The versatility of the impact of food on the human body is due not only to the presence of energy and plastic materials, but also to a huge amount of food, including minor components, as well as non-nutritive compounds. The latter may have pharmacological activity or have adverse effects.

The concept of biotransformation of foreign substances includes, on the one hand, the processes of their transport, metabolism and toxicity, on the other hand, the possibility of the influence of individual nutrients and their complexes on these systems, which ultimately ensures the neutralization and elimination of xenobiotics. However, some of them are highly resistant to biotransformation and cause damage to health. In this aspect, the term should also be noted detoxification - the process of neutralizing harmful substances that have entered into a biological system. Currently, quite a large amount of scientific material has been accumulated on the existence of general mechanisms of toxicity and biotransformation of foreign substances, taking into account their chemical nature and the state of the body. Most studied mechanism of two-phase detoxification of xenobiotics.

At the first stage, as a response of the body, their metabolic transformations into various intermediate compounds occur. This stage is associated with the implementation of enzymatic reactions of oxidation, reduction and hydrolysis, which usually occur in vital organs and tissues: liver, kidneys, lungs, blood, etc.

Oxidation xenobiotics are catalyzed by microsomal liver enzymes with the participation of cytochrome P-450. The enzyme has a large number of specific isoforms, which explains the variety of toxicants that undergo oxidation.

Recovery carried out with the participation of NADON-dependent flavoprotein and cytochrome P-450. As an example, we can cite the reduction reactions of nitro- and azo compounds into amines, and ketones into secondary alcohols.

Hydrolytic decomposition As a rule, esters and amides are subjected to subsequent deesterification and deamination.

The above biotransformation pathways lead to changes in the xenobiotic molecule - polarity, solubility, etc. increase. This contributes to their removal from the body, reducing or eliminating the toxic effect.

However, primary metabolites may be highly reactive and more toxic than the parent toxic substances. This phenomenon is called metabolic activation. Reactive metabolites reach target cells, trigger a chain of secondary catobiochemical processes that underlie the mechanism of hepatotoxic, nephrotoxic, carcinogenic, mutagenic, immunogenic effects and corresponding diseases.

Of particular importance when considering the toxicity of xenobiotics is the formation of free radical intermediate oxidation products, which, along with the production of reactive oxygen metabolites, leads to the induction of lipid peroxidation (LPO) of biological membranes and damage to living cells. In this case, an important role is played by the state of the body's antioxidant system.

The second phase of detoxification is associated with the so-called conjugation reactions. An example is the binding reactions of active -OH; -NH2; -COOH; SH-groups of xenobiotic metabolites. The most active participants in neutralization reactions are enzymes from the family of glutathione transferases, glucoronyltransferases, sulfotransferases, acyltransferases, etc.

In Fig. Figure 6 shows a general diagram of the metabolism and mechanism of toxicity of foreign substances.

Rice. 6.

The metabolism of xenobiotics can be influenced by many factors: genetic, physiological, environmental factors, etc.

It is of theoretical and practical interest to dwell on the role of individual food components in the regulation of metabolic processes and the implementation of the toxicity of foreign substances. Such participation can occur at the stages of absorption in the gastrointestinal tract, hepatic-intestinal circulation, blood transport, localization in tissues and cells.

Among the main mechanisms of biotransformation of xenobiotics, the processes of conjugation with reduced glutathione - T-y-glutamyl-D-cysteinyl glycine (TSH) - the main thiol component of most living cells, are important. TSH has the ability to reduce hydroperoxides in the glutathione peroxidase reaction and is a cofactor in formaldehyde dehydrogenase and glyoxylase. Its concentration in the cell (cellular pool) depends significantly on the protein and sulfur-containing amino acids (cysteine ​​and methionine) in the diet, so a deficiency of these nutrients increases the toxicity of a wide range of hazardous chemicals.

As noted above, an important role in preserving the structure and functions of a living cell when exposed to active oxygen metabolites and free radical oxidation products of foreign substances is played by the body's antioxidant system. It consists of the following main components: superoxide dismutase (SOD), reduced glutathione, some forms of glutathione-B-transferase, vitamins E, C, p-carotene, the trace element selenium - as a cofactor of glutathione peroxidase, as well as non-nutritive food components - a wide range of phytocompounds (bioflavonoids ).

Each of these compounds has specific action in the general metabolic conveyor, forming the body's antioxidant defense system:

• SOD, in its two forms - cytoplasmic Cu-Zn-SOD and mitochondrial-Mn-dependent, catalyzes the dismutation reaction of 0 2 _ into hydrogen peroxide and oxygen;
• ESH (taking into account its above functions) realizes its action in several directions: it maintains the sulfhydryl groups of proteins in a reduced state, serves as a proton donor for glutathione peroxidase and glutathione-D-transferase, acts as a nonspecific non-enzymatic quencher of oxygen free radicals, ultimately converting , into oxidative glutathione (TSSr). Its reduction is catalyzed by soluble NADPH-dependent glutathione reductase, the coenzyme of which is vitamin B2, which determines the role of the latter in one of the pathways of biotransformation of xenobiotics.

Vitamin E (os-tocopherol). The most significant role in the system of regulation of lipid peroxidation belongs to vitamin E, which neutralizes free radicals of fatty acids and reduced oxygen metabolites. The protective role of tocopherol has been shown under the influence of a number of environmental pollutants that induce lipid peroxidation: ozone, NO 2 , CC1 4 , Cd, Pb, etc.

Along with antioxidant activity, vitamin E has anticarcinogenic properties - it inhibits N-nitrosation of secondary and tertiary amines in the gastrointestinal tract with the formation of carcinogenic N-nitrosamines, has the ability to block the mutagenicity of xenobiotics, and affects the activity of the monooxygenase system.

Vitamin C. The antioxidant effect of ascorbic acid under conditions of exposure to toxic substances that induce lipid peroxidation manifests itself in an increase in the level of cytochrome P-450, the activity of its reductase and the rate of hydroxylation of substrates in liver microsomes.

The most important properties of vitamin C associated with the metabolism of foreign compounds are also:

• the ability to inhibit covalent binding to macromolecules of active intermediate compounds of various xenobiotics - acetomionophen, benzene, phenol, etc.;
• block (similar to vitamin E) the nitrosation of amines and the formation of carcinogenic compounds under exposure to nitrite.

Many foreign substances, such as components of tobacco smoke, oxidize ascorbic acid to dehydroascorbate, thereby reducing its content in the body. This mechanism is the basis for determining the vitamin C supply of smokers, organized groups, including workers of industrial enterprises who are in contact with harmful foreign substances.

To prevent chemical carcinogenesis, Nobel Prize laureate L. Pauling recommended the use of megadoses exceeding the daily requirement by 10 or more times. The feasibility and effectiveness of such amounts remains controversial, since saturation of human body tissues under these conditions is ensured by daily consumption of 200 mg of ascorbic acid.

Non-nutritive food components that form the body's antioxidant system include dietary fiber and biologically active phytocompounds.

Alimentary fiber. These include cellulose, hemicellulose, pectins and lignin, which are of plant origin and are not affected by digestive enzymes.

Dietary fiber can influence the biotransformation of foreign substances in the following areas:

• influencing intestinal peristalsis, they accelerate the passage of contents and thereby reduce the time of contact of toxic substances with the mucous membrane;
• change the composition of microflora and the activity of microbial enzymes involved in the metabolism of xenobiotics or their conjugates;
• have adsorption and cation exchange properties, which makes it possible to bind chemical agents, delay their absorption and accelerate excretion from the body. These properties also influence the hepatic-intestinal circulation and ensure the metabolism of xenobiotics entering the body through various routes.

Experimental and clinical studies have established that the inclusion of cellulose, carrageenin, guar gum, pectin, and wheat bran in the diet leads to inhibition of (3-glucuronidase and mucinase of intestinal microorganisms. This effect should be considered as another ability of dietary fiber to transform foreign substances by preventing the hydrolysis of conjugates these substances, removing them from the hepatic-intestinal circulation and increasing excretion from the body with metabolic products.

There is evidence of the ability of low-methoxylated pectin to bind mercury, cobalt, lead, nickel, cadmium, manganese and strontium. However, this ability of individual pectins depends on their origin and requires study and selective use. For example, citrus pectin does not exhibit a visible adsorption effect, weakly activates 3-glucuronidase of intestinal microflora, and is characterized by a lack of preventive properties in case of induced chemical carcinogenesis.

Biologically active phytocompounds. Neutralization of toxic substances with the participation of phytocompounds is associated with their basic properties:

• influence metabolic processes and neutralize foreign substances;
• have the ability to bind free radicals and reactive metabolites of xenobiotics;
• inhibit enzymes that activate foreign substances and activate detoxification enzymes.

Many of the natural phytocompounds have specific properties as inducers or inhibitors of toxic agents. Organic compounds contained in zucchini, cauliflower and Brussels sprouts, and broccoli are capable of inducing the metabolism of foreign substances, which is confirmed by the acceleration of phenacetin metabolism and the acceleration of the half-life of antipyrine in the blood plasma of subjects who received cruciferous vegetables in their diet.

Particular attention is paid to the properties of these compounds, as well as phytocompounds of tea and coffee - catechins and diterpenes (kapheol and cafestol) - stimulating the activity of the monooxygenase system and glutathione-S-transferase of the liver and intestinal mucosa. The latter underlies their antioxidant effect when exposed to carcinogens and anticancer activity.

It is advisable to dwell on the biological role of other vitamins in the processes of biotransformation of foreign substances that are not associated with the antioxidant system.

Many vitamins perform the functions of coenzymes directly in enzyme systems associated with the metabolism of xenobiotics, as well as in enzymes for the biosynthesis of components of biotransformation systems.

Thiamine (vitamin B t). It is known that thiamine deficiency causes an increase in the activity and content of components of the monooxygenase system, which is considered as an unfavorable factor that contributes to the metabolic activation of foreign substances. Therefore, the provision of vitamins in the diet can play a certain role in the mechanism of detoxification of xenobiotics, including industrial poisons.

Riboflavin (vitamin B 2). The functions of riboflavin in the processes of biotransformation of foreign substances are realized mainly through the following metabolic processes:

• participation in the metabolism of microsomal flavoproteins NADPH-cytochrome P-450 reductase, NADPH-cytochrome b 5 reductase;
• ensuring the work of aldehyde oxidases, as well as glutathione reductase through the coenzyme role of FAD with the generation of TSH from oxidized glutathione.

An experiment on animals showed that vitamin deficiency leads to a decrease in the activity of UDP-glucuronyltransferase in liver microsomes based on a decrease in the rate of glucuronide conjugation of /7-nitrophenol and o-aminophenol. There is evidence of an increase in the content of cytochrome P-450 and the rate of hydroxylation of aminopyrine and aniline in microsomes with nutritional deficiency of riboflavin in mice.

Cobalamins (vitamin B 12) and folic acid. The synergistic effect of the vitamins under consideration on the processes of biotransformation of xenobiotics is explained by the lipotropic effect of the complex of these nutrients, the most important element of which is the activation of glutathione-D-transferase and organic induction of the monooxygenase system.

Clinical trials have shown the development of vitamin B12 deficiency when the body is exposed to nitrous oxide, which is explained by the oxidation of CO 2+ in the CO e+ corrin ring of cobalamin and its inactivation. The latter causes folic acid deficiency, which is based on the lack of regeneration of its metabolically active forms under these conditions.

Coenzyme forms of tetrahydrofolic acid, along with vitamin B 12 and Z-methionine, are involved in the oxidation of formaldehyde, so a deficiency of these vitamins can lead to increased toxicity of formaldehyde and other one-carbon compounds, including methanol.

In general, we can conclude that the nutritional factor can play an important role in the processes of biotransformation of foreign substances and the prevention of their adverse effects on the body. A lot of theoretical material and factual data have been accumulated in this direction, but many questions remain open and require further experimental research and clinical confirmation.

It is necessary to emphasize the need for practical ways to implement the preventive role of the nutritional factor in the processes of metabolism of foreign substances. This includes the development of science-based diets for certain population groups where there is a risk of exposure to various food xenobiotics and their complexes in the form of dietary supplements, specialized foods and diets.

2.4.7. Ways to remove foreign substances from the body

The ways and means of natural removal of foreign compounds from the body are different. According to their practical significance, they are located as follows: kidneys - intestines - lungs - skin.

The release of toxic substances through the kidneys occurs through two main mechanisms - passive diffusion and active transport.

As a result of passive filtration, an ultrafiltrate is formed in the renal glomeruli, which contains many toxic substances, including non-electrolytes, in the same concentration as in plasma. The entire nephron can be considered as a long semi-permeable tube, through the walls of which diffuse exchange occurs between the flowing blood and the forming urine. Simultaneously with the convective flow along the nephron, toxic substances diffuse, obeying Fick’s law, through the nephron wall back into the blood (since their concentration inside the nephron is 3–4 times higher than in the plasma) along a concentration gradient. The amount of substance that leaves the body in the urine depends on the intensity of reverse resorption. If the permeability of the nephron wall for a given substance is high, then at the exit the concentrations in the urine and blood are equalized. This means that the rate of excretion will be directly proportional to the rate of urine formation, and the amount of excreted substance will be equal to the product of the concentration of the free form of the poison in the plasma and the rate of diuresis

l=kV m.

This is the minimum value of the substance removed.

If the wall of the renal tubule is completely impermeable to a toxic substance, then the amount of the substance released is maximum, does not depend on the rate of diuresis and is equal to the product of the filtration volume and the concentration of the free form of the toxic substance in the plasma:

l=kV f.

The actual output is closer to the minimum values ​​than to the maximum. The permeability of the renal tubule wall for water-soluble electrolytes is determined by the mechanisms of “non-ionic diffusion”, i.e., it is proportional, firstly, to the concentration of the undissociated form; secondly, the degree of solubility of the substance in lipids. These two circumstances make it possible not only to predict the efficiency of renal excretion, but also to control, albeit to a limited extent, the reabsorption process. In the renal tubules, non-electrolytes, highly soluble in fats, can penetrate through passive diffusion in two directions: from the tubules into the blood and from the blood into the tubules. The determining factor for renal excretion is the concentration index (K):

K = C in urine / C in plasma,

where C is the concentration of the toxic substance. K value<1 свидетельствует о преимущественной диффузии веществ из плазмы в мочу, при значении К>1 – vice versa.

The direction of passive tubular diffusion of ionized organic electrolytes depends on the pH of the urine: if tubular urine is more alkaline than plasma, weak organic acids easily penetrate into the urine; if the urine reaction is more acidic, weak organic bases pass into it.

In addition, the renal tubules carry out active transport of strong organic acids and bases of endogenous origin (for example, uric acid, choline, histamine, etc.), as well as foreign compounds of a similar structure with the participation of the same carriers (for example, foreign compounds containing amino group). Conjugates with glucuronic, sulfuric and other acids formed during the metabolism of many toxic substances are also concentrated in the urine due to active tubular transport.

Metals are excreted primarily by the kidneys not only in a free state, if they circulate in the form of ions, but also in a bound state, in the form of organic complexes that undergo glomerular ultrafiltration, and then pass through the tubules by active transport.

The release of toxic substances ingested orally begins in the oral cavity, where many electrolytes, heavy metals, etc. are found in saliva. However, ingestion of saliva usually contributes to the return of these substances to the stomach.

Many organic poisons and their metabolites formed in the liver enter the intestines with bile, some of them are excreted from the body in feces, and some are reabsorbed into the blood and excreted in the urine. An even more complex path is possible, found, for example, in morphine, when a foreign substance enters the blood from the intestines and returns to the liver again (intrahepatic circulation of the poison).

Most metals retained in the liver can bind to bile acids (manganese) and be excreted through the intestines with bile. In this case, the form in which this metal is deposited in tissues plays an important role. For example, metals in a colloidal state remain in the liver for a long time and are excreted mainly in the feces.

Thus, the following are removed through the intestines with feces: 1) substances that are not absorbed into the blood when taken orally; 2) isolated with bile from the liver; 3) entered the intestine through the membranes of its wall. In the latter case, the main method of transport of poisons is their passive diffusion along a concentration gradient.

Most volatile non-electrolytes are excreted from the body mainly unchanged in exhaled air. The initial rate of release of gases and vapors through the lungs is determined by their physicochemical properties: the lower the solubility coefficient in water, the faster their release occurs, especially the part that is in the circulating blood. The release of their fraction deposited in adipose tissue is delayed and occurs much more slowly, especially since this amount can be very significant, since adipose tissue can make up more than 20% of a person’s total mass. For example, about 50% of chloroform ingested by inhalation is released during the first 8–12 hours, and the rest is released in the second phase of release, which lasts several days.

Many non-electrolytes, undergoing slow biotransformation in the body, are released in the form of the main breakdown products: water and carbon dioxide, which is released with exhaled air. The latter is formed during the metabolism of many organic compounds, including benzene, styrene, carbon tetrachloride, methyl alcohol, ethylene glycol, acetone, etc.

Through the skin, in particular with sweat, many substances - non-electrolytes, leave the body, namely: ethyl alcohol, acetone, phenols, chlorinated hydrocarbons, etc. However, with rare exceptions (for example, the concentration of carbon disulfide in sweat is several times higher than in urine), the total amount of toxic substance removed in this way is small and does not play a significant role.

When breastfeeding, there is a risk of some fat-soluble toxic substances entering the baby's body with milk, especially pesticides, organic solvents and their metabolites.

Poisons that penetrate the body, like other foreign compounds, can undergo a variety of biochemical transformations ( biotransformation), which most often results in the formation of less toxic substances ( neutralization, or detoxification). But there are many known cases of increased toxicity of poisons when their structure in the body changes. There are also compounds whose characteristic properties begin to appear only as a result of biotransformation. At the same time, a certain part of the poison molecules is released from the body without any changes or even remains in it for a more or less long period, fixed by proteins in the blood plasma and tissues. Depending on the strength of the formed “poison-protein” complex, the effect of the poison slows down or is completely lost. In addition, the protein structure can only be a carrier of a toxic substance, delivering it to the corresponding receptors. *

* (By the term “receptor” (or “receptor structure”) we will designate the “point of application” of poisons: the enzyme, the object of its catalytic action (substrate), as well as protein, lipid, mucopolysaccharide and other bodies that make up the structure of cells or participate in metabolism. Molecular pharmacological ideas about the essence of these concepts will be discussed in Chapter. 2)

The study of biotransformation processes allows us to solve a number of practical issues in toxicology. Firstly, knowledge of the molecular essence of the detoxification of poisons makes it possible to cordon off the body’s defense mechanisms and, on this basis, outline ways of directed influence on the toxic process. Secondly, the size of the dose of poison (medicine) entering the body can be judged by the amount of their transformation products released through the kidneys, intestines and lungs - metabolites, * which makes it possible to monitor the health status of people involved in the production and use of toxic substances; In addition, in various diseases, the formation and release from the body of many biotransformation products of foreign substances is significantly impaired. Thirdly, the appearance of poisons in the body is often accompanied by the induction of enzymes that catalyze (accelerate) their transformations. Therefore, by influencing the activity of induced enzymes with the help of certain substances, it is possible to accelerate or inhibit the biochemical processes of transformation of foreign compounds.

* (Metabolites are also commonly understood as various biochemical products of normal metabolism (metabolism))

It has now been established that the processes of biotransformation of foreign substances occur in the liver, gastrointestinal tract, lungs, and kidneys (Fig. 1). In addition, according to the results of research by Professor I. D. Gadaskina, * a considerable number of toxic compounds undergo irreversible transformations in adipose tissue. However, the main importance here is the liver, or more precisely, the microsomal fraction of its cells. It is in the liver cells, in their endoplasmic reticulum, that most enzymes that catalyze the transformation of foreign substances are localized. The reticulum itself is a plexus of linoprotein tubules that penetrate the cytoplasm (Fig. 2). The highest enzymatic activity is associated with the so-called smooth reticulum, which, unlike rough reticulum, does not have ribosomes on its surface. ** It is not surprising, therefore, that with liver diseases the body’s sensitivity to many foreign substances sharply increases. It should be noted that, although the number of microsomal enzymes is small, they have a very important property - high affinity for various foreign substances with relative chemical nonspecificity. This creates the opportunity for them to enter into neutralization reactions with almost any chemical compound that enters the internal environment of the body. Recently, the presence of a number of such enzymes has been proven in other cell organelles (for example, in mitochondria), as well as in blood plasma and intestinal microorganisms.

* (Gadaskina I. D. Adipose tissue and poisons. - In the book: Current issues in industrial toxicology / Ed. N. V. Lazareva, A. A. Golubeva, E. T. Lykhipoy. L., 1970, p. 21-43)

** (Ribosomes are spherical cellular formations with a diameter of 15-30 nm, which are centers for the synthesis of proteins, including enzymes; contain ribonucleic acid (RNA))

It is believed that the main principle of the transformation of foreign compounds in the body is to ensure the highest speed of their elimination by transferring them from fat-soluble to more water-soluble chemical structures. In the last 10-15 years, when studying the essence of biochemical transformations of foreign compounds from fat-soluble to water-soluble, increasing importance is attached to the so-called monooxygenase enzyme system with a mixed function, which contains a special protein - cytochrome P-450. It is close in structure to hemoglobin (in particular, it contains iron atoms with variable valency) and is the final link in the group of oxidizing microsomal enzymes - biotransformers, concentrated mainly in liver cells. * In the body, cytochrome P-450 can be found in 2 forms: oxidized and reduced. In the oxidized state, it first forms a complex compound with a foreign substance, which is then reduced by a special enzyme - cytochrome reductase. This reduced compound then reacts with activated oxygen, resulting in the formation of an oxidized and, as a rule, non-toxic substance.

* (Kovalev I. E., Malenkov A. G. Flow of foreign substances: impact on humanity, - Nature, 1980, No. 9, p. 90-101)

The biotransformation of toxic substances is based on several types of chemical reactions, which result in the addition or elimination of methyl (-CH 3), acetyl (CH 3 COO-), carboxyl (-COOH), hydroxyl (-OH) radicals (groups), as well as sulfur atoms and sulfur-containing groups. Of considerable importance are the processes of decomposition of poison molecules up to the irreversible transformation of their cyclic radicals. But a special role among the mechanisms for neutralizing poisons is played by synthesis reactions, or conjugation, as a result of which non-toxic complexes are formed - conjugates. At the same time, the biochemical components of the internal environment of the body that enter into irreversible interaction with poisons are: glucuronic acid (C 5 H 9 O 5 COOH), cysteine ​​( ), glycine (NH 2 -CH 2 -COOH), sulfuric acid, etc. Molecules of poisons containing several functional groups can be transformed through 2 or more metabolic reactions. In passing, we note one significant circumstance: since the transformation and detoxification of toxic substances due to conjugation reactions are associated with the consumption of substances important for life, these processes can cause a deficiency of the latter in the body. Thus, a different kind of danger arises - the possibility of developing secondary painful conditions due to a lack of necessary metabolites. Thus, the detoxification of many foreign substances depends on the glycogen reserves in the liver, since glucuronic acid is formed from it. Therefore, when large doses of substances enter the body, the neutralization of which is carried out through the formation of glucuronic acid esters (for example, benzene derivatives), the content of glycogen, the main easily mobilized reserve of carbohydrates, decreases. On the other hand, there are substances that, under the influence of enzymes, are capable of splitting off glucuronic acid molecules and thereby helping to neutralize poisons. One of these substances turned out to be glycyrrhizin, which is part of the licorice root. Glycyrrhizin contains 2 molecules of glucuronic acid in a bound state, which are released in the body, and this, apparently, determines the protective properties of licorice root against many poisonings, known for a long time to the medicine of China, Tibet, and Japan. *

* (Salo V. M. Plants and medicine. M.: Nauka, 1968)

As for the removal of toxic substances and their transformation products from the body, the lungs, digestive organs, skin, and various glands play a certain role in this process. But the nights are the most important here. That is why, in case of many poisonings, with the help of special means that enhance the separation of urine, they achieve the fastest removal of toxic compounds from the body. At the same time, one must also take into account the damaging effects on the kidneys of some poisons excreted in the urine (for example, mercury). In addition, the products of the transformation of toxic substances may be retained in the kidneys, as is the case with severe ethylene glycol poisoning. * When it is oxidized, oxalic acid is formed in the body and calcium oxalate crystals fall out in the kidney tubules, preventing urination. In general, such phenomena are observed when the concentration of substances excreted through the kidneys is high.

* (Ethylene glycol is used as an antifreeze - a substance that lowers the freezing point of flammable liquids in internal combustion engines.)

To understand the biochemical essence of the processes of transformation of toxic substances in the body, let us consider several examples concerning common components of the chemical environment of modern man.

So, benzene, which, like other aromatic hydrocarbons, is widely used as a solvent for various substances and as an intermediate product in the synthesis of dyes, plastics, drugs and other compounds, is transformed in the body in 3 directions with the formation of toxic metabolites (Fig. 3). The latter are excreted through the kidneys. Benzene can remain in the body for a very long time (according to some reports, up to 10 years), especially in adipose tissue.

Of particular interest is the study of transformation processes in the body toxic metals, which have an increasingly widespread impact on people in connection with the development of science and technology and the development of natural resources. First of all, it should be noted that as a result of interaction with the redox buffer systems of the cell, during which electron transfer occurs, the valence of metals changes. In this case, the transition to a state of lower valence is usually associated with a decrease in the toxicity of metals. For example, hexavalent chromium ions transform in the body into a low-toxic trivalent form, and trivalent chromium can be quickly removed from the body with the help of certain substances (sodium pyrosulfate, tartaric acid, etc.). A number of metals (mercury, cadmium, copper, nickel) actively bind to biocomplexes, primarily to functional groups of enzymes (-SH, -NH 2, -COOH, etc.), which sometimes determines the selectivity of their biological action.

Among pesticides- substances intended to destroy harmful living beings and plants, there are representatives of various classes of chemical compounds that are toxic to humans to one degree or another: organochlorine, organophosphorus, organometallic, nitrophenol, cyanide, etc. According to available data, * about 10% of all fatal poisoning is currently caused by pesticides. The most significant of them, as is known, are FOS. By hydrolyzing, they usually lose their toxicity. In contrast to hydrolysis, the oxidation of FOS is almost always accompanied by an increase in their toxicity. This can be seen if we compare the biotransformation of 2 insecticides - diisopropyl fluorophosphate, which loses its toxic properties by removing a fluorine atom during hydrolysis, and thiophos (a derivative of thiophosphoric acid), which is oxidized into the much more toxic phosphacol (a derivative of orthophosphoric acid).

* (Buslovich S. Yu., Zakharov G. G. Clinic and treatment of acute poisoning with pesticides (pesticides). Minsk: Belarus, 1972)

Among the widely used medicinal substances sleeping pills are the most common sources of poisoning. The processes of their transformations in the body have been studied quite well. In particular, it has been shown that the biotransformation of one of the common derivatives of barbituric acid - luminal (Fig. 4) - proceeds slowly, and this underlies its rather long-term hypnotic effect, since it depends on the number of unchanged luminal molecules in contact with nerve cells. The disintegration of the barbiturate ring leads to the cessation of the action of luminal (as well as other barbiturates), which in therapeutic doses causes sleep lasting up to 6 hours. In this regard, the fate in the body of another representative of barbiturates - hexobarbital - is not without interest. Its hypnotic effect is much shorter, even when using significantly larger doses than Luminal. It is believed that this depends on the greater speed and on the greater number of ways of inactivation of hexobarbital in the body (formation of alcohols, ketones, demethylated and other derivatives). On the other hand, those barbiturates that remain in the body almost unchanged, such as barbital, have a longer-lasting hypnotic effect than luminal. It follows from this that substances that are excreted unchanged in the urine can cause intoxication if the kidneys cannot cope with their removal from the body.

It is also important to note that in order to understand the unexpected toxic effect of the simultaneous use of several drugs, due importance must be given to enzymes that affect the activity of the combined substances. For example, the drug physostigmine, when used together with novocaine, makes the latter a very toxic substance, since it blocks the enzyme (esterase) that hydrolyzes novocaine in the body. Ephedrine manifests itself in a similar way, binding to oxidase, which inactivates adrenaline and thereby prolonging and enhancing the effect of the latter.

A major role in the biotransformation of drugs is played by the processes of induction (activation) and inhibition of the activity of microsomal enzymes by various foreign substances. Thus, ethyl alcohol, some insecticides, and nicotine accelerate the inactivation of many medications. Therefore, pharmacologists pay attention to the undesirable consequences of contact with these substances during drug therapy, in which the therapeutic effect of a number of drugs is reduced. At the same time, it must be taken into account that if contact with the inducer of microsomal enzymes suddenly stops, this can lead to a toxic effect of the drugs and will require a reduction in their doses.

It should also be borne in mind that, according to the World Health Organization (WHO), 2.5% of the population has a significantly increased risk of drug toxicity, since their genetically determined half-life in the blood plasma in this group of people is 3 times longer than the average. Moreover, about a third of all enzymes described in humans in many ethnic groups are represented by variants of different activity. Hence - individual differences in reactions to one or another pharmacological agent, depending on the interaction of many genetic factors. Thus, it was found that approximately one in 1-2 thousand people has a sharply reduced activity of serum cholinesterase, which hydrolyzes dithylin, a drug used to relax skeletal muscles for several minutes during some surgical interventions. In such people, the effect of ditilin is sharply prolonged (up to 2 hours or more) and can become a source of serious illness.

Among people living in Mediterranean countries, Africa and Southeast Asia, there is a genetically determined deficiency in the activity of the enzyme glucose-6-phosphate dehydrogenase of erythrocytes (a decrease of up to 20% of normal). This feature makes red blood cells less resistant to a number of medications: sulfonamides, some antibiotics, phenacetin. Due to the breakdown of red blood cells in such individuals, hemolytic anemia and jaundice occur during drug treatment. It is quite obvious that the prevention of these complications should consist of a preliminary determination of the activity of the corresponding enzymes in patients.

Although the above material only gives a general idea of ​​the problem of biotransformation of toxic substances, it shows that the human body has many protective biochemical mechanisms that, to a certain extent, protect it from the unwanted effects of these substances, at least from small doses. The functioning of such a complex barrier system is ensured by numerous enzymatic structures, the active influence of which makes it possible to change the course of the processes of transformation and neutralization of poisons. But this is already one of our next topics. In further presentation, we will return to the consideration of individual aspects of the transformation of certain toxic substances in the body to the extent necessary for understanding the molecular mechanisms of their biological action.

Blood consists of formed elements - red blood cells, leukocytes, blood platelets and plasma fluid.

Red blood cells Most mammals have anucleate cells that live 30-120 days.

Combining with oxygen, hemoglobin in red blood cells forms oxyhemoglobin, which transports oxygen to the tissues and carbon dioxide from the tissues to the lungs. There are 5-7 million red blood cells in 1 mm3 in cattle, 7-9 in sheep, 5-8 in pigs, and 8-10 million red blood cells in horses.

Leukocytes capable of independent movement, pass through the walls of capillaries. They are divided into two groups: granular - granulocytes and non-granular - agranulocytes. Granular leukocytes are divided into: eosinophils, basophils and neutrophils. Eosinophils neutralize foreign proteins. Basophils transport biologically active substances and participate in blood clotting. Neutrophils carry out phagocytosis - the absorption of microbes and dead cells.

Agranulocytes consist of lymphocytes and monocytes. By size, lymphocytes are divided into large, medium and small, and by function into B-lymphocytes and T-lymphocytes. B-lymphocytes or immunocytes form protective proteins - antibodies that neutralize the poisons of microbes and viruses. T-lymphocytes or thymus-dependent lymphocytes detect foreign substances in the body and regulate protective functions with the help of B-lymphocytes. Monocytes are capable of phagocytosis, absorbing dead cells, microbes and foreign particles.

Blood plates participate in blood clotting and secrete serotonin, which constricts blood vessels.

Blood, together with lymph and tissue fluid, forms the internal environment of the body. For normal living conditions it is necessary to maintain a constant internal environment. The body maintains at a relatively constant level the amount of blood and tissue fluid, osmotic pressure, the reaction of blood and tissue fluid, body temperature, etc. The constancy of the composition and physical properties of the internal environment is called homeostasis. It is maintained due to the continuous functioning of the organs and tissues of the body.

Plasma contains proteins, glucose, lipids, lactic and pyruvic acids, non-protein nitrogenous substances, mineral salts, enzymes, hormones, vitamins, pigments, oxygen, carbon dioxide, nitrogen. The most proteins in plasma (6-8%) are albumins and globulins. Fibronogen globulin is involved in blood clotting. Proteins, creating oncotic pressure, maintain normal blood volume and a constant amount of water in tissues. Antibodies are formed from gamma globulins, which create immunity in the body and protect it from bacteria and viruses.

Blood performs the following functions:

• nutritious- transports nutrients (products of the breakdown of proteins, carbohydrates, lipids, as well as vitamins, hormones, mineral salts and water) from the digestive tract to the cells of the body;
• excretory- removal of metabolic products from body cells. They enter the tissue fluid from the cells, and from it into the lymph and blood. They are transported by the blood to the excretory organs - kidneys and skin - and removed from the body;
• respiratory- transports oxygen from the lungs to the tissues, and the carbon dioxide formed in them to the lungs. Passing through the capillaries of the lungs, the blood gives off carbon dioxide and absorbs oxygen;
• regulatory- carries out humoral communication between organs. Endocrine glands secrete hormones into the blood. These substances are carried by the blood to the body, acting on the organs, changing their activity;
• protective. Blood leukocytes have the ability to absorb microbes and other foreign substances entering the body; they produce antibodies that are formed when microbes, their poisons, foreign proteins and other substances penetrate into the blood or lymph. The presence of antibodies in the body provides its immunity;
• thermoregulatory. Blood performs thermoregulation due to continuous circulation and high heat capacity. In a working organ, as a result of metabolism, thermal energy is released. Heat is absorbed by the blood and distributed throughout the body, as a result of which the blood helps spread heat throughout the body and maintain a certain body temperature.

In animals at rest, approximately half of all blood circulates in the blood vessels, and the other half is retained in the spleen, liver, skin - in the blood depot. If necessary, the body supplies blood into the bloodstream. The amount of crop in animals is on average 8% of body weight. Loss of 1/3-1/2 of blood can lead to death of the animal.

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As you know, almost all foreign substances that enter the body, including drugs, are metabolized in it and then excreted. It is known that individuals differ from each other in the rate of metabolization of drugs and their removal from the body: depending on the nature of the chemical substance, this difference can be from 4 to 40 times. When metabolized and eliminated slowly, a certain drug may accumulate in the body and, conversely, some individuals may quickly eliminate the foreign substance from the body.

The removal of foreign substances is facilitated by enzymes that mebolize them. However, the presence of the latter in the body depends primarily on hereditary factors, although their activity can be affected by age, gender, food, illness, etc.

It is a reasonable assumption that a person whose enzyme system converts carcinogens into their ultimate forms more quickly and to a greater extent is more likely to develop cancer than a person who metabolizes carcinogens more slowly. And in this case very large differences were found between individuals. For example, the activity of the enzyme epoxide hydratase, which metabolizes carcinogenic PAHs, which is found in the liver microsomes of more than seventy individuals, in a person with the highest metabolic rate may be 17 times higher than in a person with the lowest metabolic rate. Other enzymes associated with carcinogen metabolism also show large interindividual differences.

It should be remembered that these enzymes vary greatly in their action in different tissues of the same individual (lungs, liver or blood cells). But their activity can also change in the same tissue of the same individual (due to aging, under the influence of disease, as a result of the action of drugs, under the influence of food or enzyme induction). It is also not worth emphasizing that the activity of enzymes associated with the metabolism of carcinogens in the tissues of different animals is different; The difference between animal and human tissues is even greater.

However, researchers still tried to approximately determine the carcinogenic danger for individuals based on the action of enzymes that convert harmful substances in the body into their ultimate forms (the so-called metabolic activation). It is assumed, although this assumption is not entirely justified, that the activity of toxic and carcinogen-detoxifying enzymes in blood lymphocytes reflects the state of enzymes also in other tissues.

When determining the action of benzo[a]pyrene hydroxylase, it was found that homogenates of lymphocytes from smokers contained 52% more of it than similar homogenates from non-smokers. A higher activity of this enzyme, causing metabolic activation of PAHs, was also found in the microsomes of lymphocytes of smokers and individuals taking medication (up to 93%). But at the same time, it was found that the activity of the enzyme glutathione-S-transferase, which neutralizes PAHs in the body, in the homogenate of lymphocytes of all groups (smokers, non-smokers and individuals taking medications) remained approximately the same. Two conclusions can be drawn from this:

1. Smoking affects more than just your lungs. It can also cause changes in other tissues, such as blood lymphocytes. This means that the readiness of one tissue to metabolize carcinogens could be judged only on the basis of determining the activity of the corresponding enzymes in other tissues, for example, lymphocytes.
2. While smoking increases the activity of the “toxic” enzyme AGG, the activity of the “detoxifying” enzyme glutathione-β-transferase remains unchanged. This could mean that in smokers, most of the carcinogens present undergo metabolic activation, while the neutralizing activity does not change. This could, in very general terms, explain the fact that smokers have a higher incidence of cancer than non-smokers, not only as a result of an increased intake of carcinogens, but also due to the increased activity of enzymes that convert carcinogens into their ultimate forms.

Enzymes and their induction

Thus, it can be reasonably assumed that individuals who have high activity of enzymes that convert chemical carcinogens into their ultimate derivatives show a higher susceptibility to cancer than others. Therefore, identifying individuals with increased activity of such toxic enzymes would allow the selection of those at high risk of cancer. Carrying out appropriate preventive measures for such individuals - eliminating their contact with chemical carcinogens, taking medications that protect against cancer - would make it possible to reduce the incidence.

Activation of these enzymes (for example, AGG, benzo[a]pyrene hydroxylase) could be a consequence of the hereditary properties of a particular individual, or due to induction, i.e., an increase in the activity of these enzymes by certain chemicals. D.V. Nebart suggests the presence of the Ar gene locus in the mouse, which is responsible for providing such a system of enzymes. The body of animals possessing this genetic trait (Ag locus) reacts to carcinogenic PAHs with their accelerated metabolization and, consequently, with an increased incidence of cancer. Conversely, in animals that do not have this hereditary trait, the metabolism is very slow and the incidence of disease is low. It can be assumed that similar genetic traits exist in other animal species or humans.

Another factor that could increase the risk of this disease by increasing toxic enzyme activity is inducing chemicals. These include, for example, polychlorinated enzymes, which themselves are not carcinogenic, but, by enhancing the activity of toxic enzymes and inducing them, can contribute to an increased risk of carcinogenesis in individuals exposed to their action.

Thus, identification of those individuals who are presumed to have a higher susceptibility to cancer as a result of exposure to chemical carcinogens could be done by testing the activity of a toxic enzyme (eg, benzo[a]-pyrene hydroxylase) in their lymphocytes. Such a test is technically very difficult to implement; moreover, according to many researchers, it is very unreliable. As already mentioned, it is very difficult, based on the activity of one enzyme in lymphocytes, to judge the activity of several enzymes in other tissues, especially if it is easily changed by sex by the action of other chemicals, age, food, disease and other factors. Therefore, caution in determining the risk of cancer in individuals based on the enzyme activity in their cells is warranted.