Mutagenic activity of dioxydine]

A previous evaluation of mutagenic activity of some drugs and perspective substances is carried out using indicator microorganisms. The mutagenicity of dioxydine, a drag with discovered antibacterial activity, is investigated. Dioxydine is shown to induce reversions in mutant of Salmonella typhimurium TA-1950, the indicator strain which demonstrates mutagenic activity of agents, producing mutations of base pair substitution type. Dioxydine proved to affect logariphmiically growing bacterial culture with great activity. Mutageni effect of dioxydine is not modified itself in microsomal oxidation system in vitro. Some data concerning participation of excision reparation enzyme (uvr-B+ gene product) in repair of lethal damages induced by dioxydine, have been obtained. The dioxydine ability to cause bacterial gene mutations in host mediated assay as well as dominant and recessive sex-linked lethal mutations in Drosophila is demonstrated. Dioxydine is capable of inducing chromosome aberrations in bone marrow cells and dominant lethal mutations in mouse germ cells.     

Mutagenic activity of psychotropic drugs]

Mutagenic activity of 33 psychotropic drugs was studied in Drosophila metanogaster according to the CLB method. The drugs are the following: leponex, neuleptil, randolectil, teralen, chlorprotixen, TPS-23, navane, pimosid, difenisid, rudotel, eunoktin, radedorm, meprobamat, trioxasin, elenium, napoton, aponal, lorasepam, nuredal, oxyphenonat, safrasin, surmantil, amitriptilin, prothioden, melipramin, saroten, tegretol, phenobarbital, diakarb, benzonal, suksilep, morpholep, sydnocarb. The increase in the mutation rate was induced by leponex (1.37% in adults and 1.21% in larvae), difenisid (1.18% in adults), two forms of the same drug eunoktin and radedorm (about 1.6% in adults), safrasin (1.06% in imago), saroten (1,36% in imago), phenobarbital (2.02% in imago). Even a slight increase of mutagenicity of widely spread psychotropic drugs is a very serious factor which needs further investigation and specification in other models and organisms.     

Mutagenic activity of radiosensitizers

Seven radiosensitizers, six derivatives of nitroimidazole (coded P1 to P5 and one imidazole derivative--P6 were investigated for mutagenicity using 3 short-term tests: Ames test, prophage lambda induction and tryptophan reversion test. Out of seven investigated compounds five were not mutagenic. Only P1 derivative induces base pair substitutions. Another derivative of nitroimidazole: metronidazole induces base pair substitution and frameshift mutations. Its positive response in the prophage lambda induction test suggests that metronidazole provokes also epigenetic changes.     

Mutagenic activity of the pesticide hexachlorobutadiene

Pesticide hexachlorobutadiene (HCBD) has been studied for its mutagenic activity in two test systems: in vivo and in vitro. The above pesticide manifested a mutagenic activity in the bone marrow cells under peroral and inhalation effect. No clastogenic action in the human peripheral lymphocyte culture was observed. Results of this study and data available in literature permit concluding that HCBD is an indirect mutagen.     

Mutagenic activity of chloramines

Mutagenesis by chloramines and hypochlorous acid (HOCl) was studied to determine whether these agents could contribute to the mutagenic and potentially carcinogenic activity of stimulated leukocytes and whether environmental exposure to these agents is a cause for concern. Mutagenic activity was measured using the S. typhimurium TA97a, TA100 and TA102 tester strains. Because chloramines and HOCl are bactericidal, react rapidly with cell components, and can destroy the histidine and biotin required for the mutagenesis assay, activity can't be compared directly with that of less toxic or reactive agents. Nevertheless, chloramines were mutagenic when tested under appropriate conditions. TA100 was the most sensitive strain, and the most active mutagens were lipophilic dichloramines (RNCl2) including derivatives of histamine, ethanolamine and putrescine. Lipophilic monochloramines (RNHCl) such as histamine-monochloramine and NH2Cl were less active. Hydrophilic chloramines such as taurine-chloramines had low activity, and HOCl was inactive. The metabolic state of the bacteria was critical. Chloramines were mutagenic when added to bacteria with glucose at 37 degrees C, but killing predominated when chloramines were added at 4 degrees C or 25 degrees C, or at 37 degrees C without glucose. Production of chloramines and HOCl by leukocytes in vivo could contribute to the association of chronic inflammation and cancer as a result of: (1) the entry of membrane-permeable chloramines into normal cells followed by attack on intracellular components including DNA, and (2) the production of secondary mutagens such as compounds with carbonyl groups or carbon-chlorine bonds. On the other hand, chlorination of water supplies is perhaps more likely to destroy than create mutagens, and chloramines from the environment are unlikely to penetrate the skin and mucous membranes.     

Mutagenic activity of the fungicide captan

A complex study of mutagenic activity of captan (a fungicide) in a series of standard test-systems has shown that the preparation induces gene mutations in certain Salmonella indicator strains (without metabolic activation), increases the frequency of mitotic crossing-over and gene conversion in yeasts (Saccharomyces), possesses a weak cytogenetic action on bone marrow cells in experimental animals, manifests no cytogenetic effect in the lymphocyte culture of human peripheral blood (including a system of microsomal activation). Genetic activity of captan cannot be a limiting criterion of its harmfulness.     

Mutagenic activity of biliary metabolites of 6-hydroxymethylbenzo[a]pyrene

The biliary excretion of the carcinogen 6-hydroxy-methylbenzo[a]pyrene was investigated in rats after i.p. administration. Mutagenicity of the parent compound and its biliary metabolites was tested in Ames Salmonella/microsome mutagenicity assay. Approximately 40% of the dose administered (0.25-0.5 mg/kg) to the rats was excreted in the bile within 6 h. 6-Hydroxymethylbenzo[a]pyrene was excreted primarily as water-soluble metabolites, including glucuronide and sulfate conjugates. Negligible quantities of unchanged 6-hydroxymethylbenzo[a]pyrene were excreted in the bile. In the presence of Aroclor-induced S9, 6-hydroxymethylbenzo[a]pyrene was a potent mutagen. The mutagenicity of bile from rats treated with 6-hydroxymethylbenzo[a]pyrene was variable in the absence of an activation system. However, the same bile samples were mutagenic in the presence of beta-glucuronidase and/or S9. These results indicate that biliary metabolites of 6-hydroxymethylbenzo[a]pyrene can be metabolically activated to mutagenic species.     

Mutagenic activity of swimming-pool water

Swimming pool water, being chlorinated and exposed to trace organics from use was investigated as a possible source of mutagens using the Salmonella/mammalian-microsome test. Procedures previously described for the extraction of trace organics from water using XAD-2 macroreticular resin were modified to allow quantitative extraction of mutagens. These procedures were superior to freeze-drying and solvent-extraction. Using a base-pair histidine mutant, strain TA100, of Salmonella typhimurium significantly mutagenic responses were observed using concentrates from 3 variations of the extraction procedure. Acidified pool-water extracts eluted with ether or acetone were mutagenic, the former enhanced in the presence of the induced microsomal fraction from rat livers. Non-acidified pool-water extracts eluted with acetone were mutagenic without microsomal activation. These results indicate the presence of more than one mutagen in what is likely a complex mixture of organic molecules in swimming-pool water.     

Mutagenic activity of selenium compounds

The mutagenicities of selenate (SeO₄²⁻) and selenite (SeO₃²⁻) 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.     

Mutagenic activity of the organophosphorus insecticide chloracetophon

Chloracetophone (0,0-dimethyl-2,2,2-trichloro-1-(1-chloroacetoxy)phosphonate) is a new organophosphorus insecticide. The LD50 for male rats is 420 mg/kg b.w. The mutagenic activity was evaluated with the method of cytogenetic analysis of rat bone marrow after acute and short-term oral exposure. In the acute study groups of male and female animals were treated with chloracetophone at a dose of 1/5 LD50 and then examined at periods of 6, 12, 24, 48 and 72 h following administration. Separate groups of animals were examined 24 h after single administration of the doses 1/5, 1/10 and 1/20 LD50. In the short-term study groups of male animals were treated for 5 successive days. The slides were prepared 6 or 24 h after the last administration. Concurrent negative and positive (cyclophosphamide 20 mg/kg b.w.) control groups were used. 50 cells at metaphase per animal were scored for chromosomal aberrations. The results did not show significant increase in the frequency of chromosomal breaks in the groups with chloracetophone.     

Mutagenic activation of xenobiotics by plant enzymes

Genetic evidence has indicated that plants can activate certain xenobiotics to mutagens, but biochemical evidence is as yet scarce. Nevertheless, plant microsomal enzymes and peroxidases have been shown to form reactive intermediates, the best studied examples being 2-aminofluorene, benzo[a]pyrene and pentachlorophenol. The latter two xenobiotics are converted to quinoid derivatives which are, in principle, able to redox cycle and generate active oxygen species. In analogy to results obtained in mammalian systems, covalent binding of reactive intermediates to DNA as well as fragmentation of DNA, are proposed as major mechanisms of action of mutagenic plant metabolites.     

The cholinolytic activity of the new anti-arrhythmia preparation Nibentan]

In the rabbit isolated right atrium and the rat atrial cells, a new class III antiarrhythmic drug Nibentan was shown to exert an anticholinergic effect contrary to Carbachol: the latter decreased the AP duration to 42 +/- 2% of the control whereas Nibentan restored it to 65 +/- 2%. The anticholinergic effect of the drug was found to be due to inhibition of the acetylcholine-activated potassium current: it was decreased by 79 +/- 3% in the rat isolated single atrial cells. In the rabbit isolated sino-atrial node, Nibentan prevented arrhythmogenic effects of vagal stimulation. The new drug may be quite efficient in treatment of flutter and atrial fibrillation.