The method of increasing the resistance of experimental animals to xenobiotics

 

(57) Abstract:

The invention relates to experimental medicine. Guinea pigs and rats exposed polycyclic aromatic hydrocarbons (PAH) total dose of 200 mg for 2-8 months with the subsequent introduction of a virulent strain of H37RvMycobacterium tuberculosis (MBT) in a dose of 0.1 mg, supplemented with glutamate sodium at a dose of 0.1 g/kg weight of the animal. MSG administered for 1-2 months, beginning with the 15th day after the introduction of a virulent strain of M. tuberculosis. This invention can be used in Oncology, immunology, Microbiology, biochemistry, pathophysiology, Phthisiology for the development of new methods of treatment. table 2.

The invention relates to the field of experimental medicine and can be used in Oncology, immunology, Microbiology, biochemistry, pathophysiology, Phthisiology for the development of new treatment methods.

Among xenobiotics is alien to the body of the compounds, the most common are polycyclic aromatic hydrocarbons (PAHs). PAH due to good solubility in lipids can easily penetrate into the body and rapidly neutralized in many organs and tissues. However, the establishment of cellular structures and this, in turn, underlies the damaging effects of PAHs, in particular their carcinogenic and mutagenic effects.

The workers of hazardous industries, which had exceeded the maximum allowable concentrations for PAHs, there is an increase as cancer and diseases on other parameters (inflammation, acute viral infection, diseases of the nervous system, and so on ) (Capitolemi Century B. results and prospects for the study of working conditions in the manufacture of coke. Actual problems of hygiene in the metals and mining industry. M. : Institute. F. F. Erisman, 1985, S. 18-23).

Known methods of increasing the resistance of experimental animals to xenobiotics, according to which the organism is exposed to PAHs and microorganisms.

In one of the ways in mice exposed one of the PAH - 7,12 - dimethylbenzanthracene, then bring in the intestines croorganisms - bifidobacteria, lactobacilli and eubacteria (Shenderov B. A. Microecological aspects of carcinogenesis. Antibiotics and chemotherapy, 1990 T. 38, 10, S. 7-12).

In another way the rats Wedag tularemia vaccine, then within 15 days after infection centuries the mutagenesis, induced by 3,4-benzo(a)pyrene in rats. Experimental Oncology, 1985, 7 so, 1, S. 38-40).

However, the introduction of these microorganisms in experimental animals are not capable of significantly change the pathogenetic mechanisms of action of PAHs and does not affect the fundamental mechanisms of resistance to the mutagenic and carcinogenic effects last.

The closest in technical essence and the achieved result is a method of increasing the resistance of experimental animals to xenobiotics, selected as a prototype (see application 95102037/14 (003911) from 13.02.95 "Method of immunomodulation in experimental animals").

The known method includes the impact of PAH total dose of 200 mg, followed by the introduction of a virulent strain of H37RvMycobacterium tuberculosis in a dose of 0.1 mg

Introduction Mycobacterium tuberculosis (MW) changes pathogenetic mechanisms of action of PAHs on the organism of experimental animals. However, this change is not enough expressed to judge the increase of resistance of the organism to the mutagenic and carcinogenic effects of these xenobiotics.

The problem to which the invention is directed, x with leveling their mutagenic and carcinogenic effects.

To solve this problem in the method of increasing the resistance of experimental animals to xenobiotics, including the effects of PAHs total dose of 200 mg, followed by the introduction of a virulent strain of H37RvMycobacterium tuberculosis in a dose of 0.1 mg, according to the invention rats and Guinea pigs impose additional glutamate sodium at a dose of 1 g/kg of the animal within 1-2 months starting from 15 days after injection of Mycobacterium tuberculosis and PAH impacts within 2-6 months.

The author found that the effect on Guinea pigs and rats PAH leads to disruption of cell-mediated immunity, which is expressed in the reduction in the percentage of T - and b-lymphocytes in the immunological and increasing 0-lymphocytes. In General, the obtained results are consistent with the literature on the immune system when exposed to PAHs on the body (I. E. Kovalev, N. Century Shipulina, N. Century Tomilin. Induction of cytochrome P-450 and the subsequent induction of the immune response in rats after repeated administration of xenobiotics. Pharmacology and toxicology, 1990, I. 53, 1, S. 51-53).

Shortcomings related to the fact that the impact of PAH on the organism of experimental animals is accompanied by depletion of cysteine and glutathione in tissues kromekote biosynthesis of arginine and urea; in the lungs increases the concentration of polyamines; in the liver significantly increased the content of inorganic sulfate. In the lungs, blood and liver increased the content of glutamic acid.

There is evidence in the literature that during carcinogenesis, especially in tumors induced PAH, dramatically increases the content-rich nitrogen metabolites (polyamine, amino acids, nucleic acids). At the same time, the content of metabolites, having in its composition sulfur (cysteine), decreases.

So, the increase of inorganic sulfate affects the charge of histones and nucleic acids and may be related to the damaging effects of PAH on the nuclear apparatus of the cell. (Hughes M. Inorganic chemistry of biological processes, Per. s angl. M. : Mir, 1983. -416 C. ). A significant accumulation of arginine and polyamines is relevant to carcinogenesis, because this process is characterized by an increase in damaged tissue arginine and polyamines - stimulants proliferative processes (Chapot B. C. Biochemical aspects of tumor growth. M. : Mir, 1975, 304 S. ).

The author found that when exposed to PAHs total dose of 200 mg within 2-6 months in the body of Guinea pigs and rats revealed rebuilding nerissa sulfur-containing substances (cysteine, glutathione).

When exposed to PAHs over a period of 8 months, the pattern of change remains constant, moreover, in a later period may be affected by factors of aging of the organism of experimental animals.

Introduction experimental animals virulent strain of H37RvMycobacterium tuberculosis in a dose of 0.1 mg after exposure to PAHs total dose of 200 mg for 2-8 months leads to the opposite dynamics of the investigated nitrogen-containing and sulfur-containing metabolites. Content glutaminol acid, polyamine, arginine, urea, inorganic sulfate in tissues sharply decreases in the levels of cysteine and glutathione increases.

Obviously, these shifts provide antimutagenic effects of MW, which is set by the author in micronuclear test. The number of microkernels in polychromatophilic bone marrow of rats is reduced by more than 2 times, while under the influence of PAH it has a threefold increase compared to intact animals; see table. 1.

Additional introduction experimental animals glutamate sodium at a dose of 0.1 g/kg weight of the animal, carried out 15 days after the introduction of the office and continued for 1-2 months, potentiates education is Intesa glutathione in the liver, where is the predominant formation of this Tripeptide and providing them the entire body. In turn, from the provision of glutathione largely depends on the resistance of the tissues to carcinogenic and mutagenic effects of xenobiotics.

The number of microkernels in polychromatophilic bone marrow of rats after administration of sodium glutamate is almost normal, closer to the intact group (table. 1).

Thus, based on antimutagenic and anticarcinogenic effects consistently entered the office and monosodium glutamate after exposure to the organism Guinea pigs and rats PAH is the ability to enhance the body's formation of cysteine and glutathione - a powerful anticarcinogenic and antimutagenic substrates.

The dose of a virulent strain of H37RvMycobacterium tuberculosis 0.1 mg selected to obtain clear results on pigs and rats. Lower doses rats are not sensitive and dose more selected cause too rapid tuberculosis in Guinea pigs, therefore, identified the author of the switching mechanisms associated with the exchange of sulfur and nitrogen, becomes less evident.

For clarity and speed of the experiment websonic leads to rapid generalization of experimental tuberculosis in Guinea pigs, and rats to distinct changes in the immune system and the metabolism of amino acids associated with the metabolism of nitrogen and sulfur in the studied tissues.

The author establishes that a substantial change of the pathogenetic mechanisms and the maximum potentiation of these changes occur at the chosen dose of monosodium glutamate 1 g/kg weight of the animal entered in 1-2 months, beginning with the 15th day after the introduction of the office. In the case of the introduction of sodium glutamate immediately after infection the office or later, for example after 1-1,5 month, the effect of joint exposure was less.

The method is as follows. Groups of experimental animals - Guinea pigs and rats injected into the trachea under ether anaesthesia, a single dose of PAH in the mixture: coal tar (COP) - 5% solution in sunflower oil 0.5 ml and 0.1% solution of carbon black (gas lamp and equally) in physiological solution 0.5 ml

After effects CC with soot total dose of 200 mg animals injected virulent strain of H37Rvmycobacteria at a dose of 0.1 mg in the groin crease. 15 days after the introduction of a virulent strain MW experimental animals subcutaneously injected glutamate sodium at a dose of 1 g/kg daily for 1-2 months.

After carrying out of the way animals have investigated the amino acid content of adaptogens in the liver, the numerical values presented in table 2.

Example 1. Watched groups of animals: control group (intact animals) Guinea pigs (rats) and group of Guinea pigs (rats) exposed to CS and soot within 4 months from the intensity of the introduction of a single dose 2 times a month with the subsequent introduction of a virulent strain37RvThe office (I group the prototype).

Animals of the first group content of cysteine and glutathione increases compared with the control group, and the content of glutamic acid in comparison with the same group decreases. However, the observed shifts are not always distinct.

Example 2. The following groups of animals: control group (intact animals) Guinea pigs (rat), Guinea pigs (rats), which was affected by the COP and soot within 2 months from the intensity of the introduction of the single phase 1 once a week with subsequent exposure to the office (group 2 - the prototype), and Guinea pigs (rats) exposed to PAHs during 2 months (intensity 1 time per week), followed by the introduction of a virulent strain of H37Rv

Example 3. Then, the observation of two groups of animals: Guinea pigs (rats) exposed to CS and soot within 8 months (intensity 1 time per month), followed by the introduction of the office (group 4 - the prototype), and Guinea pigs (rats), which affects the COP and soot 8 months (intensity 1-2 times per month), followed by the introduction of strain in the office and monosodium glutamate for 2 months (group 5 - according to the invention).

In group 4 animals compared to 5 group there is a distinct increase in the cysteine in Guinea pigs and some improvement in rats. Rats have a tendency to increase glutathione, and in animals of both species is the tendency to decrease in glutamic acid.

Weia expressed in relation to animals, exposed to the COP and soot within 2, 4, 8 months.

The data from table 2 indicate correction pathogenetic mechanisms of action of PAHs and leveling their mutagenic and carcinogenic effects.

Thus, the proposed method has a quality advantage as compared to the prototype, and other available experimental research, which is reflected in the correction of the pathogenetic mechanisms of action of PAHs and the possibility to adjust antimutagenic and anticancerogenic the body's resistance to xenobiotics. As a consequence, improves the survival of animals, clinical condition and the possibility of their use in experimental modeling.

The proposed method can be used in experimental medicine to develop ways of biotherapy of cancer.

The method of increasing the resistance of experimental animals to xenobiotics, according to which the organisms of these animals exposed to polycyclic aromatic hydrocarbons (PAH) total dose of 200 mg, including subsequent single injection of Guinea pigs and rats virulent strain of H37Rv the keys within 2-8 months and with 15 days after a single administration of virulent strains of H37RvMycobacterium tuberculosis is injected glutamate sodium at a dose of 1 g/kg weight of the animal within 1-2 months.

 

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