ADRENOCORTICOTROPIC HORMONE

From Big Medical Encyclopedia

ADRENOCORTICOTROPIC HORMONE (Latin adrenalis — epinephral, cortex — bark and Greek tropos — the direction; AKTG; synonym: adrenocorticotropin, corticotropin, corticotropine) — the peptide hormone produced by basphilic cells of a front share of a hypophysis and stimulating function of cortical substance of adrenal glands.

For the first time P. Smith in 1926 found hormonal communication between gipofiay and cortical substance of adrenal glands. The long time Adrenocorticotropic Hormone was received in the form of crude extracts of a hypophysis or partially purified drugs, in 1953 it was allocated in pure form. In 1955. Li and Bell (S. N. of Li, P. Bell) with sotr. established chemical structure And. of sheep and pigs, and the chemical structure was studied later And. of other animals.

the Scheme of the sequence of the amino-acid remains in molecules of adrenocorticotropic hormone of a chklovek in comparison with a pig, a bull and a sheep

Biosynthesis of adrenocorticotropic hormone and its turning into organism

Biosynthesis And. in a hypophysis as well as biosynthesis of other proteins, is carried out with participation of ribosomes and is suppressed with specific inhibitors of proteinaceous synthesis: puromycin and cycloheximide, and also ribonuclease, but is not suppressed with Actinomycinum of D and a deoxyribonuclease. The chemical structure of molecules A is included below. of the person and some animals (each of them includes 39 amino-acid remains). Molecules A. of the person and different types of animals differ only with the sequence of the amino-acid remains on the site of a peptide chain 25 — 33 (see the scheme). Biological properties A. are entirely caused by structure of the N-trailer site (1 — 24) of a peptide chain identical at different types of animals and the person. Eliminating of one or two amino acids from the N-trailer site, and also blocking or eliminating of a N-trailer amino group (NH 2 ) lead to considerable falling of hormonal activity. At the same time presence of N-trailer serine is not obligatory, and replacement it on glycine does not cause a noticeable inactivation of hormone. Specific specificity And. defines its immunological properties.

The peptide consisting of 24 amino-acid remains and corresponding on structure to N-trailer site A is received by a synthetic way. It has all biological properties A., but it is deprived of antigenic properties. Shortening of this peptide since the carboxyl end (on the site of a peptide chain 24 — 18) leads to gradual decrease in its activity, edges still it is found in the peptide consisting of 17 amino-acid remains.

Adrenocorticotropic hormone is steady in acid medium and is quickly inactivated in alkaline. It is easily adsorbed on glass that leads to considerable losses it during the work with dilute solutions. Under the influence of oxidizers (hydrogen peroxide) And. it is reversibly inactivated owing to oxidation of the 4th amino-acid rest of methionine in metioninsulfoksid. Deeper oxidation with formation of a metioninsulfon leads to irreversible loss of hormonal activity. At the same time methionine cannot be considered «active center» of a molecule since its replacement by the remains α-aminobutyric to - you to - you to - you or norleucine do not lead to change of biological properties A.

S-trailer site of a molecule A. about (39 — 25), differing on structure at different animals, causes immunological properties of hormone, and eliminating of several amino acids from the S-trailer site leads to considerable decrease in its antigenic properties.

Physiological effect of adrenocorticotropic hormone

Concerning the mechanism of a promoting effect And. on biosynthesis of corticosteroids in cortical substance of adrenal glands there are several theories. One of them is R.C. Haynes's theory, according to a cut And. increases in an adrenal gland activity of the adenyl cyclase catalyzing transformation of ATP in cyclic 3 ′, the 5th ?-adenosinemonophosphate (3 ′, 5 ?-AMF). 3 ′, 5 ?-AMF activates phosphorylase, edges are split by a glycogen of adrenal glands to the glyukozo-1-phosphate (glycogenolysis) turning further into glyukozo-6-phosphate. The last, exchanging through pentoses-ny a cycle, leads to increase in formation of the recovered nikotinamidadenindinukleotidfosfat (NADFN2) which is a necessary cofactor at transformation of cholesterol in pregnenolon and at a hydroxylation of steroid predecessors to end products of a steroidogenesis.

Similar views of the mechanism of action And. states to Mac-Kearns (To. W. McKerns), however, in his opinion, increase in formation of NADFN2 in adrenal glands results not from strengthening of a glycogenolysis, and owing to increase in activity glyukozo-6-fosfatdegidrogenazy.

Another is L. D. Garren's theory with sotr. Authors consider it the following three facts: a) And. shows the action only on the integral, not destroyed cells of adrenal glands; b) And. stimulates biosynthesis of hormones only at a stage of transformation of cholesterol in pregnenolon; c) action And. is suppressed in the presence of the antibiotics blocking biosynthesis of protein in an adrenal gland. According to this theory And. stimulates adenyl cyclase in membranes of cells and increases receipt cyclic 3′5 ?-AMF in cytoplasm. There 3 ′, 5 ?-AMF receptor protein — a protein kinase interacts with a complex, causing its dissociation, and thus activates a protein kinase. The last phosphorylates ribosomes and stimulates in them biosynthesis of «specific» protein with use of stable information RNA as a matrix. The formed protein carries out transfer of free cholesterol from fatty drops of cytoplasm in a mitochondrion where of it it is formed pregnenolon, and then corticosteroids. This theory does not exclude a possibility of activation in adrenal glands of phosphorylase under the influence of 3′5 -AMF.

In addition to increase in secretion of steroid hormones, And. causes also a hypertrophy adrenal glands (see), followed by increase in the general contents in them in protein and DNA. Under influence And. in adrenal glands activity of DNA-polymer elements and thymidinekinases — the enzymes participating in biosynthesis of DNA increases. Long introduction And. causes increase in activity 11-β-гидроксилазы, followed by emergence in cytoplasm of the proteinaceous activator of enzyme. Under the influence of repeated injections And. in an organism ratios of the cosecreted corticosteroids (a hydrocortisone and corticosterone) towards significant increase in secretion of a hydrocortisone also change. The same change of ratios in allocation of corticosteroids is observed after the repeating conditions of tension (stress) caused by impact of cold, an aseptic inflammation and other factors.

Except direct influence on adrenal glands, And. has a number of ekstraadrenalovy effects. He shows melanotsitostimuliruyushchy activity, edges is caused by presence at a molecule of 13 amino-acid remains of the N-trailer site repeating the sequence of amino acids in α-melanotsitostimuliruyushchy hormone (α-MSG). And. possesses also lipotropic action which is expressed in activation of a lipase of fatty tissue and increase in an exit of free fatty acids from fat depos in blood. Minimum fragment of a molecule A., NH pentapeptide is still having noticeable melanotsitostimuliruyushchy and lipotropic activity 2 - Gis-Fen-Arg-Tri-Gli-ON.

At the person and animals secretion is normal And. it is regulated by a hypothalamus which produces specific substance — an AKTG-rileasing-faktor, the stimulating allocation And. in blood (see. Hypothalamic neurohormones ). Caused And. increase in secretion of corticosteroids on a negative feedback mechanism exerts the braking impact on a hypothalamus and suppresses secretion of an AKTG-rileasing-faktora. At some morbid conditions (Simmonds's disease, Itsenko's disease — Cushing) insufficient or excess receipt is observed And. in blood, leading to heavy disbolism in an organism.

Methods of definition of adrenocorticotropic hormone in blood

it is difficult to Define Adrenocorticotropic Hormone in the circulating blood owing to its low contents in it caused by the low speed of secretion and quite bystry speed of an inactivation And. in an organism. Time of semi-life exogenous And., according to various data, makes 4 — 18 min., and endogenous — up to 1 min. An essential role in its inactivation is played by kidneys and other internals. Probable mechanism of an inactivation And. in blood enzymic hydrolysis by plasmin which splits two peptide bonds between the 8 and 9 and between the 15 and 16 the amino-acid remains is. For definition And. in blood usually use biological methods. The method offered for the first time by Sayers (M. of Sayers), is based on caused And. decrease in contents ascorbic to - you in adrenal glands of gipofizektomirovanny rats. This method to a crust, time is applied in many countries to standardization of drugs A.

Later the methods based on increase in biosynthesis of corticosteroids in adrenal glands of in vitro [Schafran and Shalli (M. of Saffran, A. Schally)], on increase in maintenance of corticosteroids in blood of adrenal glands [Lipskomb and Nelson (N. of S. Lipscomb, D. H. Nelson)] and on increase in level of steroid hormones in peripheral blood [R. Guillemin] at gipofizektomirovanny animals after introduction were offered them And. The most widespread is J. Vernikos-Danellis's method based on determination of content of corticosteroids in adrenal glands of gipofizektomirovanny rats before intravenous administration by it of the studied tests And. It is simple and yields the stablest results.

Other methods with use of blockade of a hypophysis dexamethasone instead of a hypophysectomy (see. Dexamethasonal test ) in most cases do not yield satisfactory and reproducible results. There are also radio immunological methods of definition And. [R. Yalow]. They are more sensitive. In blood it is possible to define separate fragments of a molecule A by radio immunological methods. as the S-trailer sites deprived of biological activity, but which kept immunological properties.

The considered methods have no sufficient sensitivity to carry out exact quantitative definition And. in blood of healthy people. Therefore it is considered to be that normal concentration And. in a blood plasma of the person makes less than 0,5 millnedinitsa on 100 ml. R. Ney gives the following average values of level A. in a blood plasma: 0,25 milliyedinitsa on 100 ml in the morning and 0,11 milliyedinitsa on 100 ml in the evening. Maintenance And. in plasma of the healthy person at the level of 1 milliyedinitsa on 100 ml by introduction to it And. with a speed of 0,2 PIECES/hour causes increase in concentration of corticosteroids in blood twice and their excretion with urine by 4 — 6 times. Thus, strengthening And. in blood, hardly determined by modern methods, increases the speed of secretion of corticosteroids. After surgery level A. about 0,6 — 0,9 milliyedinitsa increase by 100 ml at most of patients. Introduction of a metapiron increases contents And. only in 50% of cases. Substantial increase of its contents is observed at an addisonovy disease (2 — 36 milliyedinitsa on 100 ml) and at an adrenogenital syndrome (0,6 — 2 mplliyedinitsa on 100 ml), however after therapy by corticosteroids it decreases to not determined sizes. At Itsenko's syndrome — Cushing of various etiology the increased contents And. (0,6 — 4,8 milliyedinitsa on 100 ml) find in 50% of patients. Level A. sharply increases at all patients after bilateral adrenalectomies (see).

The syndrome of ectopic AKTG is caused by the ectopic tumor cosecreting And. The most often found tumor is the carcinoma of lungs. At such patients considerable increase of level A is observed. (1 — 13 milliyedinitsa on 100 ml). Level A. in blood even of high doses of dexamethasone do not decrease under influence, and its secretion is not controlled by ordinary regulatory mechanisms. At the same time contents And. in a hypophysis of the patient it is sharply reduced. Chemical structure ectopic And. it is not established yet, however on physical. - to chemical and immunological properties it does not differ from a hypophyseal hormone.

Adrenocorticotropic hormone as drug

(Corticotropinum, AKTG, Acethrophan, ACTH, Acthar, Acton, Actrope, Adrenocorticotrophin, Cibathen, Corticotrophinum, Cortrophin, Exacthin, Solanthyl; joint venture. Б). Belongs to group of hormones and their analogs.

Zinc-phosphate is excluded by the order of the Ministry of Health of the USSR of April 7, 1976 for No. 340 AKTG-from the nomenclature of pharmaceuticals.

For the medical purposes corticotropin is received from a hypophysis of cattle, pigs and sheep. Solution of a kortpkotroshsh has subacidic reaction (rn = 3,0 — 4,0).

Medical effect of corticotropin is similar to action of corticosteroids and is shown in the antiinflammatory and desensibilizing action, reduction of permeability of vessels, oppression of development of lymphoid and connecting fabrics Apply corticotropin at an interstitial gipoftszarnoy of insufficiency, rheumatism, infectious nonspecific polyarthritises, gout, bronchial asthma, acute lymphatic and myeloid leukemia, a mononucleosis, neurodermatitises, psoriasis and eczema.

Corticotropin is entered intramusculary. At intake it is not effective since it quickly collapses proteolitpchesky enzymes went. - kish. path. In some cases for acceleration and strengthening of effect intravenous drop administration of a kortikotroshsh is allowed the corticotropin Entered into a muscle quickly is soaked up in blood; its action lasts 6 — 8 hour. The AKTG-tsink-fosfat representing thin suspension of natural corticotropin in solution of zinc chloride, sodium phosphate and EDTA possesses more long action. Introduction it in a muscle creates the depot of hormone extending period of validity of hormone till 24 — 32 o'clock. Usual drugs of corticotropin enter the adult intramusculary 10 — 20 PIECES 3 — 4 times a day; by the end of treatment the dose is reduced to 20 — 30 PIECES a day. The course of treatment of various diseases proceeds 2 — 4 weeks. If necessary the course is repeated by 2 — 3 times with breaks of 1 — 3 week and more.

At long use of corticotropin there can be by-effects: a delay of salts and water in an organism, development of hypostases, increase in arterial pressure, tachycardia, strengthening of protein metabolism with negative nitrogenous balance, excitement, sleeplessness, a moderate hirsutism, disturbances of a menstrual cycle. Can be observed: a delay of scarring of wounds, an aggravation of the hidden centers of an infection, an ulceration of a mucous membrane of a stomach and intestines, the phenomenon of a diabetes mellitus, allergic reactions, children have a growth inhibition.

Corticotropin is contraindicated at severe forms of a hypertension, Itsenko's disease — Cushing, pregnancy, a circulatory unefficiency of the III degree, an acute endocarditis, psychoses, nephrite, osteoporosis, stomach ulcer and a duodenum, a diabetes mellitus, tuberculosis and after recently undergone operations.

Corticotropin is produced in the form of the lyophilized powder in hermetically the packed glass ampoules with a rubber bung and a metal running in with the maintenance of 10 — 20 — 30 — 40 PIECES. Dissolution of corticotropin is made just before an injection in sterile isotonic solution of sodium chloride. AKTG-tsink-fosfat is produced in the form of two solutions: one — in hermetically the packed bottles containing 100 PIECES of hormone in 4 ml 0,01 N of HC1 with addition of zinc and preservative; another — in the soldered ampoules containing 1 ml of solution of alkaline phosphate. Before the use liquid from an ampoule by means of the syringe is transferred to a bottle with And. and carefully shake up. Drugs of a kortikotroshsh store in the place protected from light at ta not higher than 10 °.

Many firms passed to production of synthetic drugs of corticotropin for the medical purposes. The Swiss firm of Sib produces drug Synacthenum (Synakthen), the Hungarian firm «Gideon Richter» — gumaktid-28 (Humaktid-28). Synacthenum is 1 — 24, gumaktid — 1 — 28 N-trailer sites of a peptide molecule natural And. of the person. The advantage of drugs is lack of antigenic properties that allows to appoint them even sick with high sensitivity to repeated injections of corticotropin of animal origin. Synacthenum is released in ampoules 0,25 mg, gumaktid-28 — in ampoules on 0,4 mg (there correspond 40 PIECES of corticotropin).

Synthetic drugs of corticotropin which activity is higher than activity of natural hormone are in vitro received. In particular, R. A. Boisson-nas with sotr. synthesized the N-trailer site of corticotropin from 25 amino-acid remains, in Krom N-trailer 1 serine is replaced with not natural stereoisomer d-serine, methionine in the 4th situation — on norleucine, the S-trailer rest asparaginic to - you — on valineamide. Such drug is not split by ekzopeptidaza, not inactivated under the influence of oxidizers, more long time remains in an organism in not changed state. According to various biological tests, it is 4 — 6 times more active than natural corticotropin.



Bibliography: Yu. A. Himiya's punks AKTG and mechanism of regulation of its secretion, Usp. sovr. biol., t. 47, in, 3, page 347, 1959, bibliogr.; Punks Yu. A., Yelizarov G. P. and Kiselyov A. G. Specific differences in chemical constitution both some physical and chemical and biological properties of hormones of a hypophysis, in book: Sovr. vopr. endokrinol., under the editorship of N. A. Yudayev, century 4, page 20, M., 1972, bibliogr.; Dixon H. B. F. Chemistry of pituitary hormones, in book: Hormones, ed. by G. Pincus a. o., v. 5, p. 1, N. Y. — L. 1964, bibliogr.; Li C. H. and. Oelofsen W. The chemistry and biology of ACTH and related peptides, in book: Adrenal cortex, ed. by A. B. Eisenstein, p. 185, Boston, 1967; Sayers G. Adrenocorticotrophin, in book: Hormones in blood, ed. by C. H. Gray a. A. L. Bacharach, v. 1, p. 169, L. — N. Y., 1967, bibliogr.


Yu. A. Pankov.

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