MicroRNA-223 is involved in the pathogenesis of atopic dermatitis by affecting histamine-N-methyltransferase.

Atopic dermatitis (AD) is one of the most prevalent skin diseases around the world. Excessive histamine plays a critical role as an inflammatory factor in the pathogenesis of AD. Deregulated microRNAs (miRNAs) were involved in atopic dermatitis by targeting various genes. MiR-223 had been reported to play a vital role in hematopoiesis. In this study, we identified upregulated miR-223 in the whole blood cells of a large group of AD patients. What's more, we found for the first time that one of the major histamine degradation enzymes, histamine-N-methyltransferase (HNMT), was increased in AD patients and AD model mice. Although there was one miR-223 binding site in the 3'- untranslated region of the HNMT gene, HNMT were not inhibited by miR-223. Taken together, it suggested that miR-223 participates in AD through upregulating HNMT indirectly to degrade the excessive histamine.

Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus.

BACKGROUND: Recent reports have indicated that nonimmune cells can produce low concentrations of histamine. This observation, together with the discovery of the high-affinity histamine H4 receptor (H4 R), has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H4 R pattern, which is deranged in oral lichen planus (OLP). OBJECTIVES: To investigate histamine metabolism and transport in HOKs of healthy controls and patients with OLP. METHODS: Tissue sections and cultured primary HOKs were studied using immunostaining, quantitative real-time polymerase chain reaction and confocal microscopy. Histamine levels were analysed using high-performance liquid chromatography. RESULTS: l-histidine decarboxylase (HDC) and organic cation transporter (OCT)3 were increased in mRNA and protein levels in patients with OLP compared with controls. In contrast, histamine N-methyltransferase (HNMT) immunoreactivity was decreased in OLP. OCT1/OCT2 and diamine oxidase were not detectable in either tissue sections or in HOKs. Immunolocalization of HDC and OCT3 in HOKs revealed moderate-to-high expression within cytoplasm and cell boundaries. Stimulation with lipopolysaccharide (LPS) or interferon-γ upregulated HDC-gene transcript in HOKs, whereas this was downregulated with high histamine concentration and tumour necrosis factor-α. LPS induced a dose-dependent release of low histamine in HOKs, while high histamine concentration downregulated epithelial adhesion proteins. CONCLUSIONS: HOKs are histamine-producing cells. They release histamine via OCT3 channels in concentrations too low to activate the classical low-affinity H1 R and H2 R, but high enough to stimulate the high-affinity H4 R in autocrine and paracrine modes. The substantially deranged histamine metabolism and transport in OLP could, in part, contribute to the disease pathogenesis.

Leucine 208 in human histamine N-methyltransferase emerges as a hotspot for protein stability rationalizing the role of the L208P variant in intellectual disability.

The degradation of histamine catalyzed by the SAM-dependent histamine N-methyltransferase (HNMT) is critically important for the maintenance of neurological processes. Recently, two mutations in the encoding human gene were reported to give rise to dysfunctional protein variants (G60D and L208P) leading to intellectual disability. In the present study, we have expressed eight L208 variants with either apolar (L208F and L208V), polar (L208N and L208T) or charged (L208D, L208H, L208K and L208R) amino acids to define the impact of side chain variations on protein structure and function. We found that the variants L208N, L208T, L208D and L208H were severely compromised in their stability. The other four variants were obtained in lower amounts in the order wild-type HNMT>L208F=L208V>L208K=L208R. Biochemical characterization of the two variants L208F and L208V exhibited similar Michaelis-Menten parameters for SAM and histamine while the enzymatic activity was reduced to 21% and 48%, respectively. A substantial loss of enzymatic activity and binding affinity for histamine was seen for the L208K and L208R variants. Similarly the thermal stability for the latter variants was reduced by 8 and 13°C, respectively. These findings demonstrate that position 208 is extremely sensitive to side chain variations and even conservative replacements affect enzymatic function. Molecular dynamics simulations showed that amino acid replacements in position 208 perturb the helical character and disrupt interactions with the adjacent ß-strand, which is involved in the binding and correct positioning of histamine. This finding rationalizes the gradual loss of enzymatic activity observed in the L208 variants.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.

The role of tumor suppressor menin in IL-6 regulation in mouse islet tumor cells.

Menin is a gene product of multiple endocrine neoplasia type1 (Men1), an inherited familial cancer syndrome characterized by tumors of endocrine tissues. To gain insight about how menin performs an endocrine cell-specific tumor suppressor function, we investigated the possibility that menin was integrated in a cancer-associated inflammatory pathway in a cell type-specific manner. Here, we showed that the expression of IL-6, a proinflammatory cytokine, was specifically elevated in mouse islet tumor cells upon depletion of menin and Men(-/-) MEF cells, but not in hepatocellular carcinoma cells. Histone H3 lysine (K) 9 methylation, but not H3 K27 or K4 methylation, was involved in menin-dependent IL-6 regulation. Menin occupied the IL-6 promoter and recruited SUV39H1 to induce H3 K9 methylation. Our findings provide a molecular insight that menin-dependent induction of H3 K9 methylation in the cancer-associated interleukin gene might be linked to preventing endocrine-specific tumorigenesis.

Molecular identification of carnosine N-methyltransferase as chicken histamine N-methyltransferase-like protein (hnmt-like).

Anserine (beta-alanyl-N(Pi)-methyl-L-histidine), a naturally occurring derivative of carnosine (beta-alanyl-L-histidine), is an abundant constituent of skeletal muscles and brain of many vertebrates. Although it has long been proposed to serve as a proton buffer, radicals scavenger and transglycating agent, its physiological function remains obscure. The formation of anserine is catalyzed by carnosine N-methyltransferase which exhibits unknown molecular identity. In the present investigation, we have purified carnosine N-methyltransferase from chicken pectoral muscle about 640-fold until three major polypeptides of about 23, 26 and 37 kDa coeluting with the enzyme were identified in the preparation. Mass spectrometry analysis of these polypeptides resulted in an identification of histamine N-methyltransferase-like (HNMT-like) protein as the only meaningful candidate. Analysis of GenBank database records indicated that the hnmt-like gene might be a paralogue of histamine N-methyltransferase gene, while comparison of their protein sequences suggested that HNMT-like protein might have acquired a new activity. Chicken HNMT-like protein was expressed in COS-7 cells, purified to homogeneity, and shown to catalyze the formation of anserine as confirmed by both chromatographic and mass spectrometry analysis. Both specificity and kinetic studies carried out on the native and recombinant enzyme were in agreement with published data. Particularly, several compounds structurally related to carnosine, including histamine and L-histidine, were tested as potential substrates for the enzyme, and carnosine was the only methyl group acceptor. The identification of the gene encoding carnosine N-methyltransferase might be beneficial for estimation of the biological functions of anserine.

Histamine transport and metabolism are deranged in salivary glands in Sjogren's syndrome.

OBJECTIVE: To study histamine transport and metabolism of salivary gland (SG) epithelial cells in healthy controls and SS patients. METHODS: Enzymes and transporters involved in histamine metabolism were analysed in cultured human submandibular salivary gland (HSG) epithelial cells and tissue sections using quantitative real-time PCR and immunostaining. HSG cells were used to study [(3)H]histamine uptake [(±1-methyl-4-phenylpyridinium (MPP)] and efflux by liquid scintillation counting. RESULTS: mRNA levels of l-histidine decarboxylase (HDC) and histamine-N-methyltransferase (HNMT) were similar in the control and SS glands, but diamine oxidase was not expressed at all. Organic cation transporter 3 (OCT3) in healthy SG was localized in the acinar and ductal cells, whereas OCT2 was restricted to the myoepithelial cells. Both transporters were significantly decreased in SS at mRNA and protein levels. OCT3-mRNA levels in HSG cells were significantly higher than those of the other studied transporters. Uptake of [(3)H]histamine was inhibited by MPP in a time-dependent manner, whereas [(3)H]histamine-preloaded HSG cells released it. CONCLUSION: Ductal epithelial cells are non-professional histamine-producing cells able to release histamine via OCTs at the resting state up to ∼100 nM, enough to excite H3R/H4R(+) epithelial cells, but not H1R, which requires burst release from mast cells. At the stimulated phase, 50-60 µM histamine passes from the interstitial fluid through the acinar cells to saliva, whereas uptake by ductal cells leads to intracellular degradation by HNMT. OCT3/histamine/H4R-mediated cell maintenance and down-regulation of high histamine levels fail in SS SGs.

Molecular mechanism of histamine clearance by primary human astrocytes.

Histamine clearance is an essential process for avoiding excessive histaminergic neuronal activity. Previous studies using rodents revealed the predominant role of astrocytes in brain histamine clearance. However, the molecular mechanism of histamine clearance has remained unclear. We detected histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, in primary human astrocytes and the astrocytes of human brain specimens. Immunocytochemical analysis and subcellular fractionation assays revealed that active HNMT localized to the cytosol, suggesting that histamine transport into the cytosol is crucial for histamine inactivation. We showed that primary human astrocytes transported histamine in a time-dependent manner. Kinetics analysis showed that two low-affinity transporters were involved in histamine transport. Histamine uptake by primary human astrocytes was not dependent on the extracellular Na(+) /Cl(-) concentration. Histamine is reported to be a substrate for three low-affinity and Na(+) /Cl(-) -independent transporters: organic cation transporter 2 (OCT2), OCT3, and plasma membrane monoamine transporter (PMAT). RT-PCR analysis revealed that OCT3 and PMAT were expressed in primary human astrocytes. Immunohistochemistry confirmed OCT3 and PMAT expression in the astrocytes of human brain specimens. Drug inhibition assays and gene knockdown assays revealed the major contribution of PMAT and the minor contribution of OCT3 to histamine transport. The present study demonstrates for the first time that the molecular mechanism of histamine clearance is by primary human astrocytes. These findings might indicate that PMAT, OCT3 and HNMT in human astrocytes play a role in the regulation of extraneuronal histamine concentration and the activities of histaminergic neurons.

Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay.

BACKGROUND: The phosphoethanolamine methyltransferase, PfPMT, of the human malaria parasite Plasmodium falciparum, a member of a newly identified family of phosphoethanolamine methyltransferases (PMT) found solely in some protozoa, nematodes, frogs, and plants, is involved in the synthesis of the major membrane phospholipid, phosphatidylcholine. PMT enzymes catalyze a three-step S-adenosylmethionine-dependent methylation of the nitrogen atom of phosphoethanolamine to form phosphocholine. In P. falciparum, this activity is a limiting step in the pathway of synthesis of phosphatidylcholine from serine and plays an important role in the development, replication and survival of the parasite within human red blood cells. RESULTS: We have employed an enzyme-coupled methylation assay to screen for potential inhibitors of PfPMT. In addition to hexadecyltrimethylammonium, previously known to inhibit PfPMT, two compounds dodecyltrimethylammonium and amodiaquine were also found to inhibit PfPMT activity in vitro. Interestingly, PfPMT activity was not inhibited by the amodiaquine analog, chloroquine, or other aminoquinolines, amino alcohols, or histamine methyltransferase inhibitors. Using yeast as a surrogate system we found that unlike wild-type cells, yeast mutants that rely on PfPMT for survival were sensitive to amodiaquine, and their phosphatidylcholine biosynthesis was inhibited by this compound. Furthermore NMR titration studies to characterize the interaction between amoidaquine and PfPMT demonstrated a specific and concentration dependent binding of the compound to the enzyme. CONCLUSION: The identification of amodiaquine as an inhibitor of PfPMT in vitro and in yeast, and the biophysical evidence for the specific interaction of the compound with the enzyme will set the stage for the development of analogs of this drug that specifically inhibit this enzyme and possibly other PMTs.

Histamine and its metabolizing enzymes in tissues of primary ductal breast cancer.

OBJECTIVES: The aim of the study was to evaluate histamine concentrations in plasma and tissues of breast cancers depending on the activity of histamine metabolic enzymes in neoplasmatic tissues of the breast gland. MATERIAL AND METHODS: In 95 women aged 38-70 years the concentration of histamine in the plasma by the immunoenzymatic method, the concentration of histamine in breast cancer tissues and metabolism enzymes of histamine: histidine decarboxylase, decarboxylase of aromatic L-amino acid, N-histamine methyltransferase, monoamine oxydase B, diamine oxydase determined using an isotope technique were assessed. The 24-hour excretion of N-methylimidazolacetate acid was evaluated by the chromatography method. RESULTS: Significant increases were found of histamine concentrations in plasma tissues of ductal breast cancers, activity of histidine decarboxylase, aromatic L-amino acid and histamine methyltransferase. CONCLUSIONS: 1. Concentrations of histamine in plasma is dependent on the concentration of histamine in the tissues of ductal breast cancers. 2. Significant increases of histamine in cancerous tissues of ductal breast cancer could suggest the participation of this monoamine in the development of breast cancer. 3. The increase of histamine concentrations in ductal breast cancer tissues can be connected with disturbances in the balance between synthesis and enzymatic activation of this monoamine. 4. The concentration of histamine in plasma of women with ductal breast cancers is dependent on the number of lymph nodes and grade of histological malignancy.

Metabolism of histamine in tissues of primary ductal breast cancer.

Histamine performs an important role in the pathologic and physiologic aspects of the breast gland. Among monoamines, histamine demonstrates the greatest proliferative activity in breast cancer. The aim of the study was to evaluate histamine concentration in plasma and tissues of breast cancer dependent on the activity of histamine metabolism enzymes in neoplasmatic tissues of the breast gland. Ninety-five women aged 38 to 70 years were divided into 2 groups. The control group (group I) consisted of 30 healthy women. Group II consisted of 65 women with primary ductal breast cancer. The concentration of histamine in plasma was assessed by immunoenzymatic method. The concentration of histamine in cancerous tissues of the breast and the metabolism of histamine enzymes, specially histidine decarboxylase, decarboxylase of aromatic L-amino acids, N-histamine methyltransferase, monoamine oxydase B, and diamine oxydase, were determined using isotope technique. In the course of 24 hours, excretion of N-methylimidazoleacetic acid was evaluated by the methods of chromatography. The statistical analysis was made based on Statistica Pl Ed (StatSoft, Cracow, Poland, 1998). A significant increase in the concentration of histamine in plasma (P < .01) and tissues of ductal breast cancers (P < .001), and in the activity of histidine decarboxylase (P < .01), aromatic L-amino acids (P < .05), and histamine methyltransferase (P < .05) was found. Activity of monoamine oxidase B (P < .01) and diamine oxidase (P < 0.01) and excretion of N-methylimidazoleacetic acid were significantly decreased compared with the control group (P < 0.001). The conclusions are as follows: (1) Concentration of histamine in the plasma of women is dependent on the concentration of histamine in the tissues of ductal breast cancers. (2) The significant increase of histamine in cancerous tissues of ductal breast cancer could suggest the participation of this monoamine in the development of breast cancer. (3) The increase of histamine concentrations in ductal breast cancer tissues can be connected with the disturbances of the balance between synthesis and enzymatic inactivation of this monoamine. (4) The concentration of histamine in the plasma of women with ductal breast cancers is dependent on the number of involved lymph nodes and the grade of histologic malignancy.

Decreased histamine catabolism in the colonic mucosa of patients with colonic adenoma.

INTRODUCTION: Alterations in mucosal histamine degradation play an important role in various gastrotinestinal diseases including colonic adenoma. In humans, histamine can be catabolized either by oxidative deamination by diamine oxidase (DAO) or by ring methylation by histamine N-methyltransferase (HNMT). The significance of HNMT in this context was investigated for the first time in this project. METHODS: About 94 colonic biopsies were endoscopically obtained from 23 patients suffering from colonic adenoma and 26 biopsies from six healthy individuals. Each sample was mechanically homogenized, homogenates were cleared by centrifugation and used for determination of protein and histamine concentrations and enzyme activities of DAO and HNMT by radiometric assay. RESULTS: In adenoma patients DAO activities were slightly and HNMT activities were significantly decreased in normal mucosa compared to controls. Activities of both enzymes were significantly lower in adenoma tissue than in healthy mucosa in the same patients. A significant correlation was found between HNMT and DAO in all investigated samples. Histamine concentrations were elevated in adenoma patients. CONCLUSIONS: Histamine catabolism is decreased in the colonic mucosa of patients with colonic adenoma.

Autonomous histamine metabolism in human melanoma cells.

Melanoma cells constitutively produce various cytokines as well as growth factors and express their corresponding receptors. Exogenous histamine is known to be a growth factor for some tumours while in other cases histamine inhibits tumour growth, and acts on G protein-coupled H1 and H2 histamine receptors. In previous studies we have detected the expression of the l-histidine decarboxylase (HDC) gene and the presence of HDC protein in human melanoma cell lines. In the present study, the activities of the histamine-forming enzyme HDC and of the degrading enzymes diamine oxidase (DAO) and histamine N-methyltransferase (HNMT) were measured in primary (WM35 and WM983) and metastatic (M1 and HT168) human melanoma cell lines. HDC activity was found in WM35 and WM983 cell lines, while detectable HNMT activity was measured in WM983, M1 and HT168 lines. In contrast, DAO showed very low activity in melanoma cell lines. Melanoma cells release a detectable amount of histamine into the medium without external stimuli. These findings support the possibility of autonomous histamine metabolism in melanoma cells. Our results suggest that not only exogenous histamine but also histamine produced and released by the melanoma cells and acting as an autocrine and paracrine factor may influence cell proliferation and modulate the in situ immune response of the host.

Guinea pig histamine N-methyltransferase: cDNA cloning and mRNA distribution.

We report here the isolation of histamine N-methyltransferase (HMT) cDNA from the guinea pig brain by the polymerase chain reaction on the basis of nucleotide sequences of rat and human counterparts. Guinea pig HMT consists of 292 amino acids, with homologies of 75.6% and 79.1% to rat and human HMT, respectively. Northern blotting analysis indicated that the 1.6-kb guinea pig HMT transcript was expressed at various levels in different tissues at the following relative abundance: jejunum, brain > lung, spleen, stomach > liver, kidney. HMT mRNA localized throughout the jejunum, and it was mainly expressed in epithelial cells and in Auerbach's plexus.

Radio-enzymatic determination of histamine: interference by fluoride and possible activation of histamine methyl transferase.

The reproducibility of a radio-enzymatic method for determining plasma histamine was found to be affected by the anti-coagulant used for collecting blood. Recovery experiments from whole blood indicated that heparin yielded values that were more accurate than with EDTA or sodium fluoride; fluoride gave a mean value which was +41% higher than with heparin (P=0.054). Addition of fluoride to a standard calibration curve, and of increasing amounts to aliquots of 5 ng histamine also yielded higher values than in controls, up to +15% (P<0.1) and +14.1% (P=0.03) respectively. Fluoride did not affect the detecting system and was not contaminated with histamine; nor did it breakdown the methyl donor, S-adenosyl-L-methionine. It is concluded that heparin is the anti-coagulant of choice and that fluoride may activate histamine methyl transferase from pig brain. Fluoride may possibly have a biological role as an enzyme-activator and a usefulness in the therapy of mastocytosis.

Interindividual variability of histamine N-methyltransferase in the human liver and kidney.

1. The aim was to investigate the possibility of interindividual variability of histamine N-methyltransferase (HNMT) in the human liver and renal cortex. The activity of HNMT was measured in 99 specimens of the human liver and in 75 specimens of the renal cortex. 2. In the liver the activity of HNMT was positively skewed. It ranged 2.9-fold with a median of 1.72 pmol/min/mg. In the renal cortex the activity of HNMT was normally distributed and ranged 2.6-fold with a mean and coefficient of variation of 1.35 pmol/min/mg and 21%, respectively. 3. The activities of catechol methyltransferase and thiopurine methyltransferase were measured in the renal cortex and any correlations with HNMT activity were assessed. There was a weak but significant correlation (r = 0.294, p = 0.010) between HNMT and catechol methyltransferase activities whereas HNMT activity was not correlated with thiopurine methyltransferase activity. 4. These results are consistent with the view that HNMT is well expressed in the human liver and renal cortex and that it varies among subjects.

Histamine in the chick pineal gland: origin, metabolism, and effects on the pineal function.

The chick pineal gland contains histamine and tele-methylhistamine. The levels of both substances are elevated after treatment of chicks with the amino acid precursor of histamine, L-histidine (1 g/kg, ip). In control and L-histidine-loaded animals the pineal levels of histamine and tele-methylhistamine are higher in light-exposed than in dark-adapted animals (measured at the end of the light phase and in the middle of the dark phase of 12 hr light, 12 hr dark illumination cycle, respectively). The chick pineal gland contains histamine-immunofluorescent cells displaying mast cell morphology; they are seen in the vicinity of the capsule and in the parenchyma. Enzymatic studies showed the presence of the activity of histamine synthesizing and inactivating enzyme, i.e., L-histidine decarboxylase (HDC) and histamine-methyltransferase (HMT). The detected enzyme activities were sensitive to specific inhibitors of HDC (alpha-fluoromethylhistidine and alpha-hydrazinohistidine) and HMT (quinacrine and metoprine); inhibitors of aromatic amino acid decarboxylase alpha-methyl-DOPA and NSD-1015 were inactive on HDC. Exogenous histamine added to organ-cultured chick pineals strongly stimulated endogenous cyclic AMP accumulation and moderately increased melatonin secretion. The data, considered collectively, suggest that in avians histamine, probably originating from the pineal mast cell compartment, may function as a regulator of pineal gland activity.

Nitrogen dioxide exposure increases airway contractile response to histamine by decreasing histamine N-methyltransferase activity in guinea pigs.

To determine the mechanism responsible for nitrogen dioxide (NO2)-induced airway hyperresponsiveness, we examined the effects of NO2 exposure on the contractile response to histamine and the level of histamine N-methyltransferase (HMT) activity, a histamine-degrading enzyme, in guinea pig trachea in vitro. Guinea pigs were divided into seven groups. Each group received continuous NO2 exposure (2.0 ppm) for either 2, 6, 12, 24, 48, or 96 h. The remaining group did not receive NO2 exposure (control). HMT activity in trachea was decreased from the control value of 70.3 +/- 7.7 pmol/min/mg protein to 34.6 +/- 6.7 pmol/min/mg protein by 12 h exposures of NO2. However, 24 and 48 h exposures of NO2 did not significantly alter HMT activity. In contrast, HMT activity exceeded the control value by 96 h exposures of NO2 (85.5 +/- 5.1 pmol/min/mg protein). Twelve hour exposures of NO2 shifted the concentration-response curves to histamine to lower concentrations and significantly reduced the median effective concentration (EC50) of histamine (log M) from the control value of -5.16 +/- 0.09 to -6.15 +/- 0.14 (P < 0.01). In contrast, the EC50 concentration of histamine (log M) increased from the control value of -5.20 +/- 0.10 to -4.90 +/- 0.11 by 96 h exposures of NO2 (P < 0.05). However, NO2 exposure did not alter the contractile response to acetylcholine. Morphologically, tracheal epithelial cells had vacuoles after 12 h exposures of NO2, but denudation of the epithelium did not occur during this experiment. In situ hybridization for HMT mRNA demonstrated that the level of HMT mRNA increased dominantly in tracheal epithelial cells after 96 h exposures of NO2. The present results indicated that the decrease in the level of HMT activity in the trachea was closely associated with the increase in the airway contractile response to histamine, suggesting that NO2-induced transient airway hyperresponsiveness to histamine is due to the decreased capacity of histamine catabolism in airway.

Helicobacter pylori infection: physiopathologic implication of N alpha-methyl histamine.

BACKGROUND/AIMS: In the gastric mucosa of Helicobacter pylori-infected subjects, we previously detected N alpha-methyl histamine (N alpha-MeHA), a minor catabolite of histamine and a potent agonist of histamine H3 receptors. The origin of N alpha-MeHA and its effects on gastric histamine and somatostatin in infected subjects were investigated. METHODS: Ten noninfected patients and 13 patients with intense colonization were compared. N alpha-MeHA content and its synthetic enzyme activity, N alpha-histamine methyltransferase, binding of [3H]N alpha-MeHA, histamine and somatostatin contents, and histidine decarboxylase activity were assayed in antral and fundic biopsy specimens and in cultured H. pylori strains. RESULTS: Gastric histamine and somatostatin contents as well as histidine decarboxylase activity were decreased in infected patients and were restored to normal after antimicrobial treatment. Both N alpha-MeHA and N alpha-histamine methyltransferase activity were present in the mucosa of infected patients and in cultured strains and were very low in noninfected patients or after eradication of H. pylori. [3H]N alpha-MeHA bound to gastric mucosa but not to cultured strains. The [3H]N alpha-MeHA specific binding sites were characterized as H3 receptors. The amount of bound [3H]N alpha-MeHA seemed correlated positively with somatostatin content and histidine decarboxylase activity and negatively with N alpha-MeHA content and N alpha-histamine methyltransferase activity. CONCLUSIONS: H. pylori is the main source of gastric N alpha-MeHA that may lower histidine decarboxylase activity and somatostatin content through H3 receptors.