High Histamine Research Articles

Spontaneous basophil responses in food-allergic children are transferable by plasma and are IgE-dependent

Early studies showed that up to 80% of children with food allergy demonstrate high spontaneous basophil histamine release (SBHR).1 An association with IgE was suggested because basophils from food-allergic (FA) children additionally released histamine to the IgE-dependent histamine-releasing factor.2 However, the exact mechanism(s) responsible for SBHR, including the dependency for IgE, remains poorly understood. We recently reported that SBHR significantly decreased in children undergoing sublingual immunotherapy/oral immunotherapy (SLIT/OIT) for cow's milk allergy,3 prompting further investigations of this response and other markers of basophil hyperresponsiveness.

Importance of Histamine-Producing Clostridium perfringens in Scombrotoxin-Forming Fish

It has been suggested that anaerobic histamine-producing bacteria (HPB) are important contributors to scombrotoxin fish poisoning (SFP). In order to assess the role of Clostridium perfringens in SFP, we developed a real-time PCR method for rapid detection of histamine-producing (HP) C. perfringens. The real-time PCR assay was 100% inclusive for detecting 23 HP C. perfringens and did not detect any of the other 116 HP or non-HP isolates examined. The efficiency of the assay with or without internal amplification control DNA was 102%; in the presence of background flora and inhibitory matrices, it was 90 to 99%. To investigate the importance of HP C. perfringens in SFP, we examined histamine production by C. perfringens in inoculated fish samples incubated under anaerobic conditions. C. perfringens produced low histamine levels in tuna (19 ppm) and Spanish mackerel (3 ppm), whereas gram-negative HPB produced high histamine levels (6,345 ppm in tuna; 1,223 ppm in Spanish mackerel) under the same conditions. When one bonito, two bigeye tuna, nine mahi-mahi, and five yellowfin tuna were examined for the presence of HPB, none (0 of 17) of the samples contained HP C. perfringens or other gram-positive HPB, whereas 86% of the samples contained gram-negative HPB. Our study indicates that histamine production by C. perfringens in scombrotoxin-forming fish was minimal compared with that by gram-negative HPB and that C. perfringens may not be an important bacterial species associated with SFP.

Bispyrimidines as Potent Histamine H4 Receptor Ligands: Delineation of Structure–Activity Relationships and Detailed H4 Receptor Binding Mode

The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific.

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

To study histamine transport and metabolism of salivary gland (SG) epithelial cells in healthy controls and SS patients. 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. 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. 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.

Determination and Frying Loss of Histamine in Striped Marlin Fillets Implicated in a Foodborne Poisoning

An incident of foodborne poisoning causing illness in 67 victims due to ingestion of fried fish fillets occurred in June 2011, in southern Taiwan. Of the five suspected fish fillets, one fried sample contained 62.0 mg/100 g and one raw sample contained 89.6 mg/100 g histamine, levels which are greater than the potential hazard action level (50 mg/100 g) in most illness cases. Given the allergy-like symptoms of the victims and the high histamine content in the suspected fish samples, this foodborne poisoning was strongly suspected to be caused by histamine intoxication. Five histamine-producing bacterial strains capable of producing 59 to 562 ppm of histamine in Trypticase soy broth supplemented with 1.0% L-histidine were identified as Enterobacter aerogenes (two strains), Raoultella ornithinolytica (two strains), and Morganella morganii (one strain). The degradation loss of histamine in suspected raw fillets was 28% after they were fried at 170°C for 5 min.

Lack of Association of Plasma Histamine with Diamine Oxidase in Chronic Idiopathic Urticaria

BackgroundChronic idiopathic urticaria (CIU) is considered a complex and multifactorial disease. Excessive histamine intake may induce an attack of urticaria. The main enzyme for histamine metabolism is diamine oxidase (DAO).ObjectivePlasma histamine concentrations and DAO activities were evaluated to determine whether there are abnormalities in the histamine metabolism of CIU patients.MethodsSeventy-five CIU patients and twenty-five healthy control subjects were included in the study. Blood was taken from all subjects to measure plasma levels of the histamine and DAO.ResultsMean plasma histamine levels were significantly higher in CIU patients (11.59±10.98 nM) than in the control subjects (8.75±2.55 nM) (p=0.04). Mean DAO activities were lower in patients of CIU (80.86±26.81 histamine degrading unit [HDU]/ml) than in the controls (81.60±9.67 HDU/ml), but without significant difference. In 15 CIU patients with gastrointestinal symptoms, the mean histamine concentration was higher (12.43±7.97 nM) and DAO activity was lower (77.93±27.53 HDU/ml) than in the remaining 60 CIU patients without gastrointestinal symptoms (11.38±11.67 nM and 81.58±26.82 HDU/ml), without significant difference. The relationship between DAO activity and plasma histamine concentrations showed a significant negative linear value (p=0.001). There were no significant relationships between plasma histamine concentrations and symptom severity score.ConclusionIn CIU patients, a high plasma histamine concentration may not be explained by DAO activity. CIU patients with gastrointestinal (GI) symptoms showed no significantly lower DAO activity. Larger group studies are required to elucidate the relationship between plasma histamine concentrations and DAO activity, especially of CIU patients with GI symptomsto understand the difference in CIU patients with and without GI symptoms.

Histamine levels in commercially important fresh and processed fish of Oman with reference to international standards

Histamine was investigated in fresh (378), frozen (441), canned (290) and dried (24) fish samples of scombroid and non-scombroid species of Oman using a high performance liquid chromatography with a fluorescence detector. Of the 1133 fish samples tested, histamine was detected in 551 samples with a detection rate of about 41.8% among fresh fish, 61.0% of frozen fish, 78.9% of canned fish and 91.6% of dried fish samples and the mean histamine levels were 2.6, 5.8, 3.1 and 104mgkg−1, respectively. A total of 3.7% and 0.79% of the total samples exceeded the FDA and EU regulatory limits for histamine. Imported dried anchovies contained high histamine levels. The study confirms that post catching and commercialisation practices of seafood are adequate, warranting good quality fish and may not cause histamine risk to consumer in terms of human diet. While necessary monitoring may be done for imported dried fish products.

Interaction between lactic acid bacteria and food‐borne pathogens on putrescine production in ornithine‐enriched broth

SummaryInteractions of mixed cultures [lactic acid bacteria (LAB) and food‐borne pathogens (FBP)] on putrescine (PUT) as well as other biogenic amines (BAs) production were investigated in ornithine‐enriched broth. Significant differences in BAs production were found among the bacterial strains (P < 0.05). Conversion of ornithine into PUT by Salmonella Paratyphi A and Aeromonas hydrophila as well as Listeria monocytogenes and Staphylococcus aureus was high (>75 mg L−1), whereas other bacterial strains yielded below 50 mg L−1 of PUT. LAB strains resulted in significant reduction in PUT by Pseudomonas aeruginosa and Enterobacteriaceae, except for Escherichia coli, which was stimulated more than two‐fold PUT in the presence of Lactococcus lactis subsp. lactis. Lactobacillus plantarum had generally inhibition effect on histamine (HIS) and tyramine production by FBP, whereas Lc. lactic subsp. lactic slightly stimulated HIS by E. coli and A. hydrophila. Streptococcus thermophilus resulted in 1.5‐fold higher HIS formation by bacteria (10 mg L−1). Consequently, the interaction between LAB and specific FBP might result in significant inhibition of amine accumulation, if the correct LAB strains are used.

Comment to: The chemical mediators of some sclerotherapy complications (Les médiateurs chimiques dans certaines complications de la sclérothérapie), by Ferrara F, Ferrara G. Phlébologie 2012;65:27-31.

To evaluate the chemical reaction of the venous wall to different sclerosing agents, the Authors studied the level of blood histamine concentration before and 8-10 min after sclerotherapy injection into large 3-6 mm subcutaneous varices. A total of 45 sessions were studied: a solution of iodine 2% was used in 15 (group A), liquid 2% polidocanol in 15 (group B), polidocanol 0.5% foam in 15 (group C). Histamine basal level was 4.49, 4.48 and 4.52 µg/100 mL, respectively, while after injection an increase was found of 4.50 (102%), 4.42 (99%) and 4.46 (100%) µg/100 mL, respectively. No significant relationship was found between agents and reactions. In C group, 2 cases had visual symptoms, both showing an 150% increase in histamine. Migraine with aura seems to be associated with high hematic levels of histamine. High histamine levels caused by sclerotherapy may explain the visual symptoms frequently reported after treatments. In fact, histamine is a vessel vasoconstrictor (venous spasm) but also a small artery vasodilator (hypotension). It could, therefore, mediate these minor sclerotherapy complications. For this reason, an antihistaminic pre-medication could be justified. The recently suggested endotheline hypothesis could support this.

Characteristics of low affinity high capacity histamine uptake into neonatal rat astrocytes

Background The neurotransmitter histamine is synthesized from histidine in histaminergic neurons. Later on it is taken up into synaptic vesicles by the vesicular monoamine transporter 2 and released into the synaptic cleft upon depolarization stimuli. The released neurotransmitter is metabolised by the enzyme histamine N-methyltransferase (HNMT) producing tele-methylhistamine (tMH). In order to be enzymatically degraded or possibly recycled, histamine must be transported either into the presynaptic neuron or into surrounding glial cells. Unlike other neurotransmitters, the mechanism and the transporters by which the histamine content within the brain is regulated is currently unresolved.

OCCURANCE OF HISTAMINE IN FISH PRODUCTS ON MARKET

Histamine fish poisoning is quite common and occur in consequence of microbial decarboxylase whose activity begin early in the post-mortem but are triggered in consequence of abuse in the shelf life of fish products. In this study forty-eight samples of tuna, mackerel, anchovies, sardines, fresh or processed were sampled from fish shops and supermarkets in the City of Bologna in the period from January to July 2010. Concentration of histamine was assessed using ELISA quantitative test and presence of psicrotrophic histamine forming bacteria was searched using a modified Niven agar medium which allow detection of suspect colonies that were confirmed by PCR for detecting the presence of the histidine decarboxylase genes in their DNA. The positive colonies were then identified on the basis of their morphology, Gram reaction and biochemical characteristics with API20E. The differential capability of the Niven agar was found to be low and approximately one fifth of the suspect colonies were confirmed by the PCR test, which however included both strong and weak histamine producing strains. The presence of Morganella morganii was associated with concentration of histamine 460 mg∙kg-1 above the allowed limit in a sample of tuna sampled from a fish shop. The same bacterium was found in samples of Atlantic horse mackerel (Trachurus trachurus). High histamine concentration (between 258 and > 300 mg∙kg-1) were observed in salted European pilchard and European anchovy (228 mg∙kg-1) sold loose in supermarkets. Because temperature abuse could occur when Tuna (fresh/defrozen) are hold on chopping board to sell fresh cuts and during shelf life of salted pilchard and pickled anchovies held in opened cans in chilled display cabinets for extended period, which might results in very high histamine concentration, controls on time and temperature at the retail, in addition to those done during the harvest and processing are needed. The studies aiming at quantitatively assess the prevalence and number of histamine producing bacteria in fish products that were not involved in histamine poisoning cases and/or do not show high level of histamine are rather complex , requiring many tests for confirming the histamine forming ability of the suspect isolated strains and further studies are needed to develop techniques for enumerating the histamine producing bacteria.

A large outbreak of scombroid fish poisoning associated with eating yellowfin tuna (Thunnus albacares) at a military mass catering in Dakar, Senegal

On 26 November 2010, an outbreak of scombroid fish poisoning occurred in the French Armed Forces in Dakar, Senegal. This chemical intoxication, due to high histamine concentration in fish, is often mistaken for an allergic reaction. A case-control study was undertaken including the 71 cases and 78 randomly selected controls among lunch attendees. The usual symptoms for scombroid fish poisoning were observed in cases, i.e. flushing (85.9%), headache (83.1%), rapid/weak pulse (59.1%) and diarrhoea (47.9%). Symptoms occurred from within a few minutes to up to 3 h following the meal. Most patients quickly recovered with antihistamine and/or symptomatic treatment. Tuna was the only food item positively associated with illness (odds ratio 36.3, 95% confidence interval 6.3-210.0), with the risk of illness increasing with the quantity of fish consumed. No bacterial contamination was found in leftover food, but histamine concentration in tuna was found to be 4900 mg/kg, almost 50-fold higher than the concentration allowed by European regulations. This report is unique because of the large size of the case series - to our knowledge, the largest event of scombroid fish poisoning ever reported - and the chemical and bacteriological analyses results obtained on leftover food.

Chemical and microbial properties of mahyaveh, a traditional Iranian fish sauce

To the best of our knowledge, this is the first report on the chemical and microbial properties of traditional Iranian fish sauce, mahyaveh. Fish sauce samples used in this study originated from five different locations in the Southern part of Iran. The pH of mahyaveh samples from different locations was in the range of 4.89–7.55 and NaCl concentration was in the range of 7.48–17.1%. The overall mean of TVB-N in all the samples tested was 3098 mg/kg. Histamine, with the overall mean of 2662 mg/kg, was found to be the main biogenic amine in the Iranian fish sauce. The high histamine content can be related to the high levels of bacterial count especially enterobacteriaceae (overall mean of 3.41 log cfu/g) and lactic acid bacteria (overall mean of 4.13 log cfu/g) in this product. Spermidine was the second dominant biogenic amine, while putrescine and tyramine were present at low concentrations in samples from different locations. Consequently, the major problem associated with this product is the very high histamine content. Mahyaveh, therefore, might not be completely safe for human consumption and excessive intake of this product on a regular basis is not recommended.

DETERMINATION OF HISTAMINE IN MAHI-MAHI FILLETS (CORYPHAENA HIPPURUS) IMPLICATED IN A FOODBORNE POISONING

ABSTRACT An incident of foodborne poisoning causing illness in 53 victims due to ingestion of fish fillets occurred in January, 2009, in Kaohsiung city, southern Taiwan. The two suspected fish samples contained 11.3 and 37.7 mg/100 g of histamine, which is greater than the 5.0 mg/100 g allowable limit suggested by the United States Food and Drug Administration. Given the allergy-like symptoms of the victims and the high histamine content in the suspected fish samples, this foodborne poisoning was strongly suspected to be caused by histamine intoxication. Five histamine-producing bacterial strains capable of producing 1.23 to 36.48 ppm of histamine in trypticase soy broth (TSB) supplemented with 1.0% L-histidine (TSBH) were identified as Bacillus subtilis (four strains) and Enterobacter aerogenes (one strain) by 16S rDNA sequencing with polymerase chain reaction (PCR) amplification. Moreover, the fish species of suspected samples were identified as mahi-mahi (Coryphaena hippurus) by using PCR direct sequence analysis. PRACTICAL APPLICATIONS Based on the finding that high contents of histamine (>30 mg/100 g) were detected in the suspected mahi-mahi samples, we speculate the temperature abuse of the fillets before cooking contributed to the presence of high histamine levels in mahi-mahi fillets and resulted in foodborne poisoning. Although histamine-producing strains, Bacillus subtilis and Enterobacter aerogenes, were isolated from suspected fish samples, they might not be the main contributors to histamine accumulation because of low histamine production. These results re-emphasize proper handling temperature for seafoods and offer an important awareness that Coryphaena hippurus fillets could become a hazardous food item in causing histamine poisoning even though no quality deficiency was observed on the fillets.

A Scombroid Poisoning Causing a Life-Threatening Acute Pulmonary Edema and Coronary Syndrome in a Young Healthy Patient

Scombroid poisoning, also called histamine fish poisoning, is an allergy-like form of food poisoning that represents one of the major problems in seafood safety. It consists in a clinical syndrome associated with consumption of fish and, less frequently, cheese containing high levels of histamine [1, 2]. Usually certain families of dark meat fish are involved, mainly Scombroidae and Scomberesocidae (e.g., tuna, mackerel, skipjack, Bonito, and Cero). Other nonscombroid fish (e.g., mahi—mahi, herring, anchovies, sardines, Australian salmon, swordfish) was also reported to be associated with scombroid fish poisoning [1–5]. High fish histamine concentrations have been found responsible for this kind of poisoning. Histamine and histamine-like substances are generated from histidine by a decarboxylase activity of bacteria such as Proteus, Klebsiella, Aerobacter, Serratia, Enterobacter, and Escherichia coli [6, 7]. The presence of this bacteria and the massive histamine production detected in the fish is usually secondary to contamination of handlers and improper refrigeration [7]. The clinical presentation is generally characterized by flushing, rash, swelling of face or tongue, sweating, headache, dizziness, abdominal cramps, diarrhea, nausea, vomiting, palpitations, respiratory distress, and hypotension. The onset of symptoms generally occurs few minutes after ingestion of contaminated food. Usually the course is selflimiting and antihistamines can be used to relieve symptoms. We report a rare case of a life-threatening scombroid poisoning with myocardial ischemia and acute pulmonary edema after tuna ingestion.

Influencia de la Temperatura de Conservación sobre la Formación de Histamina en Caballa (Scomber japonicus)

The aim of the present work was to study the influence of storage temperature on the freshness of mackerel (Scomber japonicus) associated with chemical changes and organoleptic attributes of the samples maintained under different environmental conditions. Fish quality was assessed by sensory evaluation while safety was determined through histamine development during refrigerated storage at 6 oC during a week, sampling for analysis after periods of one, three, five and seven days. At room temperature of 20 oC samples were analyzed daily during three days. Refrigerated mackerel became unsafe for human consumption, reaching unacceptable histamine levels after three days, before being rejected by the sensory panel. At room temperature samples were discarded due to their high histamine content on the second day, in agreement with the rejection decision of the sensory evaluation panel.

Histamine and H3Receptor in Alcohol-Related Behaviors

Data from rat models for alcohol preference and histidine decarboxylase knockout (HDC KO) mice suggest that brain histamine regulates alcohol-related behaviors. Histamine levels are higher in alcohol-preferring than in alcohol-nonpreferring rat brains, and expression of histamine H(3) receptor (H(3)R) is different in key areas for addictive behavior. H(3)R inverse agonists decrease alcohol responding in one alcohol-preferring rat line. Conditioned place preference induced by alcohol is stronger in HDC KO mice than in control mice. The HDC KO mice display a weaker stimulatory response to acute alcohol than the wild-type (WT) mice. In male inbred C57BL/6 mice the H(3)R antagonist ciproxifan inhibits ethanol-evoked stimulation of locomotor activity. Ciproxifan also potentiates the ethanol reward, but does not alone result in the development of place preference. At least in one rat model developed to study alcohol sensitivity high histamine levels are characteristic of the alcohol-insensitive rat line, and lowering brain histamine with a HDC inhibitor increases alcohol sensitivity in the tilting plane test. However, the motor skills of HDC KO mice do not seem to differ from those of the WT mice. Current evidence suggests that the histaminergic system is involved in the regulation of place preference behavior triggered by alcohol, possibly through an interaction with the mesolimbic dopamine system. Histamine may also interact with dopamine in the regulation of the cortico-striato-pallido-thalamo-cortical motor pathway and cerebellar mechanisms, which may be important in different motor behaviors beyond alcohol-induced motor disturbances. H(3)R ligands may have significant effects on alcohol addiction.

DETERMINATION OF HISTAMINE AND BACTERIAL ISOLATION IN MARLIN FILLETS (MAKAIRA NIGRICANS) IMPLICATED IN A FOODBORNE POISONING

ABSTRACT An incident of foodborne poisoning causing illness in seven victims due to ingestion of marlin fillets occurred in August, 2008, in Kaohsiung City, southern Taiwan. The two suspected marlin samples contained 47.8 and 43.5 mg/100 g of histamine, which is greater than the 5.0 mg/100 g allowable limit suggested by the U.S. Food and Drug Administration. Given the allergy‐like symptoms of the victims and the high histamine content in the suspected marlin samples, this foodborne poisoning was strongly suspected to be due to histamine intoxication. Two histamine‐producing bacterial strains capable of producing 3.10 ppm and 4.20 ppm of histamine in trypticase soy broth (TSB) supplemented with 1.0% l‐histidine (TSBH) were identified as Bacillus subtilis by 16S rDNA sequencing with polymerase chain reaction amplification. However, major histamine‐forming bacteria might have been killed during the preparation of fillets before serving and these two B. subtilis isolates might not be the main contributors to histamine accumulation in suspected fillets. PRACTICAL APPLICATIONSBased on the finding that high contents of histamine (>40 mg/100 g) were detected in the suspected marlin samples, we speculate the temperature abuse of the fillets before cooking contributed to the presence of high histamine levels in marlin fillets and resulted in foodborne poisoning. Although two histamine‐producing Bacillus subtilis strains were isolated from suspected fish samples, both might not to be the main contributors to histamine accumulation because of low histamine production. These results re‐emphasize proper handling temperature for seafoods and offer an important awareness which Makaira nigricans fillets could become a hazardous food item in causing histamine poisoning even though no quality deficiency was observed on the fillets.

Sequencing and transcriptional analysis of the Streptococcus thermophilus histamine biosynthesis gene cluster: factors that affect differential hdcA expression.

Histamine, a toxic compound that is formed by the decarboxylation of histidine through the action of microbial decarboxylases, can accumulate in fermented food products. From a total of 69 Streptococcus thermophilus strains screened, two strains, CHCC1524 and CHCC6483, showed the capacity to produce histamine. The hdc clusters of S. thermophilus CHCC1524 and CHCC6483 were sequenced, and the factors that affect histamine biosynthesis and histidine-decarboxylating gene (hdcA) expression were studied. The hdc cluster began with the hdcA gene, was followed by a transporter (hdcP), and ended with the hdcB gene, which is of unknown function. The three genes were orientated in the same direction. The genetic organization of the hdc cluster showed a unique organization among the lactic acid bacterial group and resembled those of Staphylococcus and Clostridium species, thus indicating possible acquisition through a horizontal transfer mechanism. Transcriptional analysis of the hdc cluster revealed the existence of a polycistronic mRNA covering the three genes. The histidine-decarboxylating gene (hdcA) of S. thermophilus demonstrated maximum expression during the stationary growth phase, with high expression levels correlated with high histamine levels. Limited expression was evident during the lag and exponential growth phases. Low-temperature (4 degrees C) incubation of milk inoculated with a histamine-producing strain showed lower levels of histamine than did inoculated milk kept at 42 degrees C. This reduction was attributed to a reduction in the activity of the HdcA enzyme itself rather than a reduction in gene expression or the presence of a lower cell number.

Histamine receptors and cancer pharmacology

Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H(4) receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H(4) receptor in cancer progression representing a promising molecular target and avenue for cancer drug development.