Human Endogenous Metabolite

Human articular chondrocytes in culture proliferate more when histamine is present. Numerous cell types, including chondrocytes, fibroblasts, macrophages, endothelial cells, epithelial cells, and T cells, have been shown to exhibit altered behavior in vitro when exposed to histamine. Additionally, histamine affects the expression of many cytokines' receptors as well as how many of them are produced. Histamine receptor expression allows histamine to control various cellular functions. Histamine stimulates the production of matrix metalloproteinases (MMPs)-13 and -3 (collagenase 3 and stromelysin-1, respectively) by histidine decarboxylase (HAC) in vitro[1].

Histamine is a known contributor to allergic and inflammatory responses and a key regulator of many physiological functions, such as angiogenesis, vasopermeability, and cell proliferation[1]. Histamine causes venula hyperpermeability while dilating the vasculature and boosting blood flow. Changes in the location of vascular endothelial cadherin (VE-cadherin) at the endothelial cell junction are indicative of its disruption of the endothelial barrier formation of venula[3].

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Histamine can be used for building animal disease models such as gastrointestinal ulcer models. After intravenous injection of histamine hydrochloride, the maximum concentration and AUC of histamine in liver and liver tumor tissues were higher than those in subcutaneous tissues [4].
Inducing gastrointestinal ulcers [5]
1) Pathogenic principle
Histamine can cause an increase in gastric acid secretion, a decrease in mucus production, pancreatic reflux, poor gastric blood flow, and ultimately lead to gastric ulcers. Pressure can also increase gastrointestinal peristalsis, making gastric folds more susceptible to damage when exposed to acid.
2) Specific methods
Guinea Pig: male • albino • 360-420 g
Administration: 5 mg/kg • i.p. • single dose
3) Indicators of successful construction of gastrointestinal ulcer model
The ulcer appears as a dot or elongated shape. After dissection of the model, the ulcer index (length of the lesion) was measured under a microscope to be 3.4 mm.

In 80 cm² culture flasks, cells are grown to confluence using 10% fetal calf serum (FCS) and Dulbecco's modified Eagle's medium (DMEM). At first or second passage, cells are seeded into 96 well culture plates, at densities of approximately 2×10³ cells/well. After a day, the cells are treated with either DMEM + 2% FCS on its own (control) or DMEM + 2% FCS plus histamine at a concentration of 1-100 μmol/l (each treatment requiring a minimum of eight wells). Every 48 hours, the medium—containing or not—is replaced, and after six days, the rate of cell growth is calculated.

New Zealand adult healthy albino rabbits 50, 100, 200 μg/kg s.c.

Absorption, Distribution and Excretion
Readily absorbed after parenteral administration.
HISTAMINE IS READILY ABSORBED AFTER PARENTERAL INJECTION...
THE VARIOUS METAB, WHICH HAVE LITTLE OR NO PHARMACOLOGICAL ACTIVITY, ARE EXCRETED IN URINE.
HISTAMINE & N-METHYLHISTAMINE ACCUM IN TISSUE DEPOTS.

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Metabolism / Metabolites
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.
IN MAN THERE ARE 2 MAJOR PATHS OF HISTAMINE METAB. MORE IMPORTANT ONE INVOLVES RING METHYLATION & IS CATALYZED BY...HISTAMINE-N-METHYLTRANSFERASE (IMIDAZOLE-N-METHYLTRANSFERASE, INMT). MOST OF PRODUCT, METHYLHISTAMINE, IS CONVERTED BY MONOAMINE OXIDASE TO METHYL IMIDAZOLE ACETIC ACID (METHYL IMAA).
IN OTHER PATH, HISTAMINE UNDERGOES OXIDATIVE DEAMINATION CATALYZED MAINLY BY DIAMINOXIDASE (DAO), ALSO CALLED "HISTAMINASE"... THE PRODUCTS ARE IMIDAZOLE ACETIC ACID (IMAA) &, EVENTUALLY, ITS RIBOSIDE.
.../MUCH OF VERY LARGE AMT OF HISTAMINE GIVEN ORALLY/ IS CONVERTED BY INTESTINAL BACTERIA TO N-ACETYLHISTAMINE.

Interactions
INHIBITORY EFFECT OF METHAMIDE (POTENT H2 ANTAGONIST) ON GASTRIC ACID SECRETION ELICITED BY CONTINUOUS HISTAMINE IV INFUSION IN MAX EFFECTIVE DOSE (20 UMOLE/HR) IN DOGS IS SHOWN TO BE APPROX 20%/10 UMOLE/KG AFTER 1.5 HR. COMPARABLE EFFECTS WERE OBSERVED IN NORMAL HUMANS IN SAME STUDY. /H2-RECEPTOR ANTAGONISTS, FROM TABLE/
IN GUINEA PIGS, DEATH BY ASPHYXIA FOLLOWS QUITE SMALL DOSES OF HISTAMINE, YET ANIMAL MAY SURVIVE A HUNDRED LETHAL DOSES OF HISTAMINE IF GIVEN AN H1-BLOCKING DRUG. IN SAME SPECIES, H1 ANTAGONISTS OFFER STRIKING PROTECTION AGAINST ANAPHYLACTIC BRONCHOSPASM, BUT THIS IS NOT SO IN MAN... /H1-RECEPTOR ANTAGONISTS/

[1]. Ann Rheum Dis . 2003 Oct;62(10):991-4.

[2]. Asian Pacific Journal of Tropical Medicine. 2010, 3(2): 112-116.

[3]. PLoS One . 2015 Jul 9;10(7):e0132367.

[4]. Histamine pharmacokinetics in tumor and host tissues after bolus-dose administration in the rat. Life Sci. 2002 Jan 11;70(8):969-76.
[5]. Effects of cimetidine, a histamine H2-receptor antagonist, on various experimental gastric and duodenal ulcers. Am J Dig Dis. 1977 Aug;22(8):677-84.

Histamine is a member of the class of imidazoles that is 1H-imidazole substituted at position C-4 by a 2-aminoethyl group. It has a role as a human metabolite, a mouse metabolite and a neurotransmitter. It is an aralkylamino compound and a member of imidazoles. It is a conjugate base of a histaminium.
A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter.
Histamine has been reported in Cynanchum caudatum, Phytolacca japonica, and other organisms with data available.
Histamine is a metabolite found in or produced by Saccharomyces cerevisiae.
An amine derived by enzymatic decarboxylation of HISTIDINE. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter.
See also: Histamine Dihydrochloride (has salt form); Histamine Phosphate (has salt form); Acetylcholine Chloride; Histamine; Serotonin (component of) ... View More ...

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Drug Indication
Histamine phosphate is indicated as a diagnostic aid for the evaluation of gastric acid secretory function.

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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.
...CONTRACTS MANY SMOOTH MUSCLES, SUCH AS...BRONCHI & GUT, BUT...RELAXES OTHERS...OF FINE BLOOD VESSELS. IT IS...POTENT STIMULUS TO GASTRIC ACID PRODUCTION & ELICITS...OTHER EXOCRINE SECRETIONS. ...BRONCHOCONSTRICTION & CONTRACTION OF GUT...INVOLVE H1 RECEPTORS...GASTRIC SECRETION...INVOLVE ACTIVATION OF H2 RECEPTORS...
...AT CELLULAR LEVEL, MANY RESPONSES TO HISTAMINE ARE CLEARLY ATTRIBUTABLE TO INCR IN MEMBRANE PERMEABILITY THAT ALLOWS COMMON INORG IONS (MAINLY CATIONS) TO FLOW DOWN ELECTROCHEM GRADIENTS & ALTER TRANSMEMBRANE POTENTIAL. IT DOUBTLESS EXPLAINS STIMULANT ACTIONS...OF HISTAMINE ON NERVE ENDINGS OR GANGLION CELLS...
...ESSENTIALLY SIMILAR ACTION /TO THAT AT CELLULAR LEVEL/ APPEARS TO ACCOUNT FOR SECRETION, AT LEAST AS IT OCCURS IN CHROMAFFIN CELLS OF ADRENAL MEDULLA. HERE HISTAMINE...MIMIC PHYSIOLOGICAL SECRETAGOGUE ACH IN DEPOLARIZING THE PLASMALEMMA.
MODE OF ACTION OF HISTAMINE...TO PRODUCE SMOOTH MUSCLE RELAXATION, INCL VASODILATION, HAS NOT BEEN DEFINED.
CLASSICAL...ANTIHISTAMINES ARE...CAPABLE OF BLOCKING...H1 RECEPTORS ONLY... H2 RECEPTORS...ARE INHIBITED PREFERENTIALLY BY H2-RECEPTORS ANTAGONISTS.

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Therapeutic Uses
EXPTL USE: IN VET MEDICINE PRIMARILY FOR EXPTL PRODN OF ULCERS IN DOGS & HOGS, & OCCASIONALLY TO DETERMINE STATUS OF HYDROCHLORIC ACID SECRETION IN STOMACH OF DOGS BY USE OF "DIAGNEX BLUE-TEST" OR "GASTRO-TEST"...
EXPTL USE: ...ATTEMPTS HAVE BEEN MADE TO DESENSITIZE PT /TO HISTAMINE ALLERGIES/ WITH COURSES OF HISTAMINE INJECTIONS. THERE IS NO EXPTL EVIDENCE THAT SUCH REGIMES INDUCE SIGNIFICANT TOLERANCE...& PROCEDURE HAS NOT MET WITH GENERAL ACCEPTANCE.
PRACTICAL APPLICATIONS OF HISTAMINE FALL INTO TWO CATEGORIES: 1ST, ITS USES AS DIAGNOSTIC AGENT, WHICH FOR MOST PART ARE ON A SOUND PHYSIOLOGICAL BASIS; &, 2ND, ITS MORE CONTROVERSIAL USES IN THERAPY, ESP OF DISEASES OF ALLERGY.
AS DIAGNOSTIC AGENT IT IS OF VALUE IN TESTING FOR FUNCTIONAL CAPACITY OF GASTRIC GLANDS. IF NO ACID IS SECRETED FOLLOWING INJECTION OF 0.25-0.5 MG (USUALLY AS 1:1000 SOLN), A TRUE GASTRIC ACHYLIA EXISTS.
For more Therapeutic Uses (Complete) data for HISTAMINE (10 total), please visit the HSDB record page.

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Drug Warnings
/WHEN HISTAMINE IS EMPLOYED TOPICALLY TO EYE IN CONCN FROM 0.1 TO 10% IT CAUSES/ VASODILATION & EDEMA OF CONJUNCTIVA.

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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.

C5H9N3

111.1451

111.079

C, 73.52; H, 7.14; N, 9.03; O, 10.31

51-45-6

51-45-6; 56-92-8 (HCl); 51-74-1 (phosphate)

774

White to yellow solid powder

1.1±0.1 g/cm3

331.0±17.0 °C at 760 mmHg

83-84ºC

180.3±8.1 °C

0.0±0.7 mmHg at 25°C

1.567

-0.92

2

2

2

8

64.7

0

N1([H])C([H])=NC([H])=C1C([H])([H])C([H])([H])N([H])[H]

NTYJJOPFIAHURM-UHFFFAOYSA-N

InChI=1S/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8)

2-(1H-imidazol-5-yl)ethanamine

LS82-556; LS 82-556; 2-(1H-imidazol-5-yl)ethanamine; 1H-Imidazole-4-ethanamine; Ergamine; Ergotidine; 2-(4-Imidazolyl)ethylamine; 5-Imidazoleethylamine; LS-82-556

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~22 mg/mL (~197.9 mM)
Water: ~22 mg/mL
Ethanol: ~22 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)