TOXINS (Greek toxikon poison) — biologically active agents produced by microorganisms, plants and animals, the general property to-rykh is ability to break a homeostasis at certain groups of prokariot or eukaryotes; T. are of great importance in a pathogeny inf. diseases. They are used for creation of preventive and medical drugs and also as means for studying of biological processes at molecular level. K T. various chemical connections belong: the derivatives of nucleotides, polypeptides, simple and complex proteins having in some cases enzymatic activity, substances of the steroid nature and complex connections (lipopolisakharida, etc.).
An example of the toxins representing derivatives of nucleotides (see. Nucleic acids ), beta exotoxin — one of entomopathogenic Bacillus thuringiensis toxins, derivative a dezoksiadenozina about a pier is. it is powerful (weighing) 730. Toxins of the polypeptide nature about a pier. thermostable enterotoxins Escherichia coli, Yersinia enterocolitica and nek-ry other enterobakteriya are weighing from 4 to 10 thousand. Proteinaceous T. (see. Proteins ) are eurysynusic in the nature, kilerny (lethal) T in particular concern to them., developed by fungi of the sorts Saccharomyces, Cryptococcus, Torulopsis, Pichia, capable to have lethal effect on germinative forms of other yeast-like fungi. Simple proteins are also nek-ry T. a plant origin (such, e.g., as modetsin, the ricin, abrine produced respectively by plants of Aden ia digitata, Abrus precator ius and Ricinus communis), T. dragon (neurotoxins of Najahaje, Bunga-rus caeruleus, hemorrhagic Vipera lebetina poison), scorpions, knidariya and other animals, poisonous for the person, entomopathogenic T. bacteria of Bacillus alvei, you. thuringiensis and nek-ry types of pseudo-monads, and also T. the majority of microorganisms, pathogenic for the person and animals. K T. the steroid nature belong aflatoxins (see), the sorts Aspergillus developed by fungi (A. flavus, A. parasiticus, A. ochraceus, etc.), ochratoxins, producers to-rykh are Aspergillus ochraceus, Peni-cillium viridie and nek-ry other types of fungi (see. Mikotoksikoza ). Typical representative T. the complex nature the lp-iopolisakharidny complex of a cell wall of gram-negative bacteria, in structure to-rogo, except polysaccharide and a lipid is And, also a nek-swarm the amount of the thermostable polypeptides keeping functional activity and after warming up at t°80 — 100 ° enters (see. Lipopolisakharida ).
The main criterion at reference of this or that substance to T. its ability to break a homeostasis (see) any the organism acting as a test object at assessment of the striking action of the studied connection serves.
Result of action of T. there can be a death of an organism or jump of its functions necessary for normal life activity (mobility, ability to a taxis at protozoa and the low-developed organisms, normal metamorphoses at insects, disturbance in system of coagulant proteins of a hemolymph at arthropods, an imbalance of a water salt metabolism, disturbance in thermal control and in a fibrinolysis at mammals and birds, etc.). So, e.g., about properties of kilerny T. sakharomitst and cryptococci judge by their ability to reduce quantity of viable individuals in intensively breeding population of yeast or yeast-like fungi. Lethal effect of abrine determine by results of intravenous administration it to rabbits. The paralytic effect of poison of a cobra is estimated at hypodermic introduction to mice and in experiences of immobilization of an infusorian of Paramecium caudatum. The pyrogenic effect of staphylococcal exotoxin of a serotype With or a lipopolisakharidny complex of a cell wall Salmonella typhimurium reveal at intravenous administration them to rabbits on subsequent change of rectal temperature. Ability of a lipopolisakharidny complex to influence functional activity of system of coagulant blood proteins or a hemolymph define as in vivo, modeling intravascular microthrombosis at a lab. animals, and in vitro — in the test of jellification of a lysate of amoebocides of a crab of Limulus. Property inherent in Vibrio cholerae choleragen to break a water salt metabolism in an organism can be estimated as in vivo (on newborn krolchata), and in vitro (on the intertwined cultures of ovarian cells of hamsters).
Biol. models not only allow to carry this or that natural compound to the category T., but also help to find out the nature of the reactions causing intoxication (see). On biol. modeling also the tests used for identification of T are based. in biol. products, as well as methods of studying biol. substrates on T. Odnako's presence in them bioasseys often do not give the chance to receive the answer in a short time therefore at express diagnosis of intoxication search of T. in bioasseys carry out by means of chemical or immunochemical indicators. Chemical indicators (see) widely apply at identification of aflatoxins, ochratoxins, a lipopolisakharidny complex in tests of chemiluminescence (see. Fluorescence ), thin-layer and high-speed solution chromatography (see), and immunochemical indicators — at detection of various T., capable as in pure form, and in the conjugated state to induce development of antibodies at rabbits and others a lab. animals. As immunochemical indicators use such highly sensitive tests as reaction of passive hemagglutination (see. Hemagglutination ), reaction enzyme-mechennykh of antibodies (see the Enzimimmunologichesky method), etc.
T., (zootoxins) formed by animals and plants (see. Poisonous animals , Noxious plants ), in pathology of the person play a smaller role, than T. microorganisms. More than 80 toxins of microorganisms, action to-rykh are described and emitted for a cell in rather pure look it is carried out in four main ways: impact on a membrane (cover) of a cell, the direct damaging action on internal components of a cell, modification of functional activity of a cell, influence on process of interaction of cells among themselves and with intercellular substance. According to the nature of functional activity all known microbic T. it is possible to divide into 5 main types: membranotoksina, cytotoxins, functional blockers, eksfoliatina — eritrogenina, modulators of reactions of cells to endogenous mediators.
Three groups of the substances capable to lyse membranes of cells of eukaryotes (see treat membranotoksina. Eukariotny organisms ): leukocidins (see), hemolysins (see. Hemolysis ) and toxins with fosfatidazny activity. In turn, hemolysins are subdivided into three subgroups — steady against effect of oxygen, collapsing under the influence of oxygen and other (the hemolysins which are not changing the properties depending on availability of oxygen).
Cytotoxins (see) include three groups of the toxicants capable to block processes of life activity in cells an eukaryote and to cause their death: antielongator, dermonekrotizin (necrotoxins) and cytotoxins with enterotropic activity. The group of antielongator is made by the cytotoxins capable to block synthesis of protein at a stage of lengthening of a polypeptide chain, group of dermonekrotizin — T., causing a necrosis of certain cellular elements, and with enterotropic activity carry T to group of cytotoxins., the destroying cells of an intestinal epithelium.
Functional blockers are presented by enterotoxins (see), neurotoxins and actually currents-sinami-blockers, napr, Yersinia pestis toxin, lethal for mice.
Eksfoliatiny-eritrogenina include two groups T. — eksfoliatina of staphylococcus and an eritrogenina of a streptococcus, and also the pyrogenic action is inherent in eritrogenina of a streptococcus.
T belong to modulators of reactions of cells to endogenous mediators., not possessing the direct striking action, but perverting reaction of cells to nek-ry endogenous mediators (a histamine, a mitozstimuliruyushchy factor, etc.).
On the origin of T. microorganisms subdivide on three the main a class: exotoxins — the products allocated by microorganisms on Wednesday in the course of the life activity, endotoxins — the products which are strongly connected with a stroma of microbic cells and passing into a cultural filtrate only after death of microbic population, mesotoxins — the toxicants which are unsteadily connected with a stroma of a microbic cell and in certain conditions diffusing to the environment at preservation at cells producers of their initial viability.
Being guided by two main signs of this or that microbic T. — its origin and the nature of functional activity, it is possible to carry out a detailed intra group differentiation of T. E.g., Staphylococcus aureus leukocidin consists of two components — F and S about a pier. weighing 32 000 and 38 000 respectively, to-rye in this quality are quite close to Pseudomonas aeruginosa leukocidin, molecular weight to-rogo 27 000. Both compared leukocidin of a termolabilna and after 10 — 30 min. warming up at t ° 56 — 60 ° are inactivated; both of them lyse leukocytes, but do not affect erythrocytes. Staphylococcal leukocidin has no lethal activity, and Ps leukocidin. aeruginosa at intravenous administration to mice in a dose of 4 — 8 mkg causes their death that is caused by its belonging to the endotoxins which are characterized by toxicity of high degree.
Shigella dysenteriae cytotoxin has a pier. weight apprx. 72 000 also consists of two main subunits about a pier. weighing 32 000, 29 000 and additional subunits about a pier. weighing 4000 and 7000, localization to-rykh is definitely not established. This T. relatively termostabilen also maintains warming up at t ° 60 ° within 10 min. without loss of toxic activity; warming up at the same temperature within 30 min. reduces its toxicity no more than by 20 — 25%. Toxin letalen for mice at intraperitoneal introduction, and synthesis by its bacteria is sharply blocked at increase in concentration of iron in the environment of cultivation from 0,1 to 1,0 mkg] in ml. Its striking action is explained with ability to slow down transfer of amino acids with acceptor RNA on the growing polypeptide chain therefore it is carried in group of so-called antielongator. Enters into the same group and gistotoksin A Ps. aeruginosa. Pier. the weight of this toxin apprx. 72 000, consists it of subunits about a pier. weighing 45 000 and 27 000. Gistotoksin And is completely inactivated after 60 min. warming up at t ° 70 °, and intensity of its synthesis by a strain producer is in direct dependence on the content of iron in the environment of cultivation. The striking action of a gistotoksin And explain it with the inactivating action on the second elongation factor, the polypeptide chain synthesized on ribosomes — transferase II.
T. from group of antielongator — gistotoksin Corynebacterium diphtheriae about a pier. weighing 63 000 also consists of subunits about a pier. weighing 24 000 and 39 000. Synthesis of this protein a strain producer also is in direct dependence on the content of iron in a medium, and the toxic protein collecting in a filtrate termolabilen and after 30 min. warming up at t°60 ° completely loses the virulence. The striking action of a diphtheritic gistotokspn is also explained by its ability to inactivate transferase II and to block thus transfer of amino acids with acceptor RNA on a ribosomal matrix.
The listed properties T. groups of antielongator testify to similarity of T different by origin. with almost identical molecular structure, differing in sensitivity to warming up and details of the mechanism of intoxication of cells of eukaryotes (mice concerning a rezistentna to action of a gistotokspn of Cor. diph-theriae in comparison with Sh cytotoxin. dysenteriae and gistotoksiny And Ps. aeruginosa). However the described higher than A T. in two cases (Ps toxins. aeruginosa and Cor. diphtheriae) represent true exotoxins (ekzoprotein), and dysenteric cytotoxin is typical endotoxin therefore it is possible to believe that these distinctions are determined during evolution.
In the same case, when microbic T. one type and group have an identical origin, similarity their the fullest. It is possible to give the comparative characteristic of the hemolysins sensitive to effect of oxygen as an example. Several such toxins — Au-streptoli-zin pneumolysin, listeriolizin are known, tetanolysin, Clostridium perfringens Θ-toxin of serotypes (serovars) And yes With, Clostridium histo-lyticum hemolysin, and - Clostridium novyi toxin of type A and Clostridium botulinum hemolysins of serotypes of C and D, alveolizin, tyuringiolizin, tsereolizin — and all of them are exotoxins (ekzoprotein). Pier. weight of these T. varies within 47 000 — 69 000, and specific hemolitic activity concerning erythrocytes of a ram, a rabbit or a horse reaches 2 x 10 6 — 4 X 10 6 HU (the international hemolitic units) on 1 mg of protein. They are termolabilna and are inactivated after short-term warming up at t ° 56 — 70 °, all of them have serological relationship and lose lytic activity after a pre-incubation with cholesterol. The last property is especially important as, obviously, all of them are fixed on covers of erythrocytes in those sites of a membrane where cholesterol somehow participates in creation of a superficial receptor.
Similarity of T. comes to light at comparative analysis of thermolabile enterotoxins of bacteria. 6 enterotoxins which are ekzoprotenna (Vibrio cholerae choleragen, enterotoxins Vibrio parahaemolyticus, Aeromonas hyd-rophila, Salmonella typhimurium, Shigella dysenteriae, Bacillus ce-reus) and 2 enterotoxins from a class of mesotoxins are known (enterotoxins E. coli, Salmonella enteritidis), and all these connections (except for S. enteritidis enterotoxin, molecular weight to-rogo 120 000) have molecular weight apprx. 80 000, often meeting is gray l. relationship, the thermolability expressed in a varying degree and ability to lose toxic activity (during the testing on ovarian cells) after a preinkubation with a ganglioside of GM
the Listed and other similar examples (similarity in a structure and properties at thermolabile enterotoxins, cytotoxins with enterotropic activity, etc.) allow to believe that at evolution different types of pathogenic microorganisms were taken in the course of natural selection ability to synthesize the polypeptides, same on a structure, proteins or complex connections. These connections are capable at hit in internal environment of any other organisms to imitate signals of natural regulators of a homeostasis. However such imitation only partially reproduces the usual course of regulatory process, and at some more remote stages blocks it.
Such interpretation of the mechanism of action of microbic T. is confirmed by series of observations about similarity in a structure of nek-ry toxins and hormones. So, e.g., the sites of polypeptide chains of Vibrio cholerae choleragen and thermolabile E. coli enterotoxin responsible for communication with receptors of susceptible cells have structural looking alike similar sites of polypeptide chains of thyrotropin, a chorionic gonadotrophin and lyuteinpziruyushchy hormone.
There is also other option of imitation of signals of regulators of a homeostasis. Staphylococcal and - the lysine is fixed on those sites of receptors of susceptible cells, lecithin and (or) phosphatidylsincaline is a part to-rykh. Obviously, the same phospholipids are also a part of those receptors, to-rye are involved at transmembrane transfer in a cell of nek-ry enzymes, in particular, such as a malate dehydrogenase. A receptor for other staphylococcal toxin — and-lizpna is one more connection from group of gangliosides — Nan-gal-gle-N the Expert ganglioside, the speaker as a component of the receptor providing fixing on a cellular surface of nek-ry endogenous and exogenous mitogens. And for dysenteric cytotoxin as a receptor that structure of a cellular membrane acts, the cut is a part a H-atsetil-D-glyukozamin — the main component of disaccharide, the making group substance A of blood of the person.
After imitation of signals of regulators of a homeostasis the association of a cell with microbic resulted from T., it transmembranno or by a pinocytic (see) penetrates in cytosol where shows the toxic action. Gistotoksin A Ps. aeruginosa and diphtheritic gistotoksin realize, e.g., the enzymatic potentiality, catalyzing reaction between nikotinamidadenin - dinucleotide and transferase II. As a result of this reaction complex connection — adenosine-diphosphate-ri-bozil-transferase II, not capable to take part in transfer of amino acids with acceptor RNA on a ribosomal matrix forms. In the same way vegetable poisons the abrine and ricin produced by Abrus rgesa-torius and Ricinus communis realize the toxic action.
At V. cholerae choleragen, thermolabile E. coli enterotoxin and another similar to them on function T. after a penetration in cytosol potential ability to activate adenylatecyclase works.
In turn, it induces sharp accumulation in a cell of cyclic adenosinemonophosphate, activation of the protein kinases which are built in cellular membranes, and as a result — change of permeability of membranes (see. Membranes biological ) for ions, water and organic matters.
Yersinia pestis toxin, lethal for mice, fixed on a surface of susceptible cells by association with a beta adrenoceptor, a final point of application after a penetration in cytosol also has adenylatecyclase, but unlike choleragen of plague T., lethal for mice, inactivates adenylatecyclase and brings a cell out of control by such factors of a homeostasis as Epinephrinum, a glucagon, etc.
The reactions at molecular level which are the cornerstone of processes of intoxication (see) and leading to irreversible changes in internal environment of the organism treated to action T., well explain the reasons of partial failures of a serotherapy (see) similar states. Since the time of E. Beringa and E. Ra it is known that anti-toxic serums (see) successfully stop intoxication in microbic T. only when they are entered at early stages of a disease or in an initial stage of a toksinemiya (the phase of intoxication, in time a cut toxin circulates in blood and a lymph). Administration of antitoxin (see) during later period or it is ineffective, or does not render at all to lay down. actions. Modern data on molecular mechanisms of intoxication allow to interpret this contradiction with exhaustive completeness.
Specific antitoxin can neutralize microbic T. at circulation of the last and to prevent its fixings on receptors of susceptible cells. Also neutralization of the molecules T fixed on cells is possible., when the specific antibody interferes with dissociation of an initial toxic molecule (prototoxin) on subunits and a penetration in cytosol of the fragments bearing toksoforny determinants. If such penetration was made, antibodies are the fenced-off cellular membranes from the toxic factors which got into cytosol and there is a situation when the serotherapy is powerless against intoxication. Therefore the main efforts within the last 50 years were directed to creation of prophylactics of toksinemiya. At mass immunization (see) the contingents of the population atoksichny derivatives of toxins — anatoxins (see) it is possible to prevent intoxication.
For neutralization of T. usually use Ramón's way — a formal detoxication. Also a number of new methods of receiving the neutralized derivatives of microbic T is offered. for specific prevention. In particular, for creation of anticholeraic anti-toxic immunity at people per os recommend to use drug from the subunits of a polypeptide chain of choleragen responsible for its fixing on the cellular receptors containing a ganglioside of GMi. Drug, similar on properties, from subunits of Clostridium tetani tetanospasmin is approved in Ying-those Pasteur in Paris as immunogen for prevention of tetanic intoxication. In the same in-those the synthetic immunogen for prevention of diphtheritic intoxication representing a conjugate from the adjuvant muramildipeptid and an oligopeptid creating the toksoforny center of a molecule of a diphtheritic gistotoksin is developed. However during the use of both a traditional way of Ramón, and modern techniques microbic
T. V as the USSR always acts as raw materials for preparation of anatoxins and production of a number of microbic T is abroad arranged., which are used during the receiving the drugs for inoculations used in medicine and veterinary science.
Nek-ry microbic entomopathogenic T are produced., the pages intended for protection - x. plants. From the medical point of view replacement of pesticides (see) in agriculture on entomopathogenic toxins it is reasonable as they unlike pesticides do not kumulirutsya in a human body and animals and do not make on them negative impact.
According to a foreign press development of antineoplastic drugs is begun in recent years, the active beginning to-rykh are antineoplastic antibodies, gibridizovanny with nek-ry microbic toxins (diphtheritic gistotoksin, pyocyanic exotoxin A, etc.), capable to block synthesis of protein in tumor cells.
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M. V. Dalin.