Assessment of the relationship between the antimutagenic action of riboflavin and glutathione and the levels of antioxidant enzymes

In this study the role of antioxidant enzymes on the antimutagenic actions of riboflavin and reduced glutathione against mutagenic potentials of 4-nitroquinoline 1-oxide and mitomycin C have been investigated. For this purpose the activities of catalase and superoxide dismutase enzymes have been determined in Salmonella typhimurium TA102 and TA100 strains preincubated with different combinations of 4-nitroquinoline 1-oxide, mitomycin C, riboflavin and reduced glutathione for thirty minutes. Also in part of the same samples, the mutagenicity has been determined for each combination of chemicals by using Salmonella preincubation test. The correlation between the levels of antioxidant enzymes and mutagenicity and antimutagenicity has been investigated.While riboflavin displayed a weakly antimutagenic effect on 4-nitroquinoline 1-oxide mutagenicity in TA102 and TA100 (0.25, 0.35 inhibition respectively), it did not have any effect on the strong mutagenicity of mitomycin C in both strains. Reduced glutathione, a well known antioxidant, had no antimutagenic effect against the mutagenicity of both compounds in TA102 and TA100 strains. The antioxidant enzymes, catalase and superoxide dismutase, seemed to have no direct effect on the antimutagenic action of riboflavin and mutagenic action of 4-nitroquinoline 1-oxide and mitomycin C because no change in the activities of catalase and superoxide dismutase was detected in relation to antimutagenicity of riboflavin and mutagenicity of 4-nitroquinoline 1-oxide and mitomycin C in both strains. It should be noted that many antimutagens have more than one mechanism of action and their effect depends on the mutagens being tested.     

Antimutagenic effect of heteroxylans,arabinogalactans, pectins and mannans in the Euglena assay

A series of plant cell wall polysaccharides – heteroxylans, arabinogalactans, pectins and mannans exerted antimutagenic (antibleaching) activity against acridine orange- and ofloxacin-induced mutagenicity in the Euglena assay. All polysaccharides tested exhibited a significant dose-dependent antibleaching activity and the percentage inhibition of mutagenicity ranged from 52 to 96%. It can be assumed that the antimutagenicity of the polysaccharides depends on their structural and compositional properties as well as on the different mode of action of both the mutagens tested.     

An investigation on the antimutagenic properties of South African herbal teas

The antimutagenic properties of South African herbal teas were investigated using the Salmonella typhimurium mutagenicity assay. Aqueous extracts of fermented and unfermented rooibos tea (Aspalathus linearis) and honeybush tea (Cyclopia intermedia) both possess antimutagenic activity against 2-acetylaminofluorene (2-AAF) and aflatoxin B(1) (AFB(1))-induced mutagenesis using tester strains TA98 and TA100 in the presence of metabolic activation. A far less inhibitory effect was noticed against the direct acting mutagens, methyl methanesulfonate (MMS), cumolhydroperoxide (CHP), and hydrogen peroxide (H(2)O(2)) using TA102, a strain designed to detect oxidative mutagens and carcinogens. Depending on the mutagen used, the unfermented tea exhibited the highest protective effect. A similar response regarding the protection against mutagenesis was obtained when utilising different variations of the double layer Salmonella assay. The double layer technique proved to be more effective to detect the protective effect of the different tea preparations against the direct acting mutagens. With respect to indirect mutagens, the highest protection was noticed when the carcinogen was metabolically activated in the presence of the tea extract as compared with when the tea extract was incubated in a separate layer with the bacteria. The current data suggest that two mechanisms seem to be involved in the antimutagenicity of the tea extracts towards carcinogens that require metabolic activation: (i) the tea components may interfere with cytochrome P450-mediated metabolism of these mutagens and (ii) the direct interaction between the tea constituents, presumably the polyphenolic compounds, with the promutagens and/or the active mutagenic metabolites. However, the mild and/or lack of protection and in some cases even enhancement of mutagenesis induced by direct acting or oxidative mutagens, provide new perspectives regarding the role of the polyphenolic compounds known to exhibit antioxidant properties, in the protection against mutagenesis in the Salmonella assay. The present study provides the first evidence on the antimutagenic activity of honeybush tea and further evidence on the antimutagenicity of rooibos tea.     

A comparative study on the antimutagenicity of atorvastatin and lovastatin against directly acting mutagens

Elevated levels of oxidative DNA lesions have been noted in many tumors and such damage is strongly implicated in the etiology of cancer. The cumulative risk of cancer increases with the fourth power of age and is associated with an accumulation of oxidative DNA damage. Many agents, synthetic or natural, that can inhibit mutation have been depicted as cancer chemopreventive agents. Antimutagenicity of the 3-hydroxy-3-methylgutaryl-CoA (HMG-CoA) reductase inhibitors atorvastatin and lovastatin was studied using the Ames Salmonella typhimurium assay. Directly acting mutagens, sodium azide (NaN₃) and 4-nitro-o-phenylenediamine (NPDA), were used to induce mutation in Salmonella strains TA98 and TA100. The antimutagenicity of lovastatin and atorvastatin was found to be significant (p < 0.01) and dose-dependent. The percentage inhibition of a 3 mg lovastatin-treated plate was found to be 79.9% and 61.8% against NPDA- and NaN₃-induced mutation to TA98 and TA100, respectively. Atorvastatin (0.5 mg/plate) inhibited NPDA-and NaN₃-induced mutation to TA98 and TA100 by 78.6% and 45.5%, respectively. Atorvastatin showed antimutagenic activity at lower concentrations than lovatstatin. The results of the present study regarding the antimutagenic activity of atorvastatin and lovastatin suggested their therapeutic application as cancer chemopreventive agents.     

Production of nitric oxide, tumor necrosis factor-alpha and interleukin-6 by RAW264.7 macrophage cells treated with lactic acid bacteria isolated from kimchi

The multistage induction theory is generally regarded as the mechanism of carcinogenesis. In order to prevent the initiation stage of carcinogenesis, it is meaningful to discover the functional components of edible plants. The objective of this research was to test the antimutagenicity of the functional components of several typical traditional herbs used in Japan. The traditional herbs, gennoshoko (Geranium nepalense var. thunbergii), yomogi (Artemisia vulgaris var. indica), senburi (Swertia japonica), iwa-tobacco (Conandron ramondioides), sarunokoshikake (Elfvingia applanata), kanzo (Glycyeehiza uralensis Fisch) and matatabi (Actinidia polygama) were examined by Ames mutagenesis assay test with Salmonella typhimurium TA98 and TA100 against mutagens, Trp-P-1, Trp-P-2 and B(a)P. The water-soluble components or volatile oil of the herbs were extracted in boiling water. The extracts of gennoshoko showed strong antimutagenicity against B(a)P with S. typhimurium TA98 and TA100, as well as Trp-P-1 and Trp-P-2 with S. typhimurium TA98. Yomogi, senburi and iwa-tobacco were also proved to have good antimutagenicity against Trp-P-1 and Trp-P-2 with S. typhimurium TA98, but weaker antimutagenicity against B(a)P. Other herbs did not show any obvious antimutagenicity against these mutagens. In addition, the volatile oil of yomogi also had remarkable antimutagenic effect against the mutagens we used with S. typhimurium TA98.     

Antimutagenicity of secondary metabolites from higher plants.

Higher plants contain both mutagens and antimutagens and are susceptible to mutagenesis but screening programs for detection of antimutagenesis rarely employ higher plant systems. Short-term bacterial and mammalian tissue culture systems are the norm. Using modified screening tests for detecting antimutagenic agents, higher plants have been shown to contain a variety of structurally novel antimutagenic agents. Systematic bioassay-directed methodology resulted in the isolation in pure form and biological and chemical characterization of the responsible individual active components from various plants. The methodology in use is illustrated by the isolation of cinnamic acid, cinnamyl cinnamate and cinnamyl ricinoleate as the active constituents of the classic medicinal plant product, Styrax asiatica. The methods which may be used to reveal structure-activity relationships and to explore putative molecular modes of action are illustrated with excerpts from the same study.     

Antimutagenicity profiles of some natural substances.

Selected antimutagenicity listings and profiles have been prepared from the literature on the antimutagenicity of retinoids and the carotenoid beta-carotene. The antimutagenicity profiles show: (1) a single antimutagen (e.g., retinol) tested in combination with various mutagens or (2) antimutagens tested against a single mutagen (e.g., aflatoxin B1). Data are presented in the profiles showing a dose range for a given antimutagen and a single dose for the corresponding mutagen; inhibition as well as enhancement of mutagenic activity is indicated. Information was found in the literature on the testing of selected combinations of 16 retinoids and carotenoids vs. 33 mutagens. Of 528 possible antimutagen-mutagen combinations, only 82 (16%) have been evaluated. The most completely evaluated retinoids are retinol (28 mutagens), retinoic acid and retinol acetate (7 mutagens each), and retinal and retinol palmitate (6 mutagens each). beta-Carotene is the most frequently tested carotenoid (15 mutagens). Of the remaining retinoids and carotenoids, 8 were evaluated in combination with a single mutagen and the other 2 were tested against only 2 or 3 mutagens. Most of the data on antimutagenicity in vitro are available for S. typhimurium strains TA98 and TA100. Substantial data also are available for sister-chromatid exchanges in vitro and chromosome aberrations in vitro and in vivo. This report emphasizes the metabolic as well as the antimutagenic effects of retinoids in vitro and in vivo.     

Evaluation of mutagenic and antimutagenic properties of some bioactive xanthone derivatives using Vibrio harveyi test

Aims: Drug safety evaluation plays an important role in the early phase of drug development, especially in the preclinical identification of compounds’ biological activity. The Vibrio harveyi assay was used to assess mutagenic and antimutagenic activity of some aminoalkanolic derivatives of xanthone (1–5), which were synthesized and evaluated for their anticonvulsant and hemodynamic activities. Methods and Results: A novel V. harveyi assay was used to assess mutagenic and antimutagenic activity of derivatives of xanthone 1–5. Two V. harveyi strains were used: BB7 (natural isolate) and BB7M (BB7 derivative containing mucA and mucB genes on a plasmid pAB91273, products of these genes enhance error‐prone DNA repair). According to the results obtained, the most beneficial mutagenic and antimutagenic profiles were observed for compounds 2 and 3. A modification of the chemical structure of compound 2 by the replacement of the hydroxy group by a chloride improved considerably the antimutagenic activity of the compound. Thus, antimutagenic potency reached a maximum with the presence of tertiary amine and chloride atom in the side chain. Conclusions: Among the newly synthesized aminoalkanolic derivatives of xanthone with potential anticonvulsant properties, there are some compounds exhibiting in vitro antimutagenic activity. In addition, it appears that the V. harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of compounds. Significance and Impact of the Study: The obtained preliminary mutagenicity and antimutagenicity results encourage further search in the group of amino derivatives of xanthone as the potential antiepileptic drugs also presenting some antimutagenic potential. Furthermore, V. harveyi test may be a useful tool for compounds safety evaluation.     

Glycine betaine in beer as an antimutagenic substance against 2-chloro-4-methylthiobutanoic acid, the sanma-fish mutagen

Beer can inhibit the mutagenicity of the sanma-fish mutagen, 2-chloro-4-methylthiobutanoic acid (CMBA) in Salmonella typhimurium TA100 and TA1535. The antimutagenic component was isolated from beer and identified as glycine betaine, a compound known to be distributed widely in plants and animals including humans. Beer also contains components that interfere the antimutagenic action of glycine betaine. Glycine betaine seems to antagonize CMBA in a specific manner, since several other direct-acting mutagens tested were not subject to inhibition by glycine betaine. CMBA was stable in the presence of glycine betaine under neutral conditions. Since a treatment of Salmonella with glycine betaine before the bacteria was exposed to CMBA resulted in inhibition of the mutagenesis, the antimutagenic action of glycine betaine may be taking place inside the cells. These observations suggest that the mutagenic action of CMBA may be modified by the presence of both extracellular and intracellular glycine betaine.     

Experimental databases on inhibition of the bacterial mutagenicity of 4-nitroquinoline 1-oxide and cigarette smoke

Two antimutagenicity databases were prepared by applying a co-treatment procedure to the Salmonella reversion assay. Ninety compounds belonging to various chemical classes were quantitatively tested for antimutagenicity towards the direct-acting mutagen 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of S. typhimurium and 63 of them were additionally tested for antimutagenicity towards unfractionated mainstream cigarette smoke (CS) in strain TA98, in the presence of S9 mix. Twelve compounds (13.3%) inhibited 4NQO mutagenicity by at least 50%, with a MID₅₀ (dose inhibiting 50% of mutagenicity) varying over a 1226-fold range. Twenty-six compounds (41.3%) inhibited CS mutagenicity, with a MID₅₀ varying over a 520-fold range. Three compounds only, i.e., bilirubin, curcumin and myricetin, were capable of inhibiting the mutagenicities of both 4NQO and CS. However, myricetin and the other flavonoid rutin were at the same time mutagenic by inducing frameshift mutations following metabolic activation. There was a rather rigorous selectivity of antimutagenicity data depending on the chemical class of inhibitors and it was possible to discriminate protective effects within several pairs or series of structurally related compounds. For instance, all eight thiols and aminothiols inhibited 4NQO mutagenicity, which contrasted with the inactivity of the remaining 17 sulfur compounds tested, all of them lacking a free sulfhydryl group. The mutagenicity of CS was consistently inhibited by the majority of phenols (eight out of 10 tested) and by all two isothiocyanates, two dithiocarbamates, three indole derivatives, three tetrapyrrole compounds and three flavonoids tested. Although the results obtained cannot be extrapolated to other mutagens or test systems, they may provide a useful source of information for research in the area of antimutagenesis and for the development of chemopreventive agents.     

Inhibition of Induced Mutagenesis in Salmonella typhimurium by the Protein of Propionibacterium freudenreichii subsp. shermanii

Culture liquid and cells of Propionibacterium freudenreichii subsp. shermanii VKM-103 exerted a strong antimutagenic effect on mutations induced by 4-nitroquinoline-1-oxide, N-methyl-N′-nitro-N′-nitrosoguanidine, sodium azide (base pair substitutions) and 9-aminoacridine (frameshift mutations). No inhibitory effect was observed against mutagenesis induced by 2-nitrofluorene (frameshift mutations). The highest antimutagenic activity was found in the culture liquid of cells grown for 24 h. Acetic and propionic acids of the culture liquid produced by propionibacteria made no observable contribution to the antimutagenicity. Antimutagenic activity of the culture liquid was considerably reduced by protease treatment and by heating at 92°C for 10 min. Upon dialysis, the culture liquid lost almost all of its inhibitory activity. Cell wash solution also contained high antimutagenic activity which was lost upon protease treatment and dialysis. According to the exclusion limit of the dialysis bag, the molecular weight of the antimutagenic factor, presumably a protein, is less than 1.5 kDa. In addition, the cells of P. shermanii were capable of binding or modifying the mutagens, thereby decreasing their mutagenicity.     

Discovery and development of heat shock protein 90 inhibitors

Heat shock protein 90 (Hsp90) is an important target in cancer because of its role in maintaining transformation and has recently become the focus of several drug discovery and development efforts. While compounds with different modes of action are known, the focus of this review is on those classes of compounds which inhibit Hsp90 by binding to the N-terminal ATP pocket. These include natural product inhibitors such as geldanamycin and radicicol and synthetic inhibitors comprised of purines, pyrazoles, isoxazoles and other scaffolds. The synthetic inhibitors have been discovered either by structure-based design, high throughput screening and more recently using fragment-based design and virtual screening techniques. This review will discuss the discovery of these different classes, as well as their development as potential clinical agents.     

Antioxidant and antimutagenic activity of mannan neoglycoconjugates: mannan-human serum albumin and mannan-penicillin G acylase

The antioxidant and antimutagenic activity of the yeast cell-wall mannan and mannan conjugates--in particular the mannan of Saccharomyces cerevisiae (M-S.c.) and conjugates of mannan S. cerevisiae with human serum albumin (M-HSA1, M-HSA2) and the microbial enzyme penicillin G acylase (M-PGA)--were evaluated in vitro in the unicellular flagellate Euglena gracilis exposed to the genotoxic agents ofloxacin and acridine orange (AO). M-S.c., M-HSA1, M-HSA2 and M-PGA show a statistically significant, concentration-dependent protective antigenotoxic activity against both compounds. M-PGA was the most efficient inhibitor of ofloxacin- and AO-induced chloroplast DNA damage, whereas M-HSA2 and M-HSA1 were less effective and M-S.c. had the lowest antigenotoxic activity. It is suggested that different mechanisms may be involved in their protective effect--antioxidant activity in the case of ofloxacin-induced DNA damage and direct adsorption of AO on mannan conjugates as possible mechanisms of protection, based on spectrophotometric measurements. The important characteristics of yeast cell-wall mannans and mannan conjugates, such as their high water solubility, their broad spectrum of biological activity, low toxicity, stability and their antimutagenic effects via different modes of action, appear to be promising features for their practical application as antioxidants and antimutagenic agents.     

Plant extracts as modulators of genotoxic effects

Higher plants used extensively in traditional medicines are increasingly being screened for their role in modulating the activity of environmental genotoxicants. The property of preventing carcinogenesis has been reported in many plant extracts. The observation of a close association between carcinogenesis and mutagenesis has extended the survey to include plant extracts and plant products able to modify the process of mutagenesis, which involves alteration in the genetic material. Natural plant products may, apart from inducing mutations, modify the action of other known mutagens on the living organisms by 1) activating the existing mutagens within the cell, 2) inhibiting the production of mutagens in the cell, 3) synergising the activity of existing mutagens, or 4) activating the promutagens within the cell into mutagens. This review deals with data obtained in the course of research on the modulatory effects of plant extracts on mutagenesis and clastogenesis, two genotoxic phenomena associated with carcinogenesis. In screening for antimutagenic effects, extracts of different plant parts have been used, ranging from leafy vegetables, fruits, and underground storage organs to whole plants. The extracts were prepared mainly in water or organic solvents. Several of these assays have indicated the involvement of certain factors that are intrinsic components of the extracts, ranging from specific compounds like ascorbic acid to vegetable fibres which could act as nonspecific redox agents, free radical scavengers, or ligands for binding metals or toxic principles. The possible ways in which inhibitors of mutagenesis can act include the inhibition of interaction between genes and biochemically reactive mutagens and the inhibition of metabolic activation of indirectly acting mutagens. The effects of toxicants can be observed at the level of chromosomes (clastogenesis) through alterations in chromosome structure (chromosomal aberrations) and number (aneuploidy, polyploidy). A wide range of short-term and long-term screening procedures is available. The most common ones use higher plants or rodents in vivo as test systems for monitoring chromosomal aberrations. Experiments with a number of crude vegetable and fruit extracts have demonstrated their anticlastogenic activities against known cytotoxic agents. The individual components of the extracts—e.g., sulfhydryl and flavonoid compounds, gallic acid, ellagic acid, mucic acid, citric acid, reducing sugars, tannin—are observed to have an additive interaction with the major constituents chlorophyll and ascorbic acid, when modulating the effects of the clastogens. Under certain conditions, plant products may induce mutagenic effects, due to the presence of multiple biological properties. Some inhibitors can stimulate simultaneously both enhancing and detoxifying mechanisms, e.g., inducers of coordinated enzyme activities. Many oxidants can, depending on the redox potential, either accept or donate electrons, rendering them protective or harmful. Plants also play an active role in the accumulation, metabolism, and environmental distribution of xenobiotics. The property of plants to activate promutagens that may enter the food chain is of great significance in view of the large number and types of chemicals to which the plants are exposed. A promutagen is a chemical that is not mutagenic itself but that can be biologically transformed by a plant system into a mutagen. Several methods for studying promutagens from plants were developed both in vivo and in vitro, including plant cell-free systems. Both mutagens and antimutagens can be extracted from the same plant extract depending on the nature of solvents used for extraction. Interaction between inhibitors may lead to synergistic effects. Such combined action may take place through the different inhibitors acting at different levels or being localised at different cellular areas. The greater protection afforded by crude plant extract as compared with an equivalent amount of the purified or synthetic ingredients, as observed withPhyllanthus emblica L. andBeta vulgaris L. var.benghalensis Hort., may be related to this phenomenon. Specific biological action of a drug is due to its specific binding to a functional molecular receptor. In complex plant extracts, the variable observed effects can be attributed to the many chemically reactive species that are formed during the processing and ingestion of the extract, which could act as non-specific redox agents, scavengers of free radicals, and ligands for binding to toxicants. The final effects are obviously the outcome of interactions between the components and their individual and collective interaction with the toxicant. The specificity and efficacy of such responses will be influenced also by the physiological factors influencing the plants and the process of administration of the extract. In utilizing pharmacologically active herbs, both beneficial and potential adverse effects must be taken into account. The actual dose and form of the plant also need to be worked out.     

Activity of grape extracts from Greek varieties of Vitis vinifera against mutagenicity induced by bleomycin and hydrogen peroxide in Salmonella typhimurium strain TA102

Several in vivo and in vitro studies have shown that grape extracts could prevent certain steps in carcinogenesis and a few mechanisms have been proposed for this activity. In this study, the potential antimutagenic activity of methanolic and aqueous extracts from two Greek grape varieties of Vitis vinifera against DNA damage induced by reactive oxygen species (ROS) was assessed as a potential novel chemopreventive mechanism, using Salmonella typhimurium strain TA102. The two grape varieties were Assyrtiko (white grapes) and Mandilaria (red grapes), while the oxidant mutagens used were bleomycin (BLM) and hydrogen peroxide (H(2)O(2)). Since it has been considered that polyphenols present in grapes are their most potent biologically active compounds, we also tested the effects of polyphenol-rich fractions as well as some of the more common grape polyphenols on the activity of the two test mutagens. These polyphenols were quercetin, (+)-catechin, (-)-epicatechin, trans-resveratrol, gallic acid and protocatechuic acid. Almost all extracts showed inhibitory activity against both mutagens. On the other hand, polyphenol-rich fractions as well as individual polyphenols at concentrations found in the extracts either did not diminish or did enhance the activity of the mutagens. These results suggest that the protection of DNA from mutations induced by ROS may be one of the mechanisms accounting for the chemopreventive activity of grape extracts. However, it seems that this protective activity may not be attributed to polyphenols but rather to a synergism of many compounds in the grapes.     

Antioxidant,antibacterial, and antimutagenic activity of Piper nigrum seeds extracts

Piper nigrum is a widely used plant in traditional remedies and known for its numerous biological properties. However, fraction-based antioxidant activity and their antimutagenic potential are not yet fully investigated. Different extracts of the seeds P. nigrum were obtained by sequential extraction in different solvents. All extracts were evaluated for antibacterial and antioxidant activities using different methods. The most active fraction was analyzed for antimutagenic activity using the Ames Salmonella test. The antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) was found to be more prominent compared to ESβL producing Klebsiella pneumoniae isolates. The MIC values were found to be lower against MRSA than K. pneumoniae. The extract showing highest antioxidant activity (methanol extract) was further tested for antimutagenic activity both against direct and indirect-acting mutagens. A varying level of antimutagenic activity was shown by methanol extract at highest tested concentration (200 µg/plate). Alkaloids, phenols, and flavonoids were detected as major class of compounds in methanol extract. Gas chromatography-mass spectrometry (GC–MS) analysis showed the presence of various phytocompounds. Based on molecular docking of two major active phytocompounds (piperine and copaene), they were found to interact at the minor groove of DNA. Molecular dynamics (MD) simulation revealed that both the ligands were quite stable with DNA under physiological conditions. The ability of phytocompounds to interact with DNA might be reducing the interaction of mutagens and could be one of the possible mechanism of anti-mutagenic activity of P. nigrum extract. This study highlights the antioxidant and antimutagenic potential of Piper nigrum. The role of phytocompounds present in the bioactive extract is needed to be explored further for herbal drug research.     

The ratio of induced recessive lethals to ring-X loss has prognostic value in terms of functionality of chemical mutagens in Drosophila melanogaster

For 25 mutagens in Drosophila the ratio was determined between the induction of sex-linked recessive lethals (SLRL) and the induction of ring-X loss in male adults. For small monofunctional alkylating agents this ratio increases with decreasing s-value from 1.8 for methyl methanesulfonate (MMS) to 27 for ethylnitrosourea (ENU). For multifunctional cross-linking agents, however, the ratio varies within relatively narrow limits, ranging from 0.15 for cisplatin to 0.07 for tris-(1-aziridinyl)phosphineoxide (TEPA), while for most agents the ratio is around 0.12. The number of reactive groups seems to be of minor importance for compounds with more than one functionality as bi- and tri-functional agents show similar ratios. The systemic difference in the ratios between mono- and multi-functional agents suggests that different mechanisms are involved in the induction of SLRLs and ring-X loss. For ethyleneimine (EI) and ethyleneoxide (EO) low ratios of 0.32 and 0.60 respectively were observed which do not correlate with their s-values. An alternative chromosome-breaking mechanism may be responsible for this deviation, possibly alkylation of the phosphate backbone of DNA, followed by an intramolecular displacement of one of the deoxyribose groups by the beta-amino or the beta-hydroxy group. It is felt that the considerable difference between the ratios for monofunctional and multifunctional agents may be of prognostic value and can be used to obtain information on the mechanisms of mutagens with 'unknown' action, provided that structural features are taken into account. Hexamethylphosphoramide (HMPA), hexamethylmelamine (HEMEL), tetramethylurea (TMU) and dimethylpropyleneurea (DMPU) all show SLRL: ring-X loss ratios that match those of multifunctional agents, 0.08, 0.12, 0.08, and 0.16, respectively. The ratios for the pyrrolizidine alkaloids monocrotalin and seniciphilline, 0.053 and 0.24 respectively, also correspond with this group of mutagens. The low ratios for formaldehyde, 2-chloro-acetaldehyde and 2-chloroethyl methanesulfonate, 0.30, 0.052 and 0.36 respectively, are indicative that cross-linking may attribute considerably to their mutagenic action in Drosophila. On the other hand, not all mutagens containing 2 reactive groups act as cross-linking agents. The ratio for 1,2-dibromoethane, 2.7, indicates that it may act as a monofunctional agent. This is in accordance with the proposed activation mechanism by glutathione S-transferase, producing a monofunctional half-mustard derivative (Rannug, 1980; van Bladeren et al., 1981).     

Antimutagenic effects in humans.

The application of antimutagenicity studies to human somatic mutation is discussed, with emphasis on the potential for future studies. Five assay-gene combinations are now available for measuring human somatic mutation in lymphocytes and erythrocytes. Results with these combinations have defined the human background levels, and show clear responses of mutant frequency to a variety of mutagens. The testing of antimutagenic effects on background frequencies is feasible, but has not yet been done. The major uncertainty in such studies is the unknown age of mutant cells in the background, since only the newly forming mutants are potentially susceptible to most antimutagenic treatments. Intervention studies in the face of active mutagenicity and the use of other genotoxicity endpoints, such as chromosome aberrations, micronuclei and DNA adducts, are considered briefly.     

The interrelation of the antimutagenic action of mannitol to its effect on cellular metabolic processes]

The mannitol influence on mutagenesis of ionizing radiation and cyclophosphate has been studied in albino mongrel rats using the methods of genetic and biochemical analysis. N correlation is determined between antimutagenic action of this preparation and a decrease of malondialdehyde content in cells and free fractions of matrix lysosomes (beta-galactosidase; N-acetyl-beta-D-glucosaminidase) and firmly membrane-structurized microsomal (glucose-6-phosphatase) enzymes, whose level increases under the influence of mutagens. It is shown that, one of the way of antimutagenic actions of mannitol is connected with mutagenesis correction at the stage of origin of mutagenic products and their transport to chromosome DNA.     

Antimutagenic Properties of Bacteria: Review

Lactic acid and propionic acid bacteria, bifidobacteria, and fecal enterococci associated with the activity of humans and animals caused antimutagenic effects (AME) on many test systems designed for detecting point mutations and chromosomal aberrations. Bacterial cells and some of their metabolites attenuate the mutagenic action of several genotoxic agents, and this effect is mediated by the mechanism of dysmutagenesis and/or bioantimutagenesis. Possible mechanisms of various AMEs and possible practical applications of antimutagenic properties of bacteria are discussed.