In pathochemical classification of chemical substances of this group are referred to as alkylating poisons. Under the alkylation refers to the process of displacement of the poison molecule functional groups in General and protein of nucleoproteins in particular.

Distinguish alkylating effect of the General election and. Common alkylating agents include substances, having one or more active radicals of the following structure:

1) derivatives of sulfur mustard gas: R _ S _ CH2 _ CH2 _ Cl

2) nitrogenous derivatives of mustard gas:

3) epoxies:

4) ethylenimine:

5) esters of methansulfonate:

The second group of skin-resorptive poisons are the so-called thiol poisons. Are solids, only which selectively alkylate thiol groups of metabolites tissue. Such properties are compounds of trivalent arsenic, and a number of ORGANOMETALLIC compounds.

There are three theories of the mechanism of action, to be read in conjunction.

1. The mechanism of action of Ipatov based on the displacement of the molecule of the poison hydrogen groups at the nitrogen atom of the nitrogenous bases of nucleoproteins (nucleotidase action).

As you know, deoxyribonucleic acid (DNA) represents a chain of deoxyribonucleotides, which in turn, consist of pentose sugar, the remainder of the phosphoric acid and nitrogenous bases. According to many studies, the most interesting is the reaction of Ipatov with nitrogenous bases of DNA (adenine-thymine, guanine-cytosine). Alkylating substances more readily react with guanine. Alkylation of guanine leads to the appearance of unstable Quaternary nitrogen. As a result of the sugar-phosphate-nitrogenous frame DNA disintegrates, which leads to the depolymerization of nucleoproteins.

2. Mechanism of action based on intracellular activation of a molecule of mustard gas with the formation in the cell onium compounds and subsequent active radicals (lucapagano action) [Rodavich].

In the study of the hydrolysis of mustard gas was shown, at the beginning of the guide

rolisa formed the so-called onium compounds (onium ions). Sulphur mustard by hydrolysis forms sulfonate ions, and nitrogen mustard ethylenimmonium ions. These ions have high reactivity, due to which they are compared with products of radiolysis of water. Onium ions can interact with the nitrogen of the purine nucleus of adenine and guanine, within the structure of nucleic acids, and to alkylate them and even "stitch" chains of nucleic acids. As a result of this interaction greatly upset the functioning of nucleic acids, which leads to disruption of protein synthesis, and to the suppression of tissue regeneration. The consequence of DNA damage is the breach of chromosome apparatus, and the change in hereditary traits.

In addition, onium acids may cause ion N, IT, НО2, which is also very reactive and exert effects on cells tissues, which reminds one of the damaging action of ionizing radiation.

However, between the action of Ipatov and penetrating radiation there are significant differences. R.. Lekavicius (1967) results, showing, that the nuclei are more sensitive to mustard gas, than to penetrating radiation.

When exposed to penetrating radiation on the nuclei of the cells were observed and chromosomal, and chromatide aberration. Under the action of Ipatov observed only chromatide aberration. Cytogenetic effects of Ipatov are observed not earlier, than 8 hours, but when irradiated they are detected almost immediately. Oxygen does not burden the toxicity of alkylating compounds, but when exposed to ionizing radiation the number of aberrations in the presence of oxygen increases.

3. The theory of bridging ties (allergogenny action). The mechanism of action is based on blocking of the polypeptide chain epitim "lock".

Iparty with two or three chloroethyl radicals more active. than one chloroethyl radical. Therefore, bifunctional iparty interact with a metabolite of the two ends of its molecules, as if sewing the metabolite, as if locking on "castle", forming a bridging connection to the stud of the polypeptide or the nucleotide. The polymerization pritnyh molecules after connecting them to proteins. Clear, these proteins will lose their reaction skills and, apparently, they become autoantigens, defining some allergic effects of Ipatov.

Options DNA damage by mustard gas:

1. The elimination of nitrogenous bases.

2. Interaction with the remainder of the phosphoric acid.

3. Rupture of DNA chains.

4. Interaction with nitrogen bases.

5. Stitching 2 coiled chains of DNA.

6. Error pairing of nitrogenous bases.

The effect of Ipatov on DNA leads to toxigenicity violations, which is manifested:

1) violation of mitoses (cytostatic effect);

2) violation of the synthesis of proteins and enzymes;

3) malignant cellular damage (blastomogenn);

4) developmental disorders of the embryo and fetus (teratogenic effects);

5) disorders of the immune system;

6) a violation of the genetic characteristics of cells (mutagenic effect).

Features of the mechanism of action of alkylating poisons

with selective action (lewisite)

In laboratories Peters (England) and A. And. A Circassian (Kiev) it has been shown. that compounds with trivalent arsenic readily react with free amino acids, having a sulfhydryl group (cysteine):

However, a more stable relationship trivalent arsenic reacts with polypeptides:

Penetrating into the tissue, lewisite damages the enzyme system, rich in thiol groups. The most vulnerable were pyrovatex dasna system, which includes lipoic acid, having two thiol groups.

According to Peters (1963). And. And. A Circassian (1964), dihydrolipoic acid, a primary object of influence of the group of thiol poisons. Hydrolase (including cholinesterase), oxidase (piruwatkinaza system) and dehydrogenase, a number of enzymes ATP, finally, cholinergic receptors contain thiol groups and may be damaged when the tissue penetration of lewisite.

In addition under the action of thiol poisons, there is a lack luchaogang action.