 2.2% (v/v) liver S9 from either Aroclor-treated or untreated rats. At higher concentrations of S9 the mutagenicity of BP and of AFB was related inversely to the amount of S9 per assay. The effect of Aroclor treatment on the microsomemediated mutagenicity of AFB was assay-dependent: in the liquid assay, AFB mutagenicity was decreased, whereas in the plate assay it did not change or was increased. As virtually no bacteria-bound microsomes were detected by electron microscopy, after the bacteria had been incubated in a medium containing 1-34% (v/v) MC-treated rat-liver S9, it is concluded that, in mutagenicity assays, mutagenic metabolites generated by microsomal enzymes from certain pro-carcinogens have to diffuse through the assay medium before reaching the bacteria. Thus the mutagenicity of BP was dependent on both the concentration of rat-liver microsomes and that of total cytosolic proteins and other soluble nucleophiles such as glutathione. At a concentration of 4.4% (v/v) liver S9, the mutagenicity of BP was about 3.6 times higher than in assays containing a 4-fold higher concentration of cytosolic fraction. Studies on the glutathione-dependent reduction of BP mutagenicity in plate assays has shown that, in the presence of liver S9 concentrations greater than that required for optimal mutagenicity, the reduction in mutagenicity was related directly to the concentration of liver S9. Thus, in the Salmonella/microsome assay, when the concentration of rat-liver S9 was increased over and above the amount required for the optimal mutagenicity of BP, the mutagenic metabolites of BP were inactivated (by being trapped with cytosolic nucleophiles and/or by enzymic conjugation with glutathione); this effect increased more rapidly than their rate of formation. The concentration of liver S9 for optimal mutagenicity of test compounds requiring activation catalyzed by mono-oxygenases seems, therefore, to be related to the departure from linearity of the relationship between the rate of formation of mutagenic metabolites and the concentration of liver S9.

Aflatoxins↗
PubMed1979

Assay of 855 test chemicals in ten tester strains using a new modification of the Ames test for bacterial mutagens.

Determination of mutagenic activity in bacterial systems has become accepted as an initial step in the evaluation of the carcinogenic potential of new chemicals. In this paper, a bacterial mutagen screening technique is described in which chemicals can be tested in 10 tester strains over a 10,000-fold concentration gradient both with and without metabolic activation. Using this assay, 855 chemicals were tested, and 182 were found to be mutagenic in one or more of the tester strains. Included were 299 chemicals used in chemical manufacturing or laboratory synthesis. Of these, 20% gave a positive response in one or more strains. The high rate of positives undoubtedly reflects the high chemical reactivity of compounds in this group. In contrast, when 261 organic chemicals which were synthesized for evaluation as potential pharmaceutical or agricultural products were tested, only 8% were identified as mutagenic. The Salmonella typhimurium tester strains TA98 and TA1538 proved to be very reliable and efficient in detecting and identifying frame-shift mutagens. TA100 was the most sensitive tester strain, detecting 142 of the 182 mutagens encountered in the study. However, since TA100 detected both base substitution mutagens and frame-shift mutagens, this tester strain was not suitable for the specific identification of base substitution mutagens. Base substitution mutagens were more reliably detected by Escherichia coli tester strains WP2 and WP2 uvrA- than they were by S. typhimurium strains G46 and TA1535. The data obtained when mutagens are tested by the concentration gradient procedures can include (a) the activity spectrum in tester strains, (b) identification as either frame-shift or base substitution mutagens, (c) the minimal concentration at which auxotroph growth is inhibited, and (d) mutagenic potency in terms of minimal concentration at which mutagenicity is observed. The data obtained have been found to be of immediate use. For example, with manufacturing intermediates the data have been combined with other toxicity data and used as a basis for setting safety standards for handling such compounds in the workplace. In addition, positive bacterial mutagenicity data on selected members of new series of organic compounds can serve to alert the chemist early to the possibility that the compounds may possess undesirable toxic properties, particularly carcinogenicity. Also, this type of data should be of great value both in the planning and in the interpretation of other in vitro tests designed to evaluate the potential carcinogenicity in mammals of chemicals found to be positive in bacterial tests.

Amines↗
PubMed1978

Potential of plant genetic systems for monitoring and screening mutagens.

Plants have too long been ignored as useful screening and monitoring systems of environmental mutagens. However, there are about a dozen reliable, some even unique, plant genetic systems that can increase the scope and effectiveness of chemical and physical mutagen screening and monitoring procedures. Some of these should be included in the Tier II tests. Moreover, plants are the only systems now in use as monitors of genetic effects caused by polluted atmosphere and water and by pesticides. There are several major advantages of the plant test systems which relate to their reproductive nature, easy culture and growth habits that should be considered in mutagen screening and monitoring. In addition to these advantages, the major plant test systems exhibit numerous genetic and chromosome changes for determining the effects of mutagens. Some of these have not yet been detected in other nonmammalian and mammalian test systems, but probably occur in the human organism. Plants have played major roles in various aspects of mutagenesis research, primarily in mutagen screening (detection and verification of mutagenic activity), mutagen monitoring, and determining mutagen effects and mechanisms of mutagen action. They have played lesser roles in quantification of mutagenic activity and understanding the nature of induced mutations.Mutagen monitoring with plants, especially in situ on land or in water, will help determine potential genetic hazards of air and water pollutants and protect the genetic purity of crop plants and the purity of the food supply. The Tradescantia stamen-hair system is used in a mobile laboratory for determining the genetic effects of industrial and automobile pollution in a number of sites in the U.S.A. The fern is employed for monitoring genetic effects of water pollution in the Eastern states. The maize pollen system and certain weeds have monitored genetic effects of pesticides. Several other systems that have considerable value and should be developed and more widely used in mutagen monitoring and screening, especially for in situ monitoring, are discussed. Emphasis is placed on pollen systems in which changes in pollen structure, chemistry, and chromosomes can be scored for monitoring; and screening systems which can record low levels of genetic effects as well as provide information on the nature of induced mutations. THE VALUE OF PLANT SYSTEMS FOR MONITORING AND SCREENING MUTAGENS CAN BE IMPROVED BY: greater knowledge of plant cell processes at the molecular and ultrastructural levels; relating these processes to mutagen effects and plant cell responses; improving current systems for increased sensitivity, ease of detecting genetic and chromosome changes, recording of data (including automation), and for extending the range of genetic and chromosome end points; and designing and developing new systems with the aid of previous and current botanical and genetic knowledge.

Biological Assay↗
PubMed1979

Mutagenicity of phenanthrene and phenanthrene K-region derivatives.

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 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 mutagenicty 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, uhen 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 knowledge that a major metabolic route proceeds via these metabolites dose 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.

Drug Evaluation, Preclinical↗
PubMedDate not supplied

Metabolic activation and deactivation of mutagens and carcinogens.

The activity of some mutagens has been investigated in the Salmonella test either in the absence or in the presence of fortified rat liver microsomal fractions, together with an NADPH-generating system. With respect to their metabolic reactivity, the compounds tested could be distinguished according to four reproducible trends: (a) conversion of inert compounds into mutagenic metabolites (e.g. 2-aminofluorene and benzo(a)pyrene); (b) further enhancement of mutagenicity (e.g. 1,2-epoxybutane); (c) no effect on mutagenicity (e.g. glycidol, folpet, nitrofurantoin and 2-nitronaphtalene); (d) slight decrease (e.g. 1,1,1-trichlor 2,3-propenoxide), marked decrease (e.g. sodium nitrite, 5-nitro-2-furoic acid and captan) or even complete reversal of mutagenicity (e.g. styrene oxide, sodium azide, sodium dichromate and other Cr6+ compounds). The Salmonella/microsome test was effective in discriminating not only the mutagenic activity but also the metabolic reactivity of structurally related chemicals (e.g. the fungicides captan and folpet). In some cases, mutagens were tested also in the presence of other biological preparations (e.g. rat muscle or lung microsomal preparations, human gastric juice, serum, plasma or erythrocyte lysates). The mutagenic and metabolic properties of largely used products (e.g. an antibacterial drug containing nitrofurantoin and laboratory reagents containing sodium azide) have been also checked. The mechanisms underlying the metabolic behaviour of some of the mutagens tested have been reported. The results obtained have been correlated with the literature data on their carcinogenicity. Although these in vitro findings are only indicative of the possible metabolic fate of mutagens in the whole organism, the observed effects may be useful in order to explain the epidemiological data and the results of animal tests, and to assess the possible health hazards of mutagens.

Animals↗
PubMed1976

Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes.

A highly purified and reconstituted hepatic microsomal monooxygenase system, completely free of epoxide hydrase and consisting of cytochrome P-448 from 3-methylcholanthrene-treated rats, NADPH-cytochrome c reductase, phosphatidylcholine, and NADPH, metabolizes benzo (a)pyrene to products highly mutagenic in strains TA 98 and TA 1538 of Salmonella typhimurium. The formation of mutagenic metabolites is completely dependent on the presence of benzo (a)pyrene, NADPH, NADPH-cytochrome c reductase, and cytochrome P-448 and is partially dependent on phosphatidylcholine. Mutation frequency in both strains is linearly related to amount of cytochrome P-448 and to time of incubation. Highly purified cytochrome P-450 from phenobarbital-treated rats is relatively poor in catalyzing the formation of mutagenic metabolites from benzo (a)pyrene. Addition of 7.5 to 75 units of highly purified epoxide hydrase to the cytochrome P-448-dependent monooxygenase system decreases the number of mutations by approximately 50% and30% in strains TA 1538 and TA 98, respectively. Additional amounts of epoxide hydrase (300 units) fail to further suppress mutations, indicating that at least some, but probably not all, of the mutagenic metabolites of benzo (a)pyrene are arene oxides. In the absence of a monooxygenase system, mutations induced by benzo (a)pyrene 4,5-oxide are readily quenched by epoxide hydrase, whereas mutations induced by a diol epoxide metabolite of benzo (a)pyrene [(+/-)-7 beta, 8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo (a)pyrene] are not. Several known and potential phenolic and dihydrodiol metabolites of benzo (a)pyrene are metabolized to products mutagenic in the Salmonella. The number of mutations induced per nmol of hemoprotein is approximately 3- to 4-fold higher when trans-7,8-dihydroxy-7,8-dihydrobenzo (a)pyrene replaces benzo (a)pyrene as a substrate for the cytochrome P-448-dependent monooxygenase system. Little or no mutagenic activity is observed with trans-dihydrodiols at positions 4,5, 9,10, or 11,12 of the hydrocarbon, either in the absence or presence of the active monooxygenase system. Of the 12 possible isomeric monophenols of benzo (a)-pyrene, only 6- and 12-hydroxybenzo (a)pyrene are moderately active bacterial mutagens; 1-, 2-, 3-, 6-, 9-, and 12-hydroxybenzo (a)pyrene are premutagens (i.e. metabolized to mutagenic products); and 4-, 5-, 7-, 8-, 10-, and 11-hydroxybenzo (a)pyrene have little or no mutagenic activity with or without further oxidative metabolism. Benzo (a)pyrene 7,8-oxide, a carcinogen on mouse skin, is weakly mutagenic but can be further metabolized to a highly active bacterial mutagen(s), presumably diol epoxide(s), by a combination of epoxide hydrase and the cytochrome P-448 monooxygenase system. This is the first example of a direct role of epoxide hydrase in the metabolic activation of a chemical to a toxic product.

Animals↗