Textbook - BIOLOGICAL CHEMISTRY - Hubsky Yu.I. - 2000

Chapter V. HORMONES IN THE SYSTEM OF INTERCELLULAR INTEGRATION OF BODY FUNCTIONS

CHAPTER 24. HORMONAL REGULATION OF METABOLISM AND CELLULAR BIOLOGICAL FUNCTIONS. II. PEPTIDE AND AMINO ACID-DERIVED HORMONES

24.4. CATECHOLAMINES AND OTHER BIOGENIC AMINES

Unlike THYROID Hormones, a significant group of Amino Acid Derivatives—BIOREGULATORS with hormone and neurotransmitter properties—exert their regulatory effects on Cells via Membrane Receptors coupled with Intracellular Signaling systems. This Class of bioregulators includes the following biogenic amines:

- L-Tyrosine derivatives, catecholamines: adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine;

- L-Tryptophan derivatives, indolamines: serotonin and melatonin;

- an L-Histidine derivative (imidazoleamine): histamine.

1. Catecholamines

The catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) are synthesized in the chromaffin cells of The adrenal medulla, the ganglia of the sympathetic Nervous system, and the adrenergic structures of the Central Nervous System.

Both catecholamines exhibit The properties of both hormones and Neurotransmitters; however, adrenaline predominantly exerts a "hormonal" effect, whereas noradrenaline acts primarily as a "mediator." In accordance with these functional differences, the main site of synthesis and localization of adrenaline in the body is the adrenal medulla (accounting for about 80% of all catecholamines in this Structure), whereas noradrenaline is localized primarily in Neurons, with its concentration in the human Brain exceeding that of adrenaline by tens of times.

The precursors in the Biosynthesis of Catecholamines are the cyclic Amino Acids Phenylalanine and Tyrosine. The enzymatic synthesis reactions involve hydroxylation in the aromatic ring and side chain, decarboxylation to form the amine, and methylation of noradrenaline to adrenaline (Fig. 24.6).

Fig. 24.6. Scheme of catecholamine biosynthesis.

Adrenaline

The effects of adrenaline are mediated by its interaction with various classes of adrenoceptors (α, β) localized both in the central nervous system (Chapter 33) and in numerous effector systems of the body.

The physiological manifestations of adrenaline action are characterized by a tonic effect on the myocardium (increased force and rate of Heart contractions), the general vascular bed (hypertensive effect), and the smooth Muscles of Blood Vessels in various Internal Organs, particularly the gastrointestinal tract, Kidneys, Bronchi, Uterus, and eyes.

The biochemical effects of adrenaline are manifested mainly in the catabolic action of the hormone on carbohydrate and lipid (fat) METABOLISM, mediated by membrane receptors coupled with adenylyl cyclase enzyme cascades.

1. The Effect of adrenaline on Carbohydrate Metabolism (Chapter 13) is manifested by the activation of Glycogen phosphorylase, i.e., a glycogenolytic action (primarily in muscles and, to some extent, in The Liver and other organs), which leads to the activation of Glycogenolysis in muscles and provides energy for Muscle contraction. Hyperglycemia, which develops under conditions of increased adrenaline release (typically accompanied by The stimulation of Glucagon secretion), is important for supplying metabolic energy to other Tissues (especially the brain).

2. The effect of adrenaline on Lipid Metabolism (Chapter 14) is characterized by a lipolytic effect caused by the stimulating action of the hormone on The activity of adipocyte TG lipase in adipose tissue. The release of free Fatty acids into the bloodstream (mobilization of NEFA, which also involves glucagon) serves as a biochemical mechanism providing other tissues (such as the myocardium) with additional energy substrates.

Thus, the overall outcome of the PHYSIOLOGICAL AND BIOCHEMICAL effects of catecholamines (adrenaline and noradrenaline) is to prepare the body for the maximal utilization of energy resources and their deployment during stress responses—"fight or flight" situations aimed at the physical survival of the individual. The release of adrenaline from chromaffin cells and noradrenaline from sympathetic nerve terminals represents the biochemical embodiment of the urgent activation of the sympathoadrenal system (W. Cannon) in response to stressors. Processes of long-term adaptation of the body to damaging agents are mediated by glucocorticoids of the adrenal cortex (Chapter 25).

The degradation of adrenaline and noradrenaline is catalyzed by mitochondrial monoamine oxidases, yielding hormonally inactive aldehydes and vanillylmandelic acid.

Dopamine is a biogenic amine that serves as an intermediate in the Synthesis of the catecholamines adrenaline and noradrenaline. The synthesis of this amine and its responsive receptor structures are localized predominantly in the Hypothalamus, as well as in the mesocortical, limbic, and extrapyramidal systems of the brain. In addition to its neurotransmitter properties in the central nervous system, dopamine exhibits sympathomimetic properties similar to other catecholamines. At the same time, dopamine exerts specific effects on The Cardiovascular system, causing renal vasodilation, increasing diuresis and natriuresis, and stimulating the exocrine function of the Pancreas.

2. Indolamines

Serotonin (5-hydroxytryptamine) is a biogenic amine whose precursor is hydroxylated tryptophan (5-hydroxytryptophan), which undergoes decarboxylation in the presence of a PLP-dependent decarboxylase to form the biologically active amine:

The BIOLOGICAL Functions OF serotonin in The Human Body are diverse. In addition to its neurotransmitter action in specific (serotonergic) Regions of the central nervous System and Its participation in complex integrative mental functions, serotonin exerts regulatory effects on smooth muscle activity and, consequently, on the Functions of the cardiovascular system, gastrointestinal tract, and bronchi, while also modulating inflammatory and allergic responses, as well as blood clotting processes. The characteristics of serotonergic metabotropic receptors in The Nervous System and the MOLECULAR MECHANISMS OF serotonin action are detailed in Chapter 33.

The highest concentration of serotonin is found in the enterochromaffin cells of the duodenum, platelets, mast cells of Connective Tissue, and the central nervous system. In the human brain, serotonin is distributed unevenly, with the highest amounts concentrated in the hypothalamic region and the Midbrain.

The Catabolism of serotonin in the body, like that of other physiologically active amines, is mediated by mitochondrial monoamine oxidase. This reaction yields 5-hydroxyindoleacetaldehyde, which is subsequently oxidized to its final catabolite—5-hydroxyindoleacetic acid—that is excreted in the urine.

Melatonin

Another derivative of tryptophan is melatonin (N-acetyl-5-methoxytryptamine), a biogenic amine synthesized via the N-Acetylation and O-methylation of serotonin.

The biosynthesis of melatonin takes place in the pinealocytes of the Pineal Gland and in certain peripheral tissues, such as the gastrointestinal tract, retina, and ciliary body of the eye. Pineal melatonin production exhibits a cyclic circadian rhythm: it increases in the dark and is inhibited by bright light.

The BIOLOGICAL EFFECTS OF melatonin span a wide range of physiological functions. It serves as a universal synchronizer of endogenous biorhythms in the human body and acts as a key regulator of the Sleep-wake cycle (promoting sleep onset and modulating sleep structure), inhibits the secretion of anterior pituitary gonadotropins, somatotropin, thyroid hormones, and corticosteroids, and stimulates certain immune responses, among other functions.

It is believed that the synthesis of melatonin in the pineal gland is a vital component of the human reproductive regulatory system. Specifically, a significant drop in blood melatonin levels in boys during Puberty may serve as a regulatory signal triggering the onset of adolescence.

Melatonin possesses strong antioxidant properties as an inhibitor of free-radical oxidation reactions, which in some aspects surpass the corresponding efficacy of vitamin E (α-tocopherol). In lower animals, melatonin also regulates integumentary pigmentation.

3. Histamine is a derivative of L-histidine formed through the decarboxylation of this amino acid.

The highest amounts of histamine are found in the central nervous system and tissue basophils (mast cells) of connective tissue. The Physiological effects of histamine are related to its action on the smooth muscle of peripheral blood vessels (causing vasodilation), The regulation of Gallbladder and Urinary Bladder functions, the stimulation of Hydrochloric acid secretion in The Stomach, bronchoconstriction, its role as a neurotransmitter, and its participation in immunological reactions. The excessive accumulation of histamine in areas of inflammation and antigen-antibody interaction sites is one of the key pathogenetic mechanisms underlying allergic and anaphylactoid reactions.

The molecular mechanisms of histamine action on target cells are mediated through membrane H₁ and H₂ receptors:

H₁ receptors are coupled to the phosphoinositide cycle, the release of cytosolic Ca²⁺, the activation of guanylyl cyclase, and the accumulation of cGMP;

H₂ receptors are coupled to the activation of adenylyl cyclase and the accumulation of cAMP.

Pharmacological agents that act as histamine receptor antagonists include:

H₁ receptor antagonists—used for allergic conditions of various etiologies and Bronchial Asthma (Dimedrol, Tavegil, Claritin, Ketotifen);

H₂ receptor antagonists—used to reduce hydrochloric acid secretion in PEPTIC ULCER DISEASE (Ranitidine, Famotidine).