Histamine and histamine intolerance Maintz, Laura; Novak, Natalija
The American journal of clinical nutrition,
05/2007, Volume:
85, Issue:
5
Journal Article
Peer reviewed
Open access
Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In ...healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines. However, because of the multifaceted nature of the symptoms, the existence of histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered as an underlying pathomechanism.
Highlights ► This review provides a comprehensive summary of our knowledge on human histamine receptors. ► We critically discuss the limitations of currently available ligands. ► We highlight ...pitfalls associated with the use of histamine receptor antibodies ► We provide constructive suggestions for future research in the field.
Histamine has been implicated in urinary bladder dysfunction as an inflammatory mediator driving sensory nerve hypersensitivity. However, the direct influence of histamine on smooth muscle has not ...been thoroughly investigated. We hypothesized that histamine directly contracts urinary bladder smooth muscle (UBSM) independent of effects on nerves. Single cell quantitative RT-PCR determined that only histamine H
and H
receptors were expressed on UBSM cells. In isolated tissue bath experiments, histamine (200 µM) caused a highly variable and rapidly desensitizing contraction that was completely abolished by the H
receptor antagonist fexofenadine (5 µM) and the G
inhibitor YM254890 (1 µM). Neither the muscarinic receptor antagonist atropine (1 µM), the Na
channel blocker tetrodotoxin (1 µM), nor the transient receptor potential vanilloid type 1 antagonist capsazepine (10 µM) altered responses to histamine, suggesting that nerve activation was not involved. UBSM desensitization to histamine was not due to receptor internalization, as neither the cholesterol-depleting agent methyl-β-cyclodextrin (10 mM), the dynamin-mediated endocytosis inhibitor dynasore (100 µM), nor the clathrin-mediated endocytosis inhibitor pitstop2 (15 µM) augmented or prolonged histamine contractions. Buffer from desensitized tissues still contracted histamine-naïve tissues, revealing that histamine was not metabolized. Prolonged exposure to histamine also had no effect on contractions due to electrical field stimulation, suggesting that both efferent nerve and UBSM excitability were unchanged. Together, these data suggest that histamine, although able to transiently contract UBSM, does not have a lasting effect on UBSM excitability or responses to efferent nerve input. Thus, any acute effects of histamine directly on UBSM contractility are unlikely to alter urinary bladder function.
Histamine is commonly associated with inflammatory bladder pathologies. We sought to investigate the role of histamine on urinary bladder contractility. Histamine contracts the bladder, but this response is highly variable and desensitizes completely in minutes. This desensitization is not due to internalization of the receptor or metabolism of histamine. Because nerve-evoked contractions are also not increased in the presence of histamine, our findings suggest that histamine is not directly acting to change contractility.
Many areas of the brain along with neurotransmitters involve in processing of nociceptive, emotional and cognitive dimensions of neuropathic pain. Brian neuronal histamine through H
, H
, H
and H
...receptors mediates many physiological functions such as cognition, emotion and pain. In the present study we investigated the effects of intra-agranular insular cortex microinjection of histamine and its H
receptor agonist and antagonist on sensory and affective aspects of neuropathic pain. Spared nerve injury model of neuropathic pain was used. Two guide cannulas were surgically implanted in the right and left sides of agranular insular cortex. Sensory component (mechanical hyperalgesia) was recorded by application of von Frey filaments onto the plantar surface of the hind paw. Area under curve of mechanical hyperalgesia was calculated. Affective aspect (place escape avoidance paradigm) was recorded using an inverse white/black chamber. Histamine (0.5, 1 and 2 μg/site) and thioperamide (a histamine H
receptor antagonist, 4 μg/site) decreased, whereas immepip (a histamine H
receptor agonist, 2 μg/site) increased the percentages of paw withdrawal frequency and time spent in white side of white/black box. Prior administration of thioperamide (4 μg/site) increased the suppressive effects induced by histamine and inhibited immepip (2 μg/site)-induced hyperalgesia and aversion. Based on the present results, it is concluded that histamine and its H
receptor at the agranular insular cortex level may involve in modulation of sensory and affective components of neuropathic pain.
Histamine has the ability to influence the activity of immune cells including neutrophils and plays a pivotal role in inflammatory processes, which are a complex network of cellular and humoral ...events. One of the main functions manifested by activated neutrophils is oxidative burst, which is linked to the production of reactive oxygen species; therefore, the effects of histamine receptor agonists and antagonists on the oxidative burst of neutrophils is reviewed. A role for the well‐characterized histamine H1 and H2 receptors in this process is discussed and compared to that of the recently discovered H4 receptor.
Linked Articles
This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue‐1
Histamine plays important roles in inflammation and nervous irritability in allergic disorders, including atopic dermatitis (AD). It has been shown to regulate the expression of pruritic factors, ...such as nerve growth factor and semaphorin 3A, in skin keratinocytes via histamine H1 receptor (H1R). Furthermore, H1R antagonist reduced the level of IL-31, a cytokine involving the skin barrier and pruritus, in chronic dermatitis lesions in NC/Nga mice and patients with AD. Histamine plays roles in the induction of allergic inflammation by activating eosinophils, mast cells, basophils, and Th2 cells via histamine H4 receptor (H4R). H4R, in addition to H1R, is expressed on sensory neurons, and a decrease in scratching behaviors was observed in H4R-deficient mice and mice treated with a H4R antagonist. We found that the combined administration of H1R and H4R antagonists inhibited the itch response and chronic allergic inflammation, and had a pharmacological effect similar to that of prednisolone.
Although the oral administration of H1R antagonists is widely used to treat AD, it is not very effective. In contrast, JNJ39758979, a novel H4R antagonist, had marked effects against pruritus in Japanese patients with AD in a phase II clinical trial. Next generation antihistaminic agents possessing H1R and H4R antagonistic actions may be a potent therapeutic drug for AD.
Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) ...under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1−/−) mice. We found that H1−/− mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1−/− mice. Finally, H1−/− mice showed markedly greater changes in EEG power (notably in the 0.8–5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system.
This article is part of the Special Issue entitled ‘Histamine Receptors’.
•Long-term brain histamine deletion impairs EEG & sleep-wake quality causing sleepiness.•Such roles are largely mediated by the H1-receptor.•The cholinergic system is upregulated to ensure a wake amount in histamine-deficient mice.•This constitutes a major compensation when the brain is faced with deficient situations.•Understand how the brain remains awake in deficient situation is of physiological/clinical relevance.
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Cancer morbimortality is still a great concern despite advances in research and therapies. Histamine and its receptors' ligands can modulate different biological responses according ...to the cell type and the receptor subtype involved. Besides the wide variety of histamine functions in normal tissues, diverse roles in the acquisition of hallmarks of cancer such as sustained proliferative signaling, resistance to cell death, angiogenesis, metastasis, altered immunity and modified microenvironment have been described.
This review summarizes the present knowledge of the various roles of histamine H2 receptor (H2R) ligands in neoplasias. A bioinformatic analysis of human tumors showed dissimilar results in the expression of the H2R gene according to tumor type when comparing malignant versus normal tissues. As well, the relationship between patients' survival parameters and H2R gene expression levels also varied, signaling important divergences in the role of H2R in neoplastic progression in different cancer types.
Revised experimental evidence showed multiple effects of H2R antihistamines on several of the cited hallmarks of cancer. Interventional and retrospective clinical studies evaluated different H2R antihistamines in cancer patients with two main adjuvant uses: improving antitumor efficacy (which includes regulation of immune response) and preventing toxic adverse effects produced by chemo or radiotherapy.
While there is a long path to go, research on H2R antihistamines may provide new opportunities for developing more refined combination therapeutic strategies for certain cancer types to improve patients' survival and health-related quality of life.
Background and Purpose
Since the identification of the histamine H4 receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are ...well characterized in pharmacological assays, including radioligand competition binding studies, GTPγS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G‐protein signalling components. In this study we investigated the specific properties of H4 receptor ligands in native cells.
Experimental Approach
Histamine and five different H4 receptor agonists – 4‐methylhistamine, UR‐PI376, clobenpropit, VUF8430 and ST‐1006 – were characterized in freshly isolated human monocytes. The ligands (10 nM–10 μM) were tested as inhibitors of IL‐12p70 secretion from human monocytes and the effects of the H2 receptor antagonist ranitidine and the H4 receptor antagonist JNJ7777120 on their action was investigated.
Key Results
Histamine and all the tested agonists reduced IL‐12p70 secretion into monocyte supernatants by 40–70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H2 or H4 receptor antagonists showed that some H4 receptor ligands also had low activity at the H2 receptor.
Conclusions and Implications
Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H4 receptor ligands in native cells.
Linked Articles
This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
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