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Identification
Name Histamine Phosphate
Accession Number DB00667 (APRD01015)
Type small molecule
Groups approved
Description

Histamine stimulates gastric gland secretion, causing an increased secretion of gastric juice of high acidity. This action is probably due mainly to a direct action on parietal and chief gland cells.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Histamine
Histamine biphosphate
Histamine dihydrogen phosphate
Histamine diphosphate
Brand mixtures Not Available
Categories
  • Diagnostic aid
  • Histamine Agents
CAS number 51-74-1
Weight Average: 307.1354
Monoisotopic: 307.033437495
Chemical Formula C5H15N3O8P2
InChI Key InChIKey=ZHIBQGJKHVBLJJ-UHFFFAOYSA-N
InChI
InChI=1S/C5H9N3.2H3O4P/c6-2-1-5-3-7-4-8-5;2*1-5(2,3)4/h3-4H,1-2,6H2,(H,7,8);2*(H3,1,2,3,4)
Plain Text
IUPAC Name
2-(1H-imidazol-5-yl)ethan-1-amine; bis(phosphoric acid)
SMILES
OP(O)(O)=O.OP(O)(O)=O.NCCC1=CN=CN1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phosphonic Acids and Derivatives
  • Imidazoles
Substructures
  • Hydroxy Compounds
  • Phosphonic Acids and Derivatives
  • Aliphatic and Aryl Amines
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Phosphinic Acids and Derivatives
  • Imines
Pharmacology
Indication Histamine phosphate is indicated as a diagnostic aid for evaluation of gastric acid secretory function.
Pharmacodynamics Histamine stimulates gastric gland secretion, causing an increased secretion of gastric juice of high acidity. This action is probably due mainly to a direct action on parietal and chief gland cells.
Mechanism of action Histamine acts directly on the blood vessels to dilate arteries and capillaries; this action is mediated by both H 1- and H 2-receptors. Capillary dilatation may produce flushing of the face, a decrease in systemic blood pressure, and gastric gland secretion, causing an increased secretion of gastric juice of high acidity. Increased capillary permeability accompanies capillary dilatation, producing an outward passage of plasma protein and fluid into the extracellular spaces, an increase in lymph flow and protein content, and the formation of edema. In addition, histamine has a direct stimulant action on smooth muscle, producing contraction if H 1-receptors are activated, or mostly relaxation if H 2-receptors are activated. Also in humans, the stimulant effect of histamine may cause contraction of the intestinal muscle. However, little effect is noticed on the uterus, bladder, or gallbladder. Histamine has some stimulant effect on duodenal, salivary, pancreatic, bronchial, and lacrimal glands. Histamine also can bind to H3 and H4 receptors which are involved in the CNS/PNS neurotransmitter release and immune system chemotaxis, respectively.
Absorption Readily absorbed after parenteral administration
Volume of distribution Not Available
Protein binding Not Available
Metabolism Primarily hepatic. Histamine is rapidly metabolized by methylation and oxidation. Methylation involves ring methylation and catalyzation by the enzyme histamine-N-methyltransferase, producing N-methylhistamine, which is mostly converted to N-methyl imidazole acetic acid. 2 to 3% excreted as free histamine, 4 to 8% as N-methylhistamine, 42 to 47% as N-methyl imidazole acetic acid, 9 to 11% as imidazole acetic acid, and 16 to 23% as imidazole acetic acid riboside
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity LD50=807 mg/kg (mouse, oral). Side effects can lead to hypertension, hypotension, headache, dizziness, nervousness and tachycardia. Large overdoses can lead to seizures.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
Packagers
Dosage forms
Form Route Strength
Liquid Subcutaneous
Solution Intradermal
Solution Topical
Prices
Unit description Cost Unit
Histamine phosphate 100% cryst 14.38 USD g
Histatrol 1:10000 vial 13.18 USD ml
Histamine di-hcl powder 12.6 USD g
Patents Not Available
Properties
State solid
Melting point 139 oC
Experimental Properties
Property Value Source
logP -3.541 PhysProp
Predicted Properties
Property Value Source
water solubility ALOGPS
logP 0 ALOGPS
logP -1 ChemAxon Molconvert
logS 0 ALOGPS
pKa 0 ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 54.7 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 32.23 ChemAxon Molconvert
polarizability 11.98 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
PubChem Compound 65513 Link_out
PubChem Substance 46509118 Link_out
ChemSpider 58959 Link_out
Therapeutic Targets Database DNC000732 Link_out
PharmGKB PA449881 Link_out
Drug Product Database 2094673 Link_out
Drugs.com http://www.drugs.com/cons/histamine-phosphate-intradermal.html Link_out
ATC Codes
  • V04CG03
AHFS Codes
  • 36:89.00*
  • 36:36.00
PDB Entries Not Available
FDA label Not Available
MSDS show (49.5 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Histamine H1 receptor

Pharmacological action: yes
Actions: agonist

In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system

Organism class: human
UniProt ID: P35367 Link_out
Gene: HRH1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Miyoshi K, Das AK, Fujimoto K, Horio S, Fukui H: Recent advances in molecular pharmacology of the histamine systems: regulation of histamine H1 receptor signaling by changing its expression level. J Pharmacol Sci. 2006 May;101(1):3-6. Epub 2006 Apr 28. Pubmed
  2. Han SK, Mancino V, Simon MI: Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron. 2006 Nov 22;52(4):691-703. Pubmed
  3. Spahr L, Coeytaux A, Giostra E, Hadengue A, Annoni JM: Histamine H1 blocker hydroxyzine improves sleep in patients with cirrhosis and minimal hepatic encephalopathy: a randomized controlled pilot trial. Am J Gastroenterol. 2007 Apr;102(4):744-53. Epub 2007 Jan 11. Pubmed
  4. Suzuki K, Morokata T, Morihira K, Sato I, Takizawa S, Kaneko M, Takahashi K, Shimizu Y: A dual antagonist for chemokine CCR3 receptor and histamine H1 receptor. Eur J Pharmacol. 2007 Jun 1;563(1-3):224-32. Epub 2007 Feb 8. Pubmed
  5. Tanimoto A, Wang KY, Murata Y, Kimura S, Nomaguchi M, Nakata S, Tsutsui M, Sasaguri Y: Histamine upregulates the expression of inducible nitric oxide synthase in human intimal smooth muscle cells via histamine H1 receptor and NF-kappaB signaling pathway. Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1556-61. Epub 2007 May 3. Pubmed

2. Histamine H2 receptor

Pharmacological action: yes
Actions: agonist

The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway

Organism class: human
UniProt ID: P25021 Link_out
Gene: HRH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Francis H, Franchitto A, Ueno Y, Glaser S, DeMorrow S, Venter J, Gaudio E, Alvaro D, Fava G, Marzioni M, Vaculin B, Alpini G: H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway. Lab Invest. 2007 May;87(5):473-87. Epub 2007 Mar 5. Pubmed
  2. Soga F, Katoh N, Kishimoto S: Histamine prevents apoptosis in human monocytes. Clin Exp Allergy. 2007 Mar;37(3):323-30. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Histamine H3 receptor

Pharmacological action: yes
Actions: agonist

The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 niether modified adenylate cyclase activity nor induced intracellular calcium mobilization

Organism class: human
UniProt ID: Q9Y5N1 Link_out
Gene: HRH3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Petroianu G, Arafat K, Sasse BC, Stark H: Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Pharmazie. 2006 Mar;61(3):179-82. Pubmed
  2. Garduno-Torres B, Arias-Montano JA: Homologous down-regulation of histamine H3 receptors in rat striatal slices. Synapse. 2006 Aug;60(2):165-71. Pubmed
  3. Minick DJ, Copley RC, Szewczyk JR, Rutkowske RD, Miller LA: An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT-2331 using vibrational circular dichroism. Chirality. 2007 Sep;19(9):731-40. Pubmed
  4. Arrang JM: [The histamine H3 receptor: a new target for the treatment of arousal and cognitive disorders] Ann Pharm Fr. 2007 Jul;65(4):275-84. Pubmed

4. Histamine H4 receptor

Pharmacological action: unknown
Actions: agonist

The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist)

Organism class: human
UniProt ID: Q9H3N8 Link_out
Gene: HRH4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Blaya B, Nicolau-Galmes F, Jangi SM, Ortega-Martinez I, Alonso-Tejerina E, Burgos-Bretones J, Perez-Yarza G, Asumendi A, Boyano MD: Histamine and histamine receptor antagonists in cancer biology. Inflamm Allergy Drug Targets. 2010 Jul 1;9(3):146-57. Pubmed
  2. Yu B, Shao Y, Li P, Zhang J, Zhong Q, Yang H, Hu X, Chen B, Peng X, Wu Q, Chen Y, Guan M, Wan J, Zhang W: Copy number variations of human histamine H4 receptor gene are associated with systemic lupus erythematosus. Br J Dermatol. 2010 Jul 2. Pubmed
  3. Cowden JM, Riley JP, Ma JY, Thurmond RL, Dunford PJ: Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines. Respir Res. 2010 Jun 24;11:86. Pubmed
Enzymes

1. Histamine N-methyltransferase

Actions: substrate

Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine

UniProt ID: P50135 Link_out
Gene: HNMT
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Garcia-Martin E, Ayuso P, Martinez C, Blanca M, Agundez JA: Histamine pharmacogenomics. Pharmacogenomics. 2009 May;10(5):867-83. Pubmed
  2. Okinaga S, Ohrui T, Nakazawa H, Yamauchi K, Sakurai E, Watanabe T, Sekizawa K, Sasaki H: The role of HMT (histamine N-methyltransferase) in airways: a review. Methods Find Exp Clin Pharmacol. 1995 Nov;17 Suppl C:16-20. Pubmed

2. Cytochrome P450 2C9

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2D6

Actions: inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Solute carrier family 22 member 2

Actions: substrate, inhibitor

Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity

UniProt ID: O15244 Link_out
Gene: SLC22A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Urakami Y, Akazawa M, Saito H, Okuda M, Inui K: cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J Am Soc Nephrol. 2002 Jul;13(7):1703-10. Pubmed
  2. Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E: Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol. 1999 Jul;56(1):1-10. Pubmed
  3. Urakami Y, Okuda M, Masuda S, Akazawa M, Saito H, Inui K: Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules. Pharm Res. 2001 Nov;18(11):1528-34. Pubmed
  4. Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, Waldegger S, Lang F, Koepsell H: Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998 Aug;54(2):342-52. Pubmed
  5. Arndt P, Volk C, Gorboulev V, Budiman T, Popp C, Ulzheimer-Teuber I, Akhoundova A, Koppatz S, Bamberg E, Nagel G, Koepsell H: Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1. Am J Physiol Renal Physiol. 2001 Sep;281(3):F454-68. Pubmed

2. Solute carrier family 22 member 1

Actions: substrate, inhibitor

Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)- N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin- dependent kinase II and LCK tyrosine kinase

UniProt ID: O15245 Link_out
Gene: SLC22A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bednarczyk D, Ekins S, Wikel JH, Wright SH: Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol. 2003 Mar;63(3):489-98. Pubmed
  2. Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E: Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol. 1999 Jul;56(1):1-10. Pubmed
  3. Urakami Y, Okuda M, Masuda S, Akazawa M, Saito H, Inui K: Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules. Pharm Res. 2001 Nov;18(11):1528-34. Pubmed
  4. Busch AE, Quester S, Ulzheimer JC, Gorboulev V, Akhoundova A, Waldegger S, Lang F, Koepsell H: Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1. FEBS Lett. 1996 Oct 21;395(2-3):153-6. Pubmed
  5. Arndt P, Volk C, Gorboulev V, Budiman T, Popp C, Ulzheimer-Teuber I, Akhoundova A, Koppatz S, Bamberg E, Nagel G, Koepsell H: Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1. Am J Physiol Renal Physiol. 2001 Sep;281(3):F454-68. Pubmed

3. Solute carrier family 22 member 3

Actions: inhibitor

Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain

UniProt ID: O75751 Link_out
Gene: SLC22A3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E: Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol. 1999 Jul;56(1):1-10. Pubmed

4. Organic cation/carnitine transporter 2

Actions: inhibitor

Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also Relative uptake activity ratio of carnitine to TEA is 11.3

UniProt ID: O76082 Link_out
Gene: SLC22A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ohashi R, Tamai I, Nezu Ji J, Nikaido H, Hashimoto N, Oku A, Sai Y, Shimane M, Tsuji A: Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol Pharmacol. 2001 Feb;59(2):358-66. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:43