Epinephrine and histamines

Hormones Some lipophilic hormones (e.g. the steroid hormones, thyroxine, retinoic acid and vitamin D) diffuse across the plasma membrane and interact with intracellular receptors in the cytosol or nucleus. Other lipophilic hormones (e.g. the prostaglandins) and hydrophilic hormones (e.g. the peptide hormones insulin and glucagon and the biogenic amines epinephrine and histamine) bind to receptor proteins in the plasma membrane. 

Endogenous biogenic amines in the brain include catecholamines [NE (noradrenaline, NA), dopamine (DA), epinephrine (adrenaline)] 5-HT, histamine, and the so-called trace amines (P-phenylethylamine, tyramine, tryptamine, and octopamine). These amines have in common a arylalkylamine stmcture, and all have been implicated in the etiology of one or more psychiatric disorders and/or in therapeutic and/or adverse effects of drugs used to treat such disorders. In this review on depression, the focus in the case of biogenic amines will be on 5-HT, NE, and DA, although epinephrine and histamine and trace amines have also been implicated (see the section on Other Antidepressant Approaches and Targets ). 

The mechanism of action of the phenothiazines is still not definitely known. They tend to block important effector substances such as acetylcholine, epinephrine, and histamine. The phenothiazines produce uncoupling of phosphorylation from oxidation. They appear to act at all steps along the electron transport chain. Cytochrome oxidase, succinoxidase, and adenosine triphosphatase are inhibited. Some data indicate that the phenothiazines may decrease the permeability of storage granules for brain amines. 

Amino acids and their metabolites participate in signal transduction process - hormonal control and the synaptic transmission of nerve impulses. Some compounds, like epinephrine and histamine (see here) participate in both processes. 

Patients with previous severe reactions should have emergency treatments, such as epinephrine and histamine blockers, ready upon re-exposure in case a future reaction occurs. 

The content of the tryptophan-oxidizing enzyme system present in liver commonly is low. It can be increased as much as tenfold through the prior feeding of tryptophan by a mechanism resembling that of enzyme adaptation observed in microorganisms. A much smaller response (twofold) is obtained with certain other substances not substrates of the enzyme system, e.g., epinephrine and histamine. This latter group of compounds has no effect in adrenalectomized animals, and thus, it appears, the increase is caused through a stimulation by the pituitary-adrenal system. ... 

Histamine in the Cardiovascular System. It has been known for many years that histamine is present in sympathetic nerves and has a distribution within the heart that parallels that of norepinephrine (see Epinephrine and norepinephrine). A physiological role for cardiac histamine as a modulator of sympathetic responses is highly plausible (15). A pool of histamine in rat heart located neither in mast cells nor in sympathetic nerves has been demonstrated. The turnover of this metaboHcaHy active pool of histamine appears to be maintained by normal sympathetic activity. 

The release of arachidonate and the synthesis or interconversion of eicosanoids can be initiated by a variety of stimuli, including histamine, hormones such as epinephrine and bradykinin, proteases such as thrombin, and even serum albumin. An important mechanism of arachidonate release and eicosanoid syn-... 

Many hormones and other blood-borne substances (including drugs) also alter contractile activity of smooth muscle. Some of the more important substances include epinephrine norepinephrine angiotensin II vasopressin oxytocin and histamine. Locally produced substances that may alter contraction in the tissue in which they are synthesized include nitric oxide prostaglandins leukotrienes carbon dioxide and hydrogen ion. 

Biogenic amines arise from amino acids by decarboxylation (see p. 62). This group includes 4-aminobutyrate (y-aminobutyric acid, GABA), which is formed from glutamate and is the most important inhibitory transmitter in the CNS. The catecholamines norepinephrine and epinephrine (see B), serotonin, which is derived from tryptophan, and histamine also belong to the biogenic amine group. All of them additionally act as hormones or mediators (see p. 380). 

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

IgE-medlated release of mast cell contents. Inset, Intact mast cell with histamine stored In granules. An IgE antibody molecule Is depicted adjacent to the mast cell. Two IgE molecules combine with a mast cell (sensitization). The attachment of an antigen (allergen) to the sensitized mast cell Initiates release of histamine (and other substances) from the mast cell. This degranulation can be prevented by such agents as isoproterenol, theophylline, epinephrine, and cromolyn sodium. H antihistamines do not interfere with degranulation but instead prevent actions of histamine at various pharmacological receptors. 

Gs Epinephrine, norepinephrine, histamine, glucagon, ACTH, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and others Adenylate cyclase Ca2+ channels... 

All hydrophilic (water-soluble) molecules (which cannot diffuse across the hydrophobic interior of the lipid bilayer) bind to receptors in the plasma membrane. There are two subclasses of hydrophilic hormones (1) peptide hormones such as insulin and glucagon and (2) small charged molecules, often biogenic amines, such as epinephrine (adrenalin) and histamine that are derived from amino acids and function as hormones and neurotransmitters (see Topic N3). 

The major enzyme involved in the formation of ammonia in the liver, brain, muscle, and kidney is glutamate dehydrogenase, which catalyzes the reaction in which ammonia is condensed with 2-oxoglutarate to form glutamate (Sec. 15.1). Small amounts of ammonia are produced from important amine metabolites such as epinephrine, norepinephrine, and histamine via amine oxidase reactions. It is also produced in the degradation of purines and pyrimidines (Sec. 15.6) and in the small intestine from the hydrolysis of glutamine. The concentration of ammonia is regulated within narrow limits the upper limit of normal in the blood in humans is 70/tmol L-1. It is toxic to most cells at quite low concentrations hence there are specific chemical mechanisms for its removal. The reasons for ammonia toxicity are still not understood. The activity of the urea cycle in the liver maintains the concentration of ammonia in peripheral blood at 20/ molL. ... 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

The enzymes, amino acid decarboxylases are pyridoxal phosphate- dependent enzymes. Pyridoxal phosphate forms a Schiff s base with e amino acid so as to stabilise the a-carbanion formed by the cleavage of bond between carboxyl and a-carbon atom. The physiologically active amines epinephrine, nor-epinephrine, dopamine, serotonin, y-amino butyrate and histamine are formed through decarboxylation of the corresponding precursor amino acids... 

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