High Levels Of Histamine Research Articles

Histamine food poisoning: toxicology and clinical aspects.

Histamine poisoning can result from the ingestion of food containing unusually high levels of histamine. Fish are most commonly involved in incidents of histamine poisoning, although cheese has also been implicated on occasion. The historic involvement of tuna and mackerel in histamine poisoning led to the longtime usage of the term, scombroid fish poisoning, to describe this food-borne illness. Histamine poisoning is characterized by a short incubation period, a short duration, and symptoms resembling those associated with allergic reactions. The evidence supporting the role of histamine as the causative agent is compelling. The efficacy of antihistamine therapy, the allergic-like symptomology, and the finding of high levels of histamine in the implicated food suggest strongly that histamine is the causative agent. However, histamine ingested with spoiled fish appears to be much more toxic than histamine ingested in an aqueous solution. The presence of potentiators of histamine toxicity in the spoiled fish may account for this difference in toxicity. Several potentiators including other putrefactive amines such as putrescine and cadaverine have been identified. Pharmacologic potentiators may also exist; aminoguanidine and isoniazid are examples. The mechanism of action of these potentiators appears to be the inhibition of intestinal histamine-metabolizing enzymes. This enzyme inhibition causes a decrease in histamine detoxification in the intestinal mucosa and results in increased intestinal uptake and urinary excretion of unmetabolized histamine.

A direct, sensitive microassay for mammalian histidine decarboxylase

A microassay procedure for mammalian histidine decarboxylase based on the conversion of l-[ 3H]histidine to [ 3H]histamine, which were separated by an alkaline butanol extraction followed by thin-layer chromatography, is described. This assay is direct and simple to perform, in addition to being very sensitive and reproducible. It is useful for tissues containing high levels of endogenous histamine, because only newly formed radiolabeled histamine is measured. This report includes information on histidine decarboxylase activity at various pH levels, in different buffers, and in the presence of selected histamine active drugs. In addition, it describes histidine decarboxylase activity in several fetal rat tissues.

Changes in tissue histamine during the estrous cycle, pregnancy and pseudopregnancy in the golden hamster.

The histamine content of reproductive tissues and skeletal muscle was determined in the golden hamster during the estrous cycle, pregnancy, and pseudopregnancy. Histidine decarboxylase activity was measured in uterine implantation sites and intersites from Day 4 to Day 10 of pregnancy. Histidine decarboxylase was also measured in mesometria and placentas on selected days of gestation. During the estrous cycle, uterine and skeletal muscle histamine levels were highest on Day 2 and lowest on Day 4 of the cycle. The ovarian histamine content did not change significantly among the different stages of the cycle. While the histamine content of uterine implantation sites of attachment was high on Days 4 and measurable on Days 5 and 6 of pregnancy, the levels were below the limits of detection by Day 7. On the other hand, the highest levels of histamine were in the uterine interimplantation sites on Days 8 and 9. The ovarian levels of histamine were highest on Day 13 of pregnancy. Histamine in skeletal muscle did not change significantly during pregnancy. The histidine decarboxylase activity in the implantation sites began rising on Day 9 and increased dramatically on Day 10. Placental histidine decarboxylase activity was very high on Days 13 and 15. Overall, we observed changes in uterine and skeletal muscle histamine during the estrous cycle that may be explainable in light of previously reported changes in mast cell numbers and circulating estrogens. During pregnancy, histamine levels of implantation sites and implantation intersites varied, as did the histamine content of ovarian tissue. Histidine decarboxylase activity rises in the uterus and placental tissue after the formation of the placenta.

The effect of calcium on cardiac anaphylaxis in guinea-pig Langendorff heart preparations

This study was designed to determine the effects of different calcium concentrations on the perfused isolated guinea-pig heart preparation subjected to cardiac anaphylaxis. Following challenge both physiological and biochemical effects were determined on hearts from guinea-pigs previously sensitized to ovalbumin. Perfusion media containing either 1,2.54 or 5 mM of calcium was used. In comparison to nonsensitized controls challenged to ovalbumin, challenged sensitized hearts (CSH) perfused with 1 mM Ca2+ showed an initial increase in dF/dt, a prolonged rise in H.R. and depressed coronary flow. Raising the calcium concentration to either 2.54 or 5 mM in CSH preparations resulted in a marked increase in the release of lactate dehydrogenase (LDH) into the coronary effluent and depressed coronary flow. Perfusing CSH preparations with increasingly higher calcium concentrations more often produced severe tachyarrhythmias and fibrillation. The highest level of histamine released into the coronary effluent occurred immediately following challenge and then declined exponentially over the next 20 min. Both challenge and the administration of histamine induced an immediate but transient increase in H.R., a rise in dF/dt, and LDH release. The infusion of histamine produced an increase in coronary flow, but on porcine tubular coronary arterial segments only a direct constricting effect was obtained. The prior administration of cimetidine (10(-5) M) attenuated the rise in LDH and dF/dt in CSH and nonsensitized preparations infused with histamine (3 micrograms). However, although cimetidine did not affect the decreased coronary flow in CSH preparations, it initially attenuated the rise in coronary flow in preparations infused with histamine. These results suggest that calcium enhances the likelihood of tachyarrhythmias in cardiac anaphylaxis. The release of LDH in histamine-infused preparations and those CSH preparations perfused with 2.54 and 5 mM calcium-containing media also suggests the possibility that calcium enhances the damaging effects on the myocardial cell in cardiac anaphylaxis.

Histamine in late asthmatic reactions following house-dust mite inhalation.

In order to investigate the role of histamine in the late asthmatic reaction (LAR) following house-dust mite (HDM) inhalation, we studied, with hourly intervals, urinary N tau-methylhistamine (an important metabolite of histamine) in 14 allergic asthmatic patients before and after broncho provocation with HDM. Four patients showed an early asthmatic reaction (EAR), while 10 patients developed a LAR as well. In the hour following the EAR a significant increase in urinary N tau-methylhistamine was observed as compared to the control day (0.01 less than p less than 0.05). During the LAR no increase of this metabolite was detected in the urine of the patients. Additionally, histamine was measured in broncho alveolar lavage fluid (BAF) obtained from 6 patients during the HDM-provoked LAR and compared to histamine levels in BAF from patients without a LAR, following broncho provocation. In the LAR group higher histamine levels were found than in the other patient and control groups. For the whole patient group no correlation was found between the degree of bronchial obstruction during the LAR and the BAF histamine values. No difference was found in N tau-methylhistamine in BAF between patients with LAR and controls. Thus histamine metabolite studies in the urine failed to provide evidence of involvement of histamine in the LAR, while further data are needed to interpret the results of local sampling in the lung.

Role of histamine in tumor development

High levels of histamine and of its synthetizing enzyme, histidine decarboxylase, are found in growing experimental tumors. Jacques Bartholeyns and John Fozard describe the metabolism of histamine in normal and tumor tissue and explain how tumor growth can be markedly reduced by treatment with a specific inhibitor of HDC, monofluoromethylhistidine, indicating that newly synthesized histamine plays an important role in the tumor development process. Cimetidine, a histamine H 2 receptor antagonist also inhibits tumor development whereas an H 1 receptor antagonist, dexchlorpheniramine favors tumor growth. Newly synthesized histamine appears to play a role in the basic mechanism of cell proliferation in tumoral cells. It may also suppress the host immune system by activation of histamine H 2 receptors on suppressor lymphocytes.

Histamine production by alloantigen-activated mouse bone marrow cells

Histamine's contribution to the manifestations associated with graft-versus-host disease (GVHD) and/or hybrid resistance is unknown. Thus, we initiated studies to see whether or not mouse bone marrow cells could produce histamine upon alloantigen stimulation. Irradiated allogeneic spleen cells were shown to stimulate bone marrow cells to produce and secrete high levels of histamine. During 7 days of culture there was only a marginal increase in cell-associated histamine while the amount of histamine in the supernatant increased 10- to 20-fold. Optimal histamine production was dependent upon Lyt 1 +2 + T cells resident in the bone marrow. Further, bone marrow cells from Nude mice failed to produce high levels of histamine following alloantigen stimulation. Soluble factors produced by alloantigen-stimulated bone marrow cells or by Con A-stimulated rat spleen cells induced high levels of histamine production in bone marrow cells in the absence of alloantigen. We suggest that histamine production by alloantigen-activated bone marrow cells may modulate immune functions following bone marrow transplantation.

Acute basophilic leukemia

Acute basophilic leukemia was diagnosed in a 61-year-old black woman on the basis of 85 to 90 percent basophils in the peripheral blood as well as bone marrow and very high serum histamine level (more than 10,000 ng/ml). These complications occurred as a transformation from essential thrombocythemia. Accompanying this transformation, there was also cytogenetic change from 46XX karyotype to 46XX 2p+ in 66 to 90 percent of cells in the bone marrow. This may be the first reported occurrence of transformation of essential thrombocythemia into acute basophilic leukemia.

Factors related to gastric hypersecretion during pregnancy and lactation in rats.

We attempted to elucidate the factors involved in gastric hypersecretion of rats during pregnancy and lactation. Acid secretion in pylorus-ligated and vagally denervated fistula rats stimulated with histamine, tetragastrin, and methacholine increased from midterm pregnancy and persisted during lactation. Pepsin secretion remained unaltered during pregnancy but increased during lactation. Vagal denervation itself abolished this hypersecretion. In late pregnancy, a delayed appearance of maximal acid response to histamine was apparent, as compared to nonpregnant rats, and was abolished by aminoguanidine treatment. There was a delay in the maximal response to tetragastrin but not to methacholine. Serum histamine concentrations were 3-4 times higher in late pregnancy, as compared to nonpregnant, lactating and nonlactating rats. Gastric DNA and protein concentrations were significantly increased in lactating rats with concomitant elevation of food intake and serum gastrin levels. Those changes disappeared in nonlactating rats, and gastric secretion was much the same in the nonpregnant rats. These results indicate that acid hypersecretion during pregnancy was exclusively associated with vagal innervation plus high serum histamine levels, while acid and pepsin hypersecretion in lactating rats were associated with vagal innervation plus hyperplastic gastric mucosa and high serum gastrin levels.

High histamine levels in specific hypothalamic nuclei of Brattleboro rats lacking vasopressin

Histamine levels were determined in whole hypothalamus and specific hypothalamic nuclei of male 9-week-old homozygous Brattleboro rats lacking vasopressin and presenting the syndrome of diabetes insipidus (DI rats). These levels were compared to those in heterozygous Brattleboro rats with a partial deficit in vasopressin (HZ rats) and those in Long Evans control rats (LE rats). In whole hypothalamus, histamine levels in DI rats were higher than those found in HZ and LE rats. DI rats showed histamine levels higher than those present in LE rats in the nuclei supraopticus, paraventricularis and suprachiasmatis and in the area retrochiasmatica. Vasopressin replacement produced a selective decrease in histamine levels of DI rats, restricted to the area retrochiasmatica and nuclei supraopticus and paraventricularis. In contrast, vasopressin increased histamine levels in the area retrochiasmatica and eminentia mediana of HZ rats. In other areas normally rich in vasopressin such as the nuclei arcuatus and the eminentia mediana, the histamine content was not different among LE, HZ or DI rats. Our results suggest a physiological interaction between vasopressin and histamine systems in specific hypothalamic areas of the rat and support the hypothesis of a role of brain shitamine on the central control of water balance.

Histamine symptoms and histamine metabolism in chronic granulocytic leukaemia

Histamine metabolism was investigated in three patients with chronic granulocytic leukaemia (CGL) during symptoms suspected to be caused by histamine release. Plasma histamine levels were excessively high compared with periods when the patients were symptomless or with CGL patients without such symptoms. The patients seemed to be adapted to high plasma histamine levels as the symptoms were not typically systemic in nature, but rather localized phenomena like oedema and pruritus in the extremities. Also CGL patients without symptoms showed abnormally high plasma histamine concentrations, which were significantly related to the whole blood histamine concentration. The possibility must be considered that part of the plasma histamine increase is artificial due to rupture of the basophils during the blood collection procedure.

Tele-methylhistamine as an index of the activity of central histaminergic neurons

The activity of histaminergic neurons was examined in various brain regions. Histamine (HA) and tele-methylhistamine (t-MH) were simultaneously assayed using HPLC with fluorescence detector. The HA content was high in the hypothalamus and thalamus and low in the cerebellum and pons-medulla oblongata in the rat, mouse and guinea-pig. The t-MH content was high in the hypothalamus and amygdala in all these species, and was exceptionally high in guinea-pig hippocampus. Pargyline hydrochloride (80 mg/kg, i.p.) increased the t-MH content of the rat brain linearly up to 4 hr after injection. The increments of t-MH (Δt-MH) were large in the hypothalamus, striatum and thalamus (108.7, 80.2 and 62.1 ng/g/hr, respectively), but very slight in the cerebellum (2.9 ng/g/hr). Although relatively high HA levels were observed in the spinal cord, no increase in t-MH was detected after pargyline treatment. There was a significant correlation between At-MH and steady-state t-MH levels in different brain regions (r = 0.82, p < 0.01). The treatment with α-fluoromethylhistidine (50 mg/kg, i.p.) produced 15-60 % depletion of HA 4 hr later in various rat brain regions except for the spinal cord. The percentage of depletion was regarded as that of neuronal HA to the total HA. The half-life of neuronal HA estimated from the methyl-ation rate by a one compartment open model was in a range of 7.7-56.6 min in the following rank order: striatum < hippocampus < midbrain < amygdala < cerebral cortex < pons-medulla oblongata < thalamus < hypothalamus. These results indicate that the t-MH levels and the increments after pargyline treatment are useful as indices of the brain histaminergic function.

Angiostrongylus cantonensis: Biogenic amines in the lungs of infected rats

Levels of histamine, serotonin, norepinephrine, and dopamine were estimated sequentially in rats parasitized by the lungworm, Angiostrongylus cantonensis, between 30 and 75 days postinfection. The highest level of histamine in the infected lungs was 52.19 μg/g wet wt tissue, 13 times higher than the level found in control rats. The level of serotonin rose from the normal level of 6.41 to 10.27 μg/g wet wt tissue after the worms had lodged in the pulmonary artery for 15 days. There were no changes in norephinephrine or dopamine. Studies of host cell response to infection revealed that the increased histamine and serotonin levels corresponded to a rise in the lung population of mast cells, suggesting that these cells produced the amines.

Quantitation of Histamine in Fishes and Fishes Products by High Performance Liquid Chromatography

Quantitation of histamine in fishes and fish products was studied by an HPLC-post-column derivatization method.Histamine extracted from samples was separated on a cation exchange column with 0.5M citric buffer (pH 6.4) as a mobile phase, and then derivatized with 0.1% o-phthalaldehyde solution (in borate-KOH buffer, pH 12). o-Phthalaldehyde-histamine complex was determined with a fluorescence detector (excitation at 360nm, emission at 455nm).Commercial fishes (8 samples), fish products (6 samples) and fresh fishes (4 samples) caught in Osaka Bay were analyzed by this method.Among commercial fishes, 5.5ppm of histamine was detected in a jack mackerel. In the case of fish products, high levels of histamine were detected from two dried Japanese pilchards (1050ppm, 382ppm). No trace of histamine was detected in fresh fishes. However, when a fresh mackerel was left to stand at room temperature for 48 hours, the level of histamine in the mackerel increased to 28.4ppm (24 hours) and 1540ppm (48 hours).

Production of gastric and duodenal ulceration in the guinea pig using a long-acting form of histamine

A simple method to produce gastric and duodenal ulcers in guinea pigs has been described. By using dialysis sacks containing histamine, introduced into the peritoneal cavity, rapid development of ulceration could be observed in both stomach and duodenum. The ulcers were correlated with high and prolonged blood levels of histamine.

Capillary gas chromatographic-mass spectrometric determination of histamine in tuna fish causing scombroid poisoning

A documented case of “scombroid poisoning” is reported by confirming the presence of high histamine levels in fresh tuna fish tissues by gas chromatography-mass spectrometry. Histamine is confirmed by in situ trimethylsilylation of the tissue extract on a 12-m SP-2100 fused-silica capillary column connected directly to a mass spectrometer ion source operated in the positive ion chemical ionization mode using methane as reactant gas. The trimethylsilyl derivative of histamine is readily resolved by the high-resolution fused-silica capillary column and confirmed in the complex tissue extract by this very simple but specific procedure.

Ontogeny of histaminergic neurotransmission in the rat brain: concomitant development of neuronal histamine, H-1 receptors, and H-1 receptor-mediated stimulation of phospholipid turnover.

The ontogeny of histaminergic neurotransmission in the rat brain was studied by assessing development of histamine levels in brain regions, along with H-1 receptor binding of [3H]mepyramine and H-1 receptor-mediated cellular events. In the hypothalamus, which is rich in histaminergic innervation, levels of the amine were low at birth, increased sharply at 8 days of age, and reached adult concentrations shortly thereafter; this pattern is typical of most neurotransmitters. In contrast, regions poor in neuronal histamine showed an initially high histamine level and a subsequent decline with development, as is known to occur during general growth of tissues. The developmental profile of H-1 receptor binding sites resembled that of the neuronal histamine pool, and the increases with age resulted from changes in the number of binding sites without alterations in Kd. Cellular responses to H-1 receptor activation were assessed by determining the stimulation of phospholipid turnover evoked by intracisternally administered histamine, a process that has been shown to involve only the neuronal compartment. Again, the developmental profile was superimposable upon that of H-1 receptor binding and that of hypothalamic histamine levels. These studies indicate that ontogeny of histaminergic neurotransmission is a coordinated process, with simultaneous development of neuronal histamine, its key biosynthetic enzyme, and H-1 receptors coupled directly to cellular events.

Preventive treatment of migraine with enzyme induction by proxibarbal in a "double-blind" trial.

SYNOPSISProxibarbal is a non‐sedative barbiturate with a specific anti‐serotonin and anti‐histamine effect, due to enzyme induction of serotoninase and histaminase. Its lack of unpleasant side‐effects permits its protracted use for the preventive treatment of migraine. Its chemical structure ‐ 5‐allyl‐5‐(beta‐hydroxy‐propyl)barbituric acid ‐ allows enzyme induction within 1–3 months of treatment. Preventive treatment with 1–3 × 100 mg/day proxibarbal for 3 months eliminated migraine attacks in 25 out of 35 cases (71%). In a double‐blind study of 30 female and 5 male patients, treatment with 3 × 100 mg/day produced a drop of from 5–30 attacks to 0–1 attack per month and normalization of high urinary serotonin, 5‐HIAA or histamine levels. The typical side‐effects of anti‐serotonin drugs and antihistaminics, especially sedation or dizziness and hyperorexia, were not observed. The mechanism of this effect was proved by accelerated and increased destruction of serotonin and histamine in vitro by the serum of the patients after treatment.

Brain histamine: Plasma corticosterone, spontaneous locomotor activity and temperature

Hypothalamic histamine exhibited circadian fluctuations in male Sprague-Dawley rats; low values were found during the dark period when spontaneous locomotor activity (S.L.A.) and temperature were elevated. A relatively high hypothalamic histamine level was observed during the early period of the light cycle and was associated with decreased S.L.A. and temperature. Histamine concentration was high when corticosterone levels were low at the end of the dark cycle and during morning hours (4 a.m.–1 p.m.); but histamine levels were relatively constant while corticosterone concentration dropped during afternoon and early night hours (4p.m.–10 p.m.). Furthermore, the lowest hypothalamic histamine level (at 1 a.m.) was associated with the average plasma corticosterone value, thus no consistent relationship between histamine and corticosterone levels could be observed. Circadian fluctuation in brain histamine may support its role in brain function.

Histamine formation by bacteria isolated from skipjack tuna, Katsuwonus pelamis.

A simplified method for measuring histamine formation in bacterial cultures is described. Histamine production by Proteus morganil, Proteus vulgaris and Hafnia alvei cultures isolated from spoiled skipjack tuna was measured under twelve environmental conditions. The highest histamine concentrations were found at 19°C and 30°C depending on the bacterial species and the environmental parameter. No histamine was formed at 1°C, indicating that the rapid cooling of tuna flesh to freezing temperatures may adequately suppress histamine formation. At 19°C and 30°C, the Proteus organisms at first formed high levels of histamine, much of which was subsequently destroyed; histamine concentrations in these cultures eventually stabilized at 150 to 200mg/100ml. These observations indicate that the concentration of histamine in tuna products may depend on an equilibrium between histamine production and destruction.