Preparation of antimutagenic activity

FIELD: medicine.

SUBSTANCE: the present innovation deals with the preparation of antimutagenic activity towards chemical mutagens as betulinic acid previously known as an antimutagen towards ultraviolet and as an antioxidant. The decrease of chromosomal aberrations has been shown in animals towards chemical mutagens of dioxidine and cyclophosphamide due to the action of betulinic acid within wide range of dosages.

EFFECT: higher efficiency.

3 tbl


The present invention relates to the field of medicine and veterinary medicine and can be used to suppress the cytogenetic action of chemical mutagens. More specifically it relates to finding new and effective tools with antimutagenic activity.

The essence of the present invention is used as a tool in relation to chemical mutagens known and widely studied chemical compounds - Betulinol acid.

In [1] was shown antimutagenicity Betulinol acid with respect to such physical mutagen, as ultraviolet light. However, antimutagenicity this matter in relation to chemical mutagens were not studied at the same time reliably predict it on the basis of the specified operation is not possible, not only because of fundamental differences mutagens, but also because of the nature published in [1] studies were single, conducted in vitro using exotic cell line. In addition, the used method of assessing DNA damage, while for anti-mutagenic research is recommended [2] method of assessing chromosomal mutations.

Antimutagenic activity of Betulinol acid (BC) in relation to chemical mutagens was discovered by the inventors in research i vivo using as a test mutagens such substances, as cyclophosphamide and dioxidine, common for this kind of research.

For the evaluation of antimutagenic (mathematicorum) properties Bq used accounting method, chromosomal aberrations in bone marrow cells of mice. The method is based on visual microscopic registration of chromosomal damage in bone marrow cells of small laboratory rodents.

The study was performed on male mice of C57BL/6 weighing 18-20, Animals were kept under 12-hour light mode, standard brittoniana stern, with free access to water in the vivarium conditions of the research laboratory of pharmacological genetics research Institute of pharmacology name Century. Century. nine RAMS.

Bq is administered orally in an aqueous suspension of tween-80 at doses of 1, 10 and 100 mg/kg Mutagens: cyclophosphamide rate of 20 mg/kg and dioxidine at a dose of 200 mg/kg was injected intraperitoneally in the form of aqueous solutions. Used three modes of treatment of animals: a single joint introduction Bq with a mutagen, a preliminary five-day introduction Bq involving his co-introduction with the mutagen on the last day of treatment of animals, as well as a daily joint 5-day introduction Bq with a mutagen.

Cytogenetic preparations were prepared 24 hours after a single or, in the case of repeated injections, the last injection of the drug.

In the all versions of animal experiments for 2.5 hours before slaughter has introduced colchicine (Serva, Germany at the rate of 2.5 mg/kg to suppress the formation of chromating spindle cell division and accumulation of metaphases.

The slaughter of animals was carried out by displacement of the cervical vertebrae. Then quickly allocated thighs, cut the epiphyses and washed bone marrow cells hypotonic solution (0.55% KCl), pre-warmed to 37°C. After incubation at 37°C for 15 minutes, the cell suspension was centrifuged for 5 minutes at 1000 rpm the Supernatant was decanted, the precipitate was reasponsible and added 3 ml of pre-cooled clamp consisting of a mixture of ethanol and glacial acetic acid in a ratio of 3:1. The time of incubation of cells in the fixative was 10 minutes. Then they were re-centrifugation and change the pin (3 ml). After that, cells were incubated in the refrigerator for another 20 minutes. Suspension is again centrifuged, removing the supernatant, the precipitate resuspendable in 0.5 ml of the newly added lock and put on the wet pre-fat and a chilled glass, which was dried in the flame of an alcohol burner.

The color produced Azur-eosin. The composition of the dye included: 5 pieces Azura (0.1%), 2 parts eosin (0.1%), 10 parts of distilled water. The cytogenetic analysis of used microscope Zeiss standard-20, 10×100.

When citoh the kinetic analysis of the considered cells with achromatic gaps (gepmi), single and paired fragments of chromosomes, chromosomal and chromatide exchanges, as well as cells with multiple injuries chromosomes (more than 5 chromosomal damage in the cell). Assessment mathematicia activity produced by comparing the total number of cells with gepasi and structural damage to chromosomes in the control and experimental series of studies [3]. On each animal were analyzed in 100 metaphases in each group was investigated 4-5 animals. Statistical analysis was performed using ϕ-criteria.

The results of cytogenetic studies are presented in tables 1-3.

Table 1 presents results describing the influence of BC on the cytogenetic effects dioksidina and cyclophosphamide, applied at the rate of 200 and 20 mg/kg, respectively, after a single intraperitoneal administration of the compounds under study.

A single injection dioksidina at a dose of 200 mg/kg resulted in increase in cells with chromosomal aberrations to a value of 9.3±1.5%, which is statistically significantly higher than the control values (1.6±0.6%).

After the introduction of combination Bq dose of 1 mg/kg and dioksidina recorded 5,6±1.0% aberrant metaphases. The result is statistically significantly different from the value of the positive control, were carried out using a mutagen, and indicates a 40% reduction is AI damaging the clastogenic effect of the mutagen. Antimutagenic effect of Bq in the dose of 10 mg/kg increased to 57%. In this experiment, was registered 4.0±0.9% of damaged metaphases. After using BC at a dose of 100 mg/kg have also found a reduction effect of the mutagen, but it had no statistically significant effect (table 1).

Antimutagenic effects of Bq were confirmed using as model mutagen cyclophosphamide (table 1).

When applying Bq at doses of 10 and 100 mg/kg registered similar antimutagenic effect: reducing the damaging effect of the mutagen in both cases amounted to 60-66% (the level of chromosomal aberrations, respectively, 3.0±0.9% and 3.5±0.9% against 8.8±1.3% in the positive control). At a minimum dose of 1 mg/kg Bq showed antimutagenic capacity. The number of aberrant cells - 7.5±1.3%identified in this variant of the experiment, were not statistically significant differences from the values of the positive control, characterizing the effect of the mutagen,

In the next series, the results of which are presented in table 2, we studied the effect of 5-day pretreatment Bq on the manifestation of mutagenic effects dioksidina and cyclophosphamide. The dose range in which Bq showed antimutagenicity in this mode, the treatment of animals, significantly decreased in comparison with a single introduction. Reducing the effects of both mutagens were detected is only under the influence of BC, used in a dose of 10 mg/kg Cytogenetic activity dioksidina was reduced by 44%, cyclophosphamide 59%. BC when used in doses of 1 and 100 mg/kg did not cause significant changes in cytogenetic effects used mutagens.

In the next series of experiments investigated the influence of BC on the mutagenic effects dioksidina and cyclophosphamide in conditions 5-day joint injection. The results are presented in table 3.

After the five-day treatment of animals dioksidin at a dose of 200 mg/kg chromosomal aberrations registered in 10.5±1.5% of metaphases studied. After a joint application dioksidina and BC at a dose of 1 mg/kg revealed 6.0±1.0% of damaged cells, which corresponds to a 43% decrease in the effects of the mutagen. The results obtained after co-administration of mutagen and BC at doses of 10 and 100 mg/kg, respectively 13.8±1.6% and 7.2±1.2% aberrant metaphases. Pairwise comparison of these results with the data of the positive control did not show between them are statistically significant differences, i.e. the same as in the previous case, antimutagenic activity Bq was revealed when it is used in only one dose.

On the background of using the standard mutagen cyclophosphamide Bq showed a protective effect in the whole range of the investigated doses. After the common introduction of Bq in the Oze 1 mg/kg and mutagen registered 3.6± 0.8% aberrant metaphases, which corresponds to a 54% decrease in the cytogenetic effect. When applying Bq dose of 10 mg/kg was registered a statistically significant decrease in the cytogenetic effect of the mutagen to 4.0±0.9%, i.e. by 49%. Even more marked antimutagenic effect of BC was observed when used at the rate of 100 mg/kg Result in this variant of the experiment, - 1.8±0.6% aberrant metaphases is practically coincides with the data detected in intact control animals, and indicates complete suppression of the cytogenetic effect of the mutagen.

Studies suggest the presence of Bq antimutagenic activity. Protective effects Bq most expressed in terms of a single injection, as well as in relation to cyclophosphamide at joint re-introduction. The last observation is described along with the data of other experiments, in which the mutagenic effect of Bq in quantitative terms better defined in relation to cyclophosphamide, allow to conclude that Bq in the study is most effective when applied as model mutagen cyclophosphamide.

Thus, betulin acid in the dose range of 1-100 mg/kg possesses antimutagenic activity, reflected in the reduction of cytogenetic effects of chemical mutagens. With Epen severity of antimutagenic effect Betulinol acid indicates the prospect of its potential use as pharmacological protection of the genome.

Sources of information

1. Salti G.I., Kichina J.V., Das Gupta AS et. al. Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naevai cells: evidence for a potential role as a chemopreventive agent // Melanoma Res, Apr. 2001; 11(2):9,9-104.

2. Guidelines for the evaluation of the Carcinogenicity of pharmaceuticals and excipients in short-term tests. // Guidance on experimental (preclinical) study of new pharmacological substances. - M - Ministry of health - JJA "Remedium". - 2000. - p.66-86.

3. Malashenko, A.M., Surkov NI and other determination of the mutagenicity of chemical compounds (genetic screening) in laboratory mice (HOWTO) - M, 1977.

Use Betulinol acid as a means with antimutagenic activity against chemical mutagens.


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