Hepatocarcinogen

Chemical hepatocarcinogens are represented by numerous organic compounds, only a small number of inorganic substances have this ability.

The mechanism of action of PAHs and their derivatives

Most chemical hepatocarcinogens are polycyclic aromatic hydrocarbons and their derivatives. They are formed as a result of combustion processes of petroleum products , products of the coal and coke industry, wood , household garbage, incomplete combustion of fuel , as a result of oil smelting, when meat and fish are very hot, they are part of cigarette smoke, smog , are found in the air of cities, large oil -, coke-chemical enterprises, thermal power plants working on coal . Many PAHs, in addition to carcinogenic activity, have a teratogenic effect.

PAHs enter the body in several ways:

• air - through the respiratory tract and lungs ,
• dermal - through the skin (especially damaged) and mucous membranes,
• alimentary - that is, with food.

After penetrating into the blood, PAHs are transferred to the liver , where they are neutralized to inert water-soluble and non-carcinogenic metabolites. However, the oxidation products of PAH often cause negative cell changes, such as malignancy or tumor transformation.

Consider the effect of one of the derivatives of benzanthracene - epoxybenzantracene . Once in the hepatocyte, benzanthracene is oxidized (hydroxylated) by the microsomal system catalyzed by cytochrome P450 to epoxide. Epoxide is a highly reactive substance, due to the formation of a cycle, between the oxygen atom and the hydrocarbon molecule (the cycle has a strong voltage), as a result, it can easily bind to the nucleophilic groups of the nitrogenous bases that make up the DNA . The process of interaction of epoxide with nucleophilic groups of DNA is called alkylation. Alkylation occurs with the formation of covalently bound (often very strongly) DNA adducts with nucleic bases (especially with guanine ). The resulting adducts cause a variety of DNA damage that leads to transcriptional disturbances and mutations . In addition to the strongest carcinogenic effect, epoxybenzatetrace also has a strong toxic effect, however, if its concentration in cells is low (<5 μg / l), the products of further oxidation are less dangerous and are eliminated from the body. A higher concentration of epoxide (from 5 µg / l) in liver cells leads to tumor transformation, apoptosis and death. The accumulation of epoxide oxidation products also entails mutations and a tumor effect .

The mechanism of action of aromatic amines

Many aromatic amines are widely used in industry and in everyday life. They have a rezobtivny action - causing tumors, distant from the place of entry or introduction. These abilities have:

• 2-naphthylamine
• Benzidine
• 4-aminodiphenyl

Aromatic amines penetrate the human body in several ways:

• through the airways and lungs
• through the skin.

The mechanism of action of these carcinogens is similar to the mechanism of action of PAHs . Once in the hepatocyte, the aromatic amine is hydroxidized to epoxide, which, depending on the concentration, either damages the genetic material of the cell, causes transformation or cell death, or is neutralized by the enzyme system to safer metabolites.

The mechanism of action of aflatoxins

Aflatoxins (abbr. From A spergillus fla vus toxin s) are the strongest hepatocarcinogens produced by some species of microscopic Aspergillus fungi ( A.flavus , A.parasiticus, etc.).

All aflatoxins are contaminants and enter the human body exclusively by alimentary means, ie, with food products that have been affected by Aspergillus micromycetes (the basis is made up of products of plant origin with a high content of oils and starch - peanuts , cereals , corn , dried fruits , are less common in products animal origin - milk , meat and eggs).

The mechanism of action on hepatocytes has similarities with the mechanism of action of PAH . However, hydroxylation products have higher oxidative properties and damage cells by disrupting the structure of the integrity of biomembranes and nucleic acid alkylation.

In the aflatoxins molecules, a large number of oxygen atoms, as a result, when entering the liver cell and undergoing microsomal hydroxylation, the molecules acquire extremely reactive properties. They immediately begin to alkylate DNA chains, forming strong adducts with them. DNA alkylation leads to damage to the p53 tumor suppressor gene, up to loss of protein expression ^[1] . Thereby depriving the hepatocyte apoptosis . Further continuation of the process leads to the transformation of cells, through the activation of certain oncogenes , for example, K-ras, causing hepatocellular carcinoma ^[2] .

The alkylation rate is limited by the concentration of hydroxylation products, however, even a minimal amount causes serious damage to the hepatocytes. In addition, they have the strongest hepatotoxicity (especially Aflatoxin B1 - the most toxic, SDYAV , the minimum lethal dose for humans is less than 2 mg / kg). Aflatoxin poisoning requires immediate medical attention.

Mechanism of action of inorganic carcinogens

Among inorganic hepatocarcinogens, arsenic , cadmium compounds and hexavalent chromium should be noted. Hexavalent chromium is a genotoxic indirect hepatocarcinogen. Once in the liver cell, it enters a more stable pentavalent state, which has pronounced genotoxicity . In addition to the pentavalent state, trivalent chromium is also formed.

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1. ↑ Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA. Environmental and chemical carcinogenesis. Seminars in Cancer Biology (2004). 14: 473-486.
2. ↑ Ricordy R, Gensabella G, Cacci E, Augusti-Tocco G. In human cell lines. Mutagenesis (2002). 17: 241-249.
3. ↑ ^{1 2} Kutsenko S.A. Fundamentals of toxicology. - 2002.