Histamine Metabolism Research Articles

The Effect of Histamine Antagonists on Aortic Permeability and Histamine Metabolism in Streptozotocin-Induced Diabetes Mellitus in the Rat

The Effect of Histamine Antagonists on Aortic Permeability and Histamine Metabolism in Streptozotocin-Induced Diabetes Mellitus in the Rat

Histamine methylation in schizophrenia

Dopamine has been accepted as a possible etiological factor in schizophrenia and most studies have demonstrated that the ingestion of methionine by schizophrenics exacerbated their psychosis. Unfortunately, the methylation theory has failed to support the dopamine theory in schizophrenia. This paper will attempt to demonstrate why abnormal histamine metabolism in schizophrenia can explain the effect of methionine in worsening schizophrenia in certain patients.

Changes in histamine metabolism in the brains of mice with streptozotocin-induced diabetes.

Histamine (HA) metabolism in the brain of mice with streptozotocin (STZ)-induced diabetes was examined. The levels of tele-methylhistamine (t-MH), a major metabolite of brain HA, significantly increased 3 and 4 weeks after STZ injection. However, the HA turnover rates in the diabetic mice, determined from the accumulation of t-MH after the administration of pargyline, were not different from the control values when the animals were allowed free access to food. When the mice were starved for 15 h 4 weeks after STZ treatment, the brain levels of L-histidine decreased significantly, whereas HA turnover increased significantly. Such changes were not observed in starved control mice. Histidine decarboxylase or HA N-methyltransferase activity did not change after starvation in either diabetic or control mice. These results show that the histaminergic (HAergic) activity in the brains of diabetic mice remains within normal range as long as the animals are allowed free access to food. However, they also indicate that a marked enhancement of HAergic activity accompanied by a decrease in the brain L-histidine level occurs in starved diabetic mice.

Effects of the Histamine H3‐Agonist (R)‐α‐Methylhistamine and the Antagonist Thioperamide on Histamine Metabolism in the Mouse and Rat Brain

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.

Effect of in vivo glucocorticoid administration on histamine metabolism in rat brain synaptosomes

The effect of in vivo administration of acetonide triamcinolone (AT) on histamine (HA) metabolism in synaptosomes, highly purified from rat brain by discontinous Ficoll-sucrose gradient centrifugation, was investigated. AT decreases ability of synaptosomes to actively accumulate HA precursor, l-[U- 14C]histidine, measured after rapid centrifugation of synaptosomes through silicone oil, as well as lowers activity of HA catabolizing enzyme histamine N-methyltransferase (by 57%). In contrast, no changes in the level of HA, assayed by the single isotope enzymatic method, and the activity of HA synthesizing enzyme, histidine decarboxylase, were found. The results indicate that under applied conditions glucocorticoid administration may decrease turnover of neuronal pool of HA without significant effect on HA level.

Histamine metabolism of the human gastric mucosa--a study on the regional distribution of the amine and enzyme activities.

Histamine content, histidine decarboxylase activity and histamine methyl transferase activity of the human gastric mucosa have been studied in healthy subjects. Histamine content was evenly distributed over the gastric mucosa and no significant difference could be observed between the oxyntic and pyloric gland area. A 'specific' histidine decarboxylase was found in the human gastric mucosa and the enzyme activity was significantly higher in the corpus compared to the antral mucosa. We found no difference in enzyme activity of the mucosa obtained from three defined areas of the corpus region of the stomach. Histamine methyl transferase activity was of the same magnitude in the corpus as in the antral mucosa. In addition, with regard to histamine methyl transferase activity, we were unable to demonstrate any difference in activity in the mucosal specimens obtained from the defined areas of the stomach. The presented technique to obtain gastric mucosal tissue specimens during routine fibreoptic endoscopy of the stomach, allows studies over gastric mucosal histamine metabolism in health as well as in disease states.

Effects of Nociceptive Stimuli on Brain Histamine Dynamics

The effects of nociceptive stimuli on the metabolism of brain histamine (HA) were examined, because of a previous observation that the exposure of mice to electric foot shock increased the brain HA turnover. In mice, the exposure to tail pinch markedly increased the brain level of te/e-methylhistamine (t-MH), a predominant metabolite of brain HA, while the level of HA was not changed. The HA turnover, measured either by the accumulation of t-MH after pargyline injection or by the HA depletion after the treatment with a-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, was enhanced by the exposure to tail pinch, like the enhancement produced by the exposure to foot shock. The exposure of rats to tail pinch increased the t-MH level in the telencephalon and the midbrain. Other types of noxious stimuli, such as placing mice on a hot plate or subjecting mice to acetic acid-induced writhing, also significantly elevated the level of t-MH but not that of HA in the mouse brain. These results suggest that nociceptive stimuli produce an increase in the brain HA turnover.

Effects of nociceptive stimuli on brain histamine dynamics.

The effects of nociceptive stimuli on the metabolism of brain histamine (HA) were examined, because of a previous observation that the exposure of mice to electric foot shock increased the brain HA turnover. In mice, the exposure to tail pinch markedly increased the brain level of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, while the level of HA was not changed. The HA turnover, measured either by the accumulation of t-MH after pargyline injection or by the HA depletion after the treatment with alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, was enhanced by the exposure to tail pinch, like the enhancement produced by the exposure to foot shock. The exposure of rats to tail pinch increased the t-MH level in the telencephalon and the midbrain. Other types of noxious stimuli, such as placing mice on a hot plate or subjecting mice to acetic acid-induced writhing, also significantly elevated the level of t-MH but not that of HA in the mouse brain. These results suggest that nociceptive stimuli produce an increase in the brain HA turnover.

Significance of Histamine Metabolism in Skin Lesions of Human and Murine Lupus Erythematosus

Significance of Histamine Metabolism in Skin Lesions of Human and Murine Lupus Erythematosus

Induction and quail liver diamine oxidase (histaminase). Part II: Different responses to the inducers.

In quail liver microsomes the metabolism of histamine is prevalently sustained by diaminoxidase (DAO). Treatment with phenobarbital (PB) and clofibrate (CF) does not modify DAO activity, while that with Aroclor 1254 (PCB) and beta-naphtoflavone (BNF) significantly decreases it. The decrease of DAO activity produced by these substances is not dependent on their direct inhibition of the enzyme. DAO decrease might represent a further possibility to discriminate among different inducers; moreover, it implies that histamine metabolism might be decreased, in quail liver, by some classes of inducers.

Vecuronium inhibits histamine N-methyltransferase.

Although there have been clinical reports of significant hypotension and flushing associated with the use of vecuronium, it produces minimal cardiovascular effects in the vast majority of patients. In addition, there is no evidence that vecuronium stimulates the release of histamine. The authors performed in vitro kinetic studies to determine the effect of vecuronium on histamine N-methyltransferase (HNMT), the primary catabolic enzyme for histamine in humans. They also examined plasma from patients who had received vecuronium (0.1 or 0.2 mg/kg) to determine whether clinically used concentrations of the drug could inhibit HNMT. It was determined that vecuronium is a strong inhibitor of HNMT; apparent Ki = 1 microM. The inhibition is competitive with respect to methyl-donor and noncompetitive with respect to histamine. Vecuronium, in doses greater than or equal to 0.1 mg/kg, may delay the metabolism of histamine by HNMT in vitro.

Circadian rhythm of histamine metabolism in the rabbit central nervous system (CNS): analysis of brain and ocular structures.

The circadian rhythm of the level of histamine (HI) and histidine decarboxylase (HD) and histamine-methyltransferase (HMT) activity in 6 brain and 5 ocular structures of the rabbit was studied. Clear circadian variations of the histaminergic parameters in two brain (hypothalamus and lateral geniculate body) and two ocular (retina and iris-ciliary body) tissues were found. It is suggested that HI in some brain and ocular structures may be functionally involved in activity that depends on circadian rhythm.

Effects of zolantidine a brain-penetrating H 2-receptor antagonist, on naloxone-sensitive and naloxone-resistant analgesia

The action of zolantidine, a histamine H 2-receptor antagonist which penetrates the brain, was characterized on the analgesia elicited by brief continuous footshock of 3 intensities. Zolantidine inhibited the analgesia elicited by exposure to 3.5 mA for 3 min, with maximum inhibition observed 30 min after a dose of 5 mg/kg. This inhibition was not dose-related, possibly due to inhibition of the metabolism of histamine in brain by this drug at larger doses. While zolantidine alone, or in combination with naloxone, attenuated this analgesic response, naloxone alone had no such effect, further supporting the non-opiate nature of this response. Conversely, naloxone, but not zolantidine, strongly inhibited the analgesia elicited by 2.0 mA for 3 min, confirming the apparent opiate nature of this analgesic mechanism. Although a combination of zolantidine and naloxone still significantly attenuated this response, a tendency toward reversal of the antagonism by naloxone was observed with this combination of drugs, consistent with previous findings. Furthermore, the analgesia elicited by 2.5 mA for 3 min was resistant to both naloxone and zolantidine, alone or in combination. These results further strengthen the hypothesis that histamine and H 2-receptors in brain are important mediators of endogenous antinociception and also support the possible existence of an additional non-opiate, non-H 2-analgesic mechanism.

Dietary pyridoxine interaction with tryptophan or histidine on brain serotonin and histamine metabolism

We studied the metabolic effects of high dietary intakes of pyridoxine and of the substrate-cofactor interaction between dietary histidine or tryptophan and pyridoxine in rat brain. In the substrate-cofactor interaction study, histamine and serotonin levels were determined in rats fed elevated or requirement levels of substrate (histidine: 0.3% and 0.8%, tryptophan: 0.15% and 0.6%) and excess or requirement levels of pyrodoxine HCl (7 mg vs. 3,000 mg/kg). Excess pyridoxine intake caused a differential effect on brain histamine concentration—inhibitory with the requirement level of histidine (−29%), and stimulatory (+21%) with the elevated level of histidine. When dietary tryptophan was fed at the requirement level, excess pyridoxine caused essentially no changes in hypothalamic serotonin and 5HIAA (−2%, −2%). With elevated tryptophan intake, excess pyridoxine significantly increased serotonin and 5HIAA (+32%, +20%) in the hypothalamus. These results indicate a clear interaction between substrate and coenzyme precursor which influences brain metabolism of histamine and serotonin.

Pathogenesis of Lupus Dermatoses in Autoimmune Mice

We measured histamine concentration and its metabolizing enzymes in the skin of MRL/Mp-lpr/lpr (MRL/l) and BXSB mice to clarify the contribution of histamine metabolism to the mechanisms of the development of lupus dermatoses. The concentration of histamine seemed to differ with the mouse strain. The activity of histamine-N-methyltransferase (HMT), one of two major metabolizing enzymes, was significantly lower in the tail and back skin of MRL/l mice at the age of 5 months than in the control MRL/Mp-+/+(MRL/n) mice, although there were no characteristic differences among several mouse strains of 1 mo of age. In the back skin of MRL/l mice, an age-dependent decrease of HMT activity was observed along with a corresponding decrease in histamine concentration, whereas an age-dependent increase of both HMT activity and histamine concentration was demonstrated in BXSB mice and other control mouse strains. Autoimmune-prone male BXSB mice and non-autoimmune female BXSB mice at 5 mo of age showed similar HMT activity. Corticosteroid treatment restored HMT activity in the skin of MRL/l mice but not in MRL/n mice. In addition, the change in HMT activity in MRL/l mice treated with corticosteroid appeared earlier than changes in clinicopathological examinations including skin eruptions, dermatopathology and proteinuria. Diamine oxidase (DAO) activity, another major metabolizing enzyme, was not detected in the skin of any autoimmune or control mouse strains. These findings suggest that the low activity of HMT in the skin of MRL/l mice plays a significant pathological role in the development of spontaneous lupus-like eruption. In other mouse strains, it is assumed that HMT activity is regulated by genetic factors.

Antihistamines reverse blood-ocular barrier breakdown in experimental diabetes

Retinal and other tissue histamine synthesis is increased in experimental diabetes; histamine infusion causes blood-ocular barrier breakdown in nondiabetic rats. We have examined the hypothesis that antihistamines prevent blood-ocular barrier breakdown in streptozotocin diabetes using male Sprague-Dawley rats held 28 days. During the last 7 days they were divided into these treatment groups: control (C), untreated diabetic (D), diabetic rats receiving diphenhydramine-HCl (B), diabetic rats receiving ranitidine (R) and diabetic rats receiving diphenhydramine and ranitidine (BR). Vitreous albumin content was measured 6 hr following fluorescein isothiocyanate bovine serum albumin (FITCBSA) injection. Data show that D had a 98.3% increase in vitreous body FITCBSA over C (p < 0.05) while B and R showed respective decreases of 34.9% and 51.4% compared to D, R being significantly lower than D (p < 0.05). BR showed a decrease of 71% (p < 0.05) compared to D, and R and BR groups were not significantly different from C (p < 0.05). Leakage into the vitreous was from the retina, not the ciliary body. These data indicate that 1) experimental diabetes results in elevated blood-ocular barrier permeability, which can be reversed by diphenhydramine-HCl and ranitidine; and 2) histamine H 1- and H 2-receptor activation and interaction by altered endogenous histamine metabolism may mediate blood-ocular barrier breakdown, implicating a pathogenic role of histamine in diabetic retinopathy.

Human aldehyde dehydrogenase: metabolism of putrescine and histamine.

Imidazoleacetaldehyde and gamma-aminobutyraldehyde, metabolites of histamine and putrescine, respectively, have been shown to be substrates of human liver aldehyde dehydrogenase (EC 1.2.1.3) cytoplasmic (E1) and mitochondrial (E2) isozymes. The Km values at pH 7.4 and 500 microM NAD for imidazoleacetaldehyde and gamma-aminobutyraldehyde for the E1 isozyme are 40 and 800 microM, respectively, and for the E2 isozyme are 50 and 500 microM, respectively. The Km values with gamma-aminobutyraldehyde with both isozymes are high relative to Km values with acetaldehyde (50 microM for E1 and 1 microM for E2). Since activity with both imidazoleacetaldehyde and gamma-aminobutyraldehyde in crude liver homogenates paralleled that of aldehyde dehydrogenase (EC 1.2.1.3) during purification it appears likely that in the human liver this enzyme is responsible for metabolism of both compounds. If this is the case, interaction between metabolism of histamine and putrescine and that of alcohol is likely. Both imidazoleacetaldehyde and gamma-aminobutyraldehyde were synthesized in this laboratory and their stability has been investigated. Procedures for assaying aldehyde dehydrogenase employing synthetic metabolites of histamine and putrescine are provided.

Pattern of tissue histamine and histamine metabolism in sarcoma Sa1828

Pattern of tissue histamine and histamine metabolism in sarcoma Sa1828

Aspects of histamine metabolism.

Progress in learning the role of histamine in physiology and pathology has been impeded by difficulties in accurately measuring histamine and by the deficiencies of methods to measure its metabolites. The availability of specific, sensitive and rapid methods to measure histamine has helped in understanding the role of histamine in disease. Measuring histamine alone may provide an incomplete indication of the role of histamine in disease or in any other process. For histamine is metabolized by multiple pathways, and the kinetics of these enzymatic activities (as well as the rate of synthesis of histamine) determine the steady-state levels of histamine in tissue and in body fluids. Measurements of both histamine and its metabolites would contribute, and may be essential, to the understanding of the role of histamine in disease, just as measurements of the metabolites of other biogenic amines have been critical to understanding of their roles in diseases. Yet another reason that compels measurements of metabolites is evidence that some of the metabolites of histamine are pharmacologically, perhaps physiologically, active.

Histamine metabolism after adverse reactions due to d-tubocurarine administration.

We investigated histamine release in five female patients, submitted for gynaecological surgery, after intravenous administration of the neuromuscular blocking agent d-tubocurarine. In these patients, we measured the plasma levels of histamine and its metabolites, N tau-methylhistamine and N tau-methylimidazoleacetic acid, making use of mass fragmentographic methods. The newly developed determination of plasma N tau-methylimidazoleacetic acid had a within-day coefficient of variation of 2.7% (n = 10). Normal values of N tau-methylimidazoleacetic acid in plasma ranged from 41.3-75.6 nmol/l (n = 13). All five patients developed anaphylactoid reactions: two patients showed severe systemic reactions, one patient a minor systemic reaction and two had skin reactions only. Plasma histamine and N tau-methylhistamine levels appeared to be the most reliable biochemical parameters for confirming both the occurrence and severity of an anaphylactoid reaction. In comparison with plasma histamine, the determination of plasma N tau-methylhistamine is less hampered by artefacts caused by blood collection and plasma preparation. Together with the fact that the increase in plasma N tau-methylhistamine levels after anaphylactoid reactions lasts much longer than the increase in plasma histamine levels, this leads to the conclusion that the determination of plasma N tau-methylhistamine is a useful retrospective parameter for histamine release in this type of pathological state. The plasma N tau-methylimidazoleacetic acid levels fluctuated considerably, showing only a significant increase after administration of d-tubocurarine in the two patients who had severe anaphylactoid reactions. This parameter is, therefore, less useful in such studies.