Antimutagenic activity of afobazole in various regimens of treatment

The influence of a new 2-mercaptobenzimidazole derivative afobazole on cytogenetic effects of dioxidine and cyclophosphamide was studied by counting chromosome aberrations in bone marrow cells of C57B1/6 mice. Afobazole (1–100 mg/kg perorally) exhibited antimutagenic activity determined by its antioxidant properties. This activity depended on the dose and treatment shedule. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 11, pp. 539–542, November, 2000     

Antimutagenic Activity of Lipidovit

Antimutagenic properties of Lipidovit produced from the biomass of Blakeslea trispora fungi was studied by its effect on induction of chromosome aberrations by chemical mutagens dioxidine and cyclophosphamide in mouse bone marrow cells. Antimutagenic activity of Lipidovit depended on the scheme of treatment. It was maximum during pretreatment of animals (5 day) or administration in combination with mutagens (5 days). The preparation was ineffective after single administration in combination with mutagens. Lipidovit exhibited no comutagenic properties.     

Effect of afobazole on teratogenic activity of cyclophosphamide in rats

A new anxiolytic afobazole (1–100 mg/kg perorally, Russia) dose-dependently abolished the embryotoxic and teratogenic effects of cyclophosphamide and reduced the range of induced malformations in outbred albino rats. Our results suggest that afobazole possesses antiteratogenic activity. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 414–417, April, 2008     

Excretion of afobazole and its metabolites with urine and feces in rats

The amount of afobazole and identified metabolites was measured in the urine and feces of rats after intraperitoneal and peroral administration of the drug in a dose of 25 mg/kg. Over 1 day after intraperitoneal or peroral treatment with afobazole, urine and feces contained 0.1% initial compound (from administered dose) and 42.1% metabolites. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 418–420, April, 2008     

Tissue availability of afobazole and its major metabolites in rats

Intraperitoneally injected afobazole and its major metabolites are intensively distributed in highly vascularized tissues of rats, including the liver, spleen, and kidneys; the content of these compounds in moderately and poorly vascularized tissues (muscles and mesentery) is much lower. Afobazole and its metabolites possess intermediate ability to penetrate into the brain. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 5, pp. 528–530, May, 2007     

Neuroprotective effect of afobazole on rats with bilateral local photothrombosis of vessels in the prefrontal cortex

We studied the neuroprotective effect of a new selective anxiolytic afobazole on rats with bilateral focal ischemic stroke in the prefrontal cortex caused by photothrombosis. Intraperitoneal injection of 5 mg/kg afobazole 1 h after surgery and over the next 8 days (daily treatment) produced a neuroprotective effect. Afobazole was far superior to the reference cerebroprotective drug cavinton (4 mg/kg) by neuroprotective activity. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 2, pp. 167–169, February, 2008     

The apparent decrease in thiotepa-induced chromosome aberrations in human lymphocytes caused by an effect of WR2721 on the cell cycle as found by the definitively determined division method

Antimutagenic radioprotective compounds have been reported to decrease the yield of chemically induced chromosome aberrations even when administered long before the chemical mutagen thio-TEPA. Because thio-TEPA can induce aberrations in all parts of the cell cycle, it seemed likely that the apparent decrease in aberrations was the result of an effect of the antimutagen on the progression of cells through the cell cycle so that cells treated in the more sensitive stage would be scored. To test this possibility human lymphocytes were treated with the protective compound WR2721 and then thio-TEPA. The cells were grown in the presence of 5-bromodeoxyuridine, which allows the definitive determination of metaphases from cells that divided once, twice, or three times after treatment. The yield of aberrations observed in first division cells was the same whether or not the protector was present. A decrease in aberration yields appeared only in rapidly cycling cells that were in the second division at the time of fixation. Labeling experiments showed that in this rapidly dividing population fewer of the metaphase cells had been in G₂ when thio-TEPA was added. The results indicate that part of the decrease in aberration yields obtained by treatment with an antimutagen several hours before the addition of a mutagen is an artifact of cell selection.     

Effect of epithalon on the incidence of chromosome aberrations in senescence-accelerated mice

The incidence of chromosome aberrations in bone marrow cells of 12-month-old SAMP-1 female mice characterized by accelerated aging was 1.8 times higher than in wild-type SAMR-1 females and 2.2 times higher than in SHR females of the same age. Treatment with Epithalon (Ala-Glu-Asp-Gly) starting from the age of 2 months decreased the incidence of chromosome aberrations in SAMP-1, SAMR-1, and SHR mice by 20%, 30.1%, and 17.9%, respectively, compared to age-matched controls (p<0.05). Treatment with melatonin (given with drinking water in a dose of 20 mg/liter in night hours) had no effect on the incidence of chromosome aberrations in SHR mice. These data indicate antimutagenic effect of Epithalon, which probably underlies the geroprotective effect of this peptide.     

Dynamics of chromosomal aberrations in male mice of various strains during aging

We studied the incidence of chromosome aberrations in bone marrow cells and primary spermatocytes in various mouse strains. Experiments were performed on SAMP mice (accelerated aging), control SAMR mice, and long-living CBA and SHR mice. Experiments revealed a positive correlation between the age and the incidence of mutations in their somatic cells and gametes.     

Antimutagenic activity of β-carotene

Data are presented on the ability of synthetic β-carotene to reduce the level of cyclophosphane-induced chromosome aberrations in murine bone marrow cells. InSalmonella typhimurium cells β-carotene exhibits antimutagenic activity only against an indirect mutagen (2-acetylaminofluorene). Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 9, pp. 276–278, September, 1995 Presented by Yu. N. Solov'ev, Member of the Russian Academy of Medical Sciences     

Antimutagenic activity of spearmint

The antimutagenic activity of spearmint (Mentha spicata), a popular food flavoring agent, was studied in the Salmonella assay. Spearmint leaves were brewed in hot water for 5 min at concentrations up to 5% (w/v), and the water extracts were tested against the direct-acting mutagens 4-nitro-1,2-phenylenediamine (NPD) and 2-hydroxyamino-3-methyl-3H-imidazo[4,5-f]quinoline (N-OH-IQ) using Salmonella typhimurium strain TA98. Nontoxic concentrations of spearmint extract inhibited the mutagenic activity of N-OH-IQ in a concentration-dependent fashion, but had no effect against NPD. These experiments by design focused on the water extract consumed commonly as an herbal tea, but chloroform and methanol extracts of spearmint also possessed antimutagenic activity against N-OH-IQ. Water extract of spearmint inhibited the mutagenic activity of the parent compound, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), in the presence of rat liver S9; however, the concentration for 50% inhibition (IC50) against IQ was approximately 10-fold higher than in assays with N-OH-IQ minus S9. At concentrations similar to those used in the Salmonella assays, spearmint extract inhibited two of the major enzymes that play a role in the metabolic activation of IQ, namely, cytochromes P4501A1 and 1A2, based on ethoxyresorufin O-deethylase and methoxyresorufin O-demethylase assays in vitro. In vivo, rats were given spearmint water extract (2%; w/v) as the sole source of drinking fluid before, during, and after 2-week treatment with IQ; colonic aberrant crypt foci were inhibited significantly at 8 weeks (P < 0.05, compared with rats given IQ alone). Collectively, these findings suggest that spearmint tea protects against IQ and possibly other heterocyclic amines through inhibition of carcinogen activation and via direct effects on the activated metabolite(s).     

<Emphasis Type="Italic">In vivo</Emphasis> study of dihydroquercetin genotoxicity

Genotoxic properties of dihydroquercetin were in vivo studied by the method of chromosome aberrations counting and DNA-comet assay. Dihydroquercetin administered repeatedly (5 times, 0.15 and 1.5 mg/kg) or once in doses of 15, 150, and 2000 mg/kg induced no DNA damages in mouse bone marrow, blood, liver, and rectal cells. Single administration of this preparation in doses of 1.5 and 150 mg/kg and 5-fold administration in a dose of 1.5 mg/kg had no effect on the level of chromosome aberrations in mouse bone marrow cells. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 3, pp. 309–312, March, 2008     

Generation of free oxygen radicals and clastogenesis in bone marrow cells in MRL/1 mice

The level of chemiluminescence induced by phorbol myristate acetate or opsonized zymosan in the bone marrow cells of 5–6-month-old male MRL/1 mice is significantly higher than that in the same cells of 1–2-month-old mice. The number of chromosome aberrations induced by the prooxidant mutagen dioxydine in bone marrow cellsin vivo is significantly higher in 5–6-month-old MRL/1 mice than in 1–2-month-old mice. It is suggested that these effects are more pronounced in 5–6-month-old animals due to progressive development of rheumatic pathology in this mouse strain. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 1, pp. 22–25, January, 1997     

Chromosome studies and fertility treatment in women with ovarian failure

In vitro fertilization and embryo transfer or gamete (or zygote) intra-Fallopian transfer after ovum donation were performed in 16 patients with primary or secondary amenorrhea, associated with chromosome abnormalities. The patients showed the wide range of (mostly X) chromosome abnormalities characteristic for women with primary or premature ovarian failure. Four of these patients became pregnant and three of them have delivered healthy infants with a normal karyotype. This pregnancy rate is far superior to the accepted fertility figure in these patients. When these results were compared with the fertility treatment results of three other groups of women with absent ovarian function (1. ovarian dysgenesis; 2. surgical castration; 3. premature menopause) but with a normal 46,XX karyotype, no difference in treatment efficiency could be detected. These results offer a promising approach for the treatment of infertility in agonadal patients with chromosome aberrations.     

Induction of chromosome aberrations and mitotic arrest by cytomegalovirus in human cells

Human cytomegalovirus (CMV) is potentially an effective but often overlooked genotoxic agent in humans. We report here evidence that indicates that infection by CMV can induce chromosome alterations and mitotic inhibition. The frequency of chromosome aberrations induced was dependent on the input multiplicity of infection (m.o.i.) for human lung fibroblasts (LU), but not for human peripheral blood lymphocytes (PBLs) when both cell types were infected at the GO phase of the cell cycle. The aberrations induced by CMV were mostly chromatid breaks and chromosome pulverizations that resembled prematurely condensed S-phase chromatin. Pulverized chromosomes were not observed in LU cells infected with virus stocks that had been rendered nonlytic by UV-irradiation at 24,000 ergs/mm2 or from infection of human lymphocytes. In LU cells infected with UV-irradiated CMV, the frequency of aberrations induced was inversely dependent on the extent of the exposure of the CMV stock to the UV-light. In permissive CMV infection of proliferating LU cells at 24 hr after subculture, a high percentage (greater than 40%) of the metaphase cells were arrested at their first metaphase and displayed severely condensed chromosomes when harvested 48 hr later. A significant increase (p less than 0.05) in the chromosome aberration frequency was also observed. Our study shows that CMV infection is genotoxic to host cells. The types and extent of damage are dependent on the viral genome expression and on the cell cycle stage of the cells at the time of infection. The possible mechanisms for induction of chromosome damage by CMV are discussed.     

Antimutagenic activity of fluphenazine in short-term tests

Fluphenazine, an antipsychotic drug that belongs to the phenothiazine family, reduced the genotoxicity of direct- and indirect-acting mutagens in the Ames test, both in the presence and in the absence of promutagen-activating S9 fraction. In short-term tests on human lymphocytes, the inhibitory effect of fluphenazine on the genotoxicity of standard mutagens was strongest in the cytokinesis-blocked micronucleus assay and in the thioguanine resistance test, and weakest in the sister chromatid exchange test. Fluphenazine also considerably reduced the level of free radicals estimated in in vitro samples of human granulocytes. The results suggest that, in the range of the tested concentrations, fluphenazine could be considered for use to prevent the genotoxicity of daunorubicin, methyl methanesulfonate, benzo[a]pyrene, and mitomycin C. Reduction in the level of free radicals appears to be an important mechanism of the antimutagenic action of fluphenazine.     

Induction and transmission of chromosome aberrations in mouse oocytes after treatment with butadiene diepoxide

A study was conducted on the genotoxicity of butadiene diepoxide (DEB) in mouse oocytes. Superovulated female mice were injected intraperitoneally with DEB and mated with untreated males. Oocyte exposure occurred approximately 1.5 days before ovulation. DEB doses ranged between 26 and 52 mg/kg. Chromosome aberrations were scored in C-banded metaphases of one-cell embryos. The percentage of mated females, the average number of zygotes harvested per female, the frequencies of unfertilized oocytes and developmentally delayed zygotes did not reveal any overt sign of chemical toxicity which hindered the propensity of animals to mate or affected the ovulation, fertilization, or cell cycle progression of treated oocytes. A dose-dependent induction of chromosome aberrations was observed which was best fitted by a linear quadratic equation. Half of all the aberrations transmitted by DEB-treated oocytes were chromatid-type breaks or exchanges. Among chromosome-type aberrations, double fragments far exceeded chromosome exchanges. This spectrum of structural aberrations differed markedly from what was previously observed in one-cell embryos conceived by DEB-treated sperm, where 97% were chromosome-type aberrations and 40% were dicentrics or translocations. This difference suggests that chromosome damage in one-cell embryos can be fixed by different mutagenic pathways influenced by the targeted gamete and its specific chromatin configuration. After exposure to the same dose, oocytes transmitted to one-cell embryos between 4 and 8 times fewer aberrations than DEB-treated sperm. While the rate of aberration induction suggests that female germ cells may be less at risk than mature sperm,especially at low-dose levels, the higher threshold for reproductive toxicity observed in female than in male mice may justify inclusion of data on female germ cell mutagenicity in the genetic risk assessment of butadiene exposure. Environ. Mol. Mutagen. 30:403–409, 1997 © 1997 Wiley-Liss, Inc.     

The frequency of chromosome anomalies in human preimplantation embryos after in-vitro fertilization

Previous studies have reported chromosome aberrations in humanpre-embryos after in-vitro fertilization (IVF). Although thereason for these abnormalities is not clear, there is evidencethat they can arise during gametogenesis, fertilization or cleavage.The present study has examined further the incidence of chromosomeabnormalities in human pre-embryos after IVF, using oocytesrecovered from normal volunteer women and from women undergoinginfertility treatment in an embryo-replacement programme. Chromosomepreparations were performed for 75 pre-embryos. Of these 35(47%) gave at least one metaphase in which analysis was possible.The overall incidence of abnormal pre-embryos was 40% (14/35).The absolute frequency of aberrations was 9% for trisomies,3% for polyploidies, 26% for structural anomalies and 3% forhypodiploidies. Five pre-embryos were found to be mosaics, threeof which had each one trisomic metaphase. In five of the pre-embryosmultiple anomalies were found. In 13 of the 14 abnormal pre-embryosthe aberrations were found in only one metaphase. The presentstudy demonstrates that trisomic mosaicism may not be a rareevent in human pre-embryos. Further evidence is provided thatmitotic non-disjunction is important for the production of aberrationsin human pre-embryos     

Effect of vitamin therapy on sensitivity of peripheral blood lymphocytes to clastogenic effect of mutagens in vitro

Spontaneous and in vitro induced (with 0.01 and 0.1 mg/ml dioxidine and 0.1 and 1.0 U/ml bleomycin) chromosome aberrations were counted in cultured peripheral blood cells from 11 donors before and after 2-week therapy with a vitamin complex. The complex contained the major vitamins in doses not surpassing the recommended daily doses. Vitamins had no effect on spontaneous mutations, but increased cell resistance to clastogenic effects of dioxidine in a concentration of 0.1, but not 0.01 mg/ml. Cell sensitivity to bleomycin notably increased after vitamin therapy in some donors and decreased in others, the mean parameters in the group remained virtually unchanged.