BRAINWARE UNIVERSITY
[BP501T] CLASS NOTES [Medicinal Chemistry-II Theory]
HISTAMINE
Introduction
Histamine, meaning ‘tissue amine’ (histos—tissue) is almost ubiquitously present in animal tissues and
in certain plants, e.g. stinging nettle. It was implicated as a mediator of hypersensitivity phenomena
and tissue injury reactions. It is now known to play important physiological roles. Histamine is present
mostly within storage granules of mast cells. Tissues rich in histamine are skin, gastric and intestinal
mucosa, lungs, liver and placenta. Nonmast cell histamine occurs in brain, epidermis, gastric mucosa
and growing regions. Turnover of mast cell histamine is slow, while that of nonmast cell histamine is
fast. Histamine is also present in blood, most body secretions, venoms and pathological fluids.
Chemistry of Histamine
Histamine, known trivially as 4(5-)(2-aminoethyl)imidazole, structurally is composed of an imidazole
heterocycle and ethylamine side chain. The methylene groups of the aminoethyl side chain are
designated α and β. The side chain is attached, via the β-CH2 group, to the 4-position of an imidazole
ring. The imidazole N at position 3 is designated the pros (π) N, whereas the N at position 1 is termed
the tele (Ʈ) N. The side chain N is distinguished as Nα.
Synthesis of histamine
Histamine is β imidazolylethylamine. It is synthesized locally from the amino acid histidine and
degraded rapidly by oxidation and methylation.
Histamine is synthesized in Golgi apparatus of its principal storage cells, mast cells, and basophils.
Histamine is formed from the naturally occurring amino acid L-hisitidne (S-histidine) via the catalysis
of either the pyridoxal phosphate dependent enzyme histidine decarboxylase (HDC, EC 4.1.1.22) or L-
aromatic amino acid decarboxylase (L-AAAD). Substrate specificity is higher for HDC versus L-AAAD.
HDC inhibitors (HDCIs) include α-fluoromethylhistidine (FMH), a mechanism-based inhibitor, and
certain flavonoids.7 Although useful as pharmologic probes, HDCIs have not proved to be useful
clinically.
Histamine metabolism
There are two major paths of histamine metabolism in humans. The more important is ring
methylation to form N-methylhistamine, catalyzed by histamine-N-methyltransferase, which is
distributed widely. Most of the N-methylhistamine formed is then converted to N-methylimidazole
acetic acid by monoamine oxidase (MAO), and this reaction can be blocked by MAO inhibitors.
Alternatively, histamine may undergo oxidative deamination catalyzed mainly by the nonspecific
enzyme diamine oxidase, yielding imidazole acetic acid, which is then converted to imidazole acetic
acid riboside. These metabolites have little or no activity and are excreted in the urine. Measurement
of N-methylhistamine in urine affords a more reliable index of histamine production than assessment
of histamine itself. Artifactually elevated levels of histamine in urine arise from genitourinary tract
bacteria that can decarboxylate histidine. In addition, the metabolism of histamine appears to be
altered in patients with mastocytosis such that determination of histamine metabolites is a more
sensitive diagnostic indicator of the disease than histamine.
1
BRAINWARE UNIVERSITY
[BP501T] CLASS NOTES [Medicinal Chemistry-II Theory]
Histamine metabolism
Storage and Release
Histamine is found in almost all mammalian tissues in concentrations ranging from 1 to more than 100
µg/g. Mast cells and histamine are in particularly high concentration in skin and the mucosal cells of
the bronchi, intestine, urinary tract, and tissues adjacent to the circulation. It is found in higher
concentrations in mammalian cerebrospinal fluid than in plasma and other body fluids.
In mast cells, histamine (positively charged) is held by an acidic protein and heparin (negatively
charged) within intracellular granules. When the granules are extruded by exocytosis, Na+ ions in e.c.f.
exchange with histamine to release it free.
2
BRAINWARE UNIVERSITY
[BP501T] CLASS NOTES [Medicinal Chemistry-II Theory]
Mechanism of antigen-antibody reaction induced release of histamine from mast cell.
In sensitized atopic individual, specific reaginic (IgE) antibody is produced and gets bound to Fc epsilon
receptor I (FcεRI) on the surface of mast cells. On challenge, the antigen bridges IgE molecules
resulting in transmembrane activation of a tyrosine-protein kinase (t-Pr-K) which phosphorylates and
activates phospholipaseCγ. Phosphatidyl inositol bisphosphate (PIP2) is hydrolysed and inositol
trisphosphate (IP3) is generated which triggers intracellular release of Ca2+. The Ca2+ ions induce
fusion of granule membrane with plasma membrane of the mast cell resulting in exocytotic release of
granule contents. In the granule, positively charged histamine (Hist+) is held complexed with
negatively charged protein (Prot–) and heparin (Hep–) molecules. Cationic exchange with extracellular
Na+ (and Ca2+) sets histamine free to act on the target cells.
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BRAINWARE UNIVERSITY
[BP501T] CLASS NOTES [Medicinal Chemistry-II Theory]
Histamine Receptors
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BRAINWARE UNIVERSITY
[Course Code] CLASS NOTES [Course Name]
Histamine induced gastric acid secretion
Histamine induced gastric acid secretion
2022-23 Prepared by: Faculty Name (Department of Pharmaceutical Technology
Brainware University, Barasat)
BRAINWARE UNIVERSITY
[Course Code] CLASS NOTES [Course Name]
Pharmacological Actions of Histamine
Pathophysiological role of Histamine
2022-23 Prepared by: Faculty Name (Department of Pharmaceutical Technology
Brainware University, Barasat)
