Mutagens

Mutagens (from the Latin. Mutatio - change and others. Greek. Γεννάω - give birth) - chemical and physical factors that cause hereditary changes - mutations . Artificial mutations were first obtained in 1925 by G. A. Nadson and G. S. Filippov in yeast by the action of radioactive radiation of radium ; in 1927, G. Möller received mutations in Drosophila by the action of x-rays . The ability of chemicals to cause mutations (by the action of iodine on Drosophila ) was discovered by I. A. Rapoport . In individuals of flies developed from these larvae , the mutation frequency was several times higher than in control insects .

Content

Classification

Mutagens can be various factors that cause changes in the structure of genes , the structure and number of chromosomes . By origin, mutagens are classified into endogenous , formed during the life of the organism and exogenous - all other factors, including environmental conditions.

By the nature of occurrence, mutagens are classified into physical, chemical and biological:

Physical mutagens

ionizing radiation (x-ray and gamma radiation);
electromagnetic radiation ( ultraviolet , in some cases - visible light);
radioactive decay;.

Chemical mutagens

Chemical mutagens are the most common in the group. These include the following groups of compounds:

some alkaloids : colchicine - one of the most common mutagen selection, vincamine , podophyllotoxin ;
oxidizing agents and reducing agents ( nitrates , nitrous acid and its salts - nitrites , reactive oxygen species );
alkylating agents (e.g., iodoacetamide , epoxybenzanthracene );
urea nitro derivatives: nitrosomethylurea , nitrosoethylurea , nitrosodimethylurea - are often used in agriculture;
ethyleneimine , ethyl methanesulfonate , dimethyl sulfate , 1,4-bis-diazoacetyl butane (known as DAB);
some pesticides ( pesticides of the aldrin group , hexachloran );
some food additives (for example, aromatic hydrocarbons ( benzene , etc.), cyclamates );
oil refining products;
organic solvents ;
drugs (e.g. cytostatics , mercury preparations, immunosuppressants ).

A number of viruses can conditionally be attributed to chemical mutagens (the mutagenic factor of viruses is their nucleic acids - DNA or RNA).

Biological mutagens

specific DNA sequences - transposons ;
some viruses ( measles , rubella , flu virus );
metabolic products (products of lipid oxidation );
antigens of certain microorganisms .

Chemical Mutagen Exposure Mechanism

The mechanism of action is based on the formation of so-called DNA adducts with nucleic bases. The more such DNA adducts are formed in the molecule, the stronger the native DNA structure changes, which makes it impossible for the protein biosynthesis to proceed correctly ( transcription and replication ) and thereby generates the expression of mutant proteins. Almost all chemical mutagens are sources of malignant tumors (they are carcinogenic ), however, not all carcinogens exhibit mutagenic properties.

Consider the mechanism of action of one of the mutagens - benzene epoxide.

Benzene itself does not have mutagenic activity, i.e. is promutagen . However, as a result of biological oxidation and biotransformation in the cells of the liver , kidneys, and especially in the myeloid tissue of the red bone marrow, it acquires mutagenic properties. Once in the hepatocyte , benzene is immediately hydroxylated by a microsomal oxidation system, catalyzed by a group of enzymes of the cytochrome P450 family to epoxide. Benzene epoxide has an extremely high reactivity due to the formation of a strained cycle between the oxygen atom and the benzene molecule. He is able to very quickly alkylate nucleic acid molecules, in particular DNA . The nucleophilic substitution reaction S _N 2 lies in the mechanism of the formation of a DNA adduct by benzene epoxide: an electrophile — in this case, it is an epoxide (due to the breaking of the cycle it becomes electron-deficient) —which interacts with nucleophilic centers — NH ₂ groups (which are electron- rich ) of nitrogenous bases , - forming covalent bonds with them (often very strong). This property to alkylation is especially manifested in guanine , since its molecule has the most nucleophilic centers, with the formation, for example, of N7-phenylguanine. The resulting DNA adduct can lead to a change in the structure of DNA, thereby disrupting the correct course of transcription and replication, which is a source of genetic mutations. The accumulation of epoxide in liver cells leads to irreversible consequences: an increase in DNA alkylation, and at the same time an increase in the expression of mutant proteins that are products of a genetic mutation; inhibition of apoptosis ; transformation and even cell death. In addition to pronounced pronounced genotoxicity and mutagenicity, it also has strong carcinogenic activity, especially this effect is manifested in myeloid tissue cells (cells of this tissue are very sensitive to xenobiotics of this kind).