Effects of amine oxidases in allergic and histamine-mediated conditions.

This review provides an update on histamine, on diamine oxidase (DAO) and on their implications in allergy and various conditions or affections, such as food histaminosis, ischemia and inflammatory bowel diseases (IBD). The review also presents, in brief, patent coverage on therapies for allergy and IBD with the focus on histamine-related treatments.

Long-term high copper intake: effects on indexes of copper status, antioxidant status, and immune function in young men.

BACKGROUND: Short-term high copper intake does not appear to affect indexes of copper status or functions related to copper status, but the effects of long-term high copper intake are unknown. OBJECTIVE: A study was conducted in men to determine the effect of long-term high copper intake on indexes of copper status, oxidant damage, and immune function. DESIGN: Nine men were confined to a metabolic research unit (MRU) for 18 d and were fed a 3-d rotating menu providing an average of 1.6 mg Cu/d. The men continued the study under free-living conditions for 129 d and supplemented their usual diets with 7 mg Cu/d. The men then returned to the MRU for 18 d of the same diet as during the first period, except that copper intake was 7.8 mg/d. Plasma copper, ceruloplasmin activity, ceruloplasmin protein, plasma malondialdehyde, benzylamine oxidase activity, erythrocyte superoxide dismutase, hair copper, urinary copper, and urinary thiobarbituric acid-reactive substances were measured during each MRU period. RESULTS: Ceruloplasmin activity, benzylamine oxidase, and superoxide dismutase were significantly higher at the end of the second MRU period than at the end of the first. Urinary copper excretion, hair copper concentrations, and urinary thiobarbituric acid-reactive substances were significantly higher during the second MRU period than during the first. Polymorphonuclear cell count, the percentage of white blood cells, lymphocyte count, and interleukin 2R were affected by copper supplementation. Antibody titer for the Beijing strain of influenza virus was significantly lower in supplemented subjects after immunization than in unsupplemented control subjects. CONCLUSIONS: Under highly controlled conditions, long-term high copper intake results in increases in some indexes of copper status, alters an index of oxidant stress, and affects several indexes of immune function. The physiologic implications of these changes are unknown.

The mechanism of inhibition of benzylamine oxidase by 3,5-diethoxy-4-aminomethylpyridine (B24).

B24, 3,5-diethoxy-4-aminomethylpyridine, is a specific inhibitor of the semicarbazide-sensitive amine oxidase with high affinity for benzylamine (BnNH2.SSAO). It is a site-directed inhibitor of pig plasma benzylamine oxidase (BAO) with an affinity for the enzyme much higher than that for benzylamine. B24 inhibition is dependent on the molar ratio B24/BAO because the inhibitor reacts mole to mole with the enzyme and benzylamine appears to be ineffective in removing the inhibitor from the adduct [EI]. B24 is a weak substrate of BAO and for this reason the degree of inhibition (when the molar ratio B24/BAO is lower than 1) decreases with the incubation time as well as with the preincubation time. This decrease is dependent on the gradual release of free enzyme which reacts with the substrate, giving [ES] without any interfering free B24. When the B24/BAO molar ratio is higher than 1, the free enzyme released by the oxidative deamination of B24 reacts with the substrate, but the free B24 present competitively inhibits the formation of [ES] and the affinity of benzylamine is therefore reduced. This is the reason why B24, in the kinetic experiments in which the inhibitor is not pre-incubated with the enzyme, may appear to be a competitive inhibitor or a mixed inhibitor, mainly competitive. When B24 is preincubated with the enzyme and the initial rate of benzylamine oxidation is measured, it appears as a non-competitive inhibitor becoming a mixed one only when the B24/BAO molar ratio is high and the incubation time is long.

Evidence of semicarbazide-sensitive amine oxidase activity in guinea pig tissues.

Lung, heart tissues and blood plasma of guinea pigs were investigated to see if tissue-bound semicarbazide-sensitive amine oxidase activities with a high affinity for benzylamine (Bz.SSAO) were present in this species as well as in others. This paper shows that these enzymic activities are present in guinea pig lung and heart where they are mainly localized in the cytosol and in microsomal fraction. These activities have a high affinity for benzylamine and appear unable to oxidize histamine at an appreciable rate in agreement with the observation that the purified Bz.SSAO of guinea pig skin shows weak histaminase activity. These guinea pig Bz.SSAO activities show some homology with the pure pig plasma benzylamine oxidase. They crossreact with the antibodies raised in the rabbit against the pig plasma enzyme. Benzylamine oxidase activity was also found in guinea pig blood plasma.

Identification by gas chromatography-mass spectrometry of an adduct between pure pig plasma benzylamine oxidase and the inhibitor 3,5-diethoxy-4-aminomethylpyridine.

3,5-Diethoxy-4-aminomethylpyridine (B24) interacts with pure pig plasma benzylamine oxidase (BAO), giving a Schiff base with the carbonyl active site. This Schiff base was reduced, isolated by chemical hydrolysis of the enzyme, purified by HPLC and identified by gas chromatography-mass spectrometry (GC-MS) after derivatization. The isolated B24 adduct had the same absorption spectrum, retention time on HPLC and GC and the same mass spectrum as B24-pyridoxamine. B24, which is a reversible enzyme inhibitor, is also a weak substrate and competes with benzylamine, which is the best substrate, for the active site. These results further indicate the presence of pyridoxal-phosphate covalently linked to the pig plasma benzylamine oxidase and involved in the active site of this enzyme.

Activation of bovine plasma benzylamine oxidase (BzAO) by 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine.

We have shown previously that certain analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are potent inhibitors of human and bovine plasma benzylamine oxidase (BzAO: EC 1.4.3.6). Inhibition was competitive, reversible and allosteric. Under certain conditions competitive inhibitors of allosteric enzymes can act as allosteric activators. In the present work, 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3MPTP) was found to activate bovine plasma BzAO at low substrate and 2'-CH3MPTP concentrations. At higher 2'-CH3MPTP concentrations, the activation was negated.

Inhibition of human benzylamine oxidase (BzAO) by analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

A sensitive assay for human plasma BzAO, involving the conversion of 14C-benzylamine to 14C-benzaldehyde, was developed. MPTP and several of its analogues were found to be competitive inhibitors of the enzyme. Ki values for the MPTP analogues in the presence of human plasma BzAO were determined. The analogues had a different rank order of inhibition of human plasma BzAO compared with the rank order of inhibition of bovine plasma BzAO found previously. MPTP and 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP), which are potent nigrostriatal toxins, were weak inhibitors of human plasma BzAO.

Nature of the organic cofactor of pig plasma benzylamine oxidase.

The identification of the organic cofactor of pig plasma benzylamine oxidase is described. Acid hydrolysis of the enzyme in argon in the presence of phenylhydrazine (6 h at 115 degrees C in 0.027 M sulphuric acid) allowed the isolation of an adduct which was purified by HPLC and identified as phenylhydrazone of pyridoxal by spectrophotometry, spectrofluorimetry and mass spectrometry.

Plasma benzylamine oxidase activity in cerebrovascular disease.

The plasma benzylamine oxidase level (BzAO) was determined in 60 patients with different types of acute cerebrovascular disease, such as cerebral bleeding, subarachnoid bleeding and cerebral infarction. Patients with cerebral infarction included both apoplectic and multiple types. A decreased plasma level of the enzyme was found following a stroke in patients with cerebral bleeding, subarachnoid bleeding, and the apoplectic type of cerebral infarction. The BzAO level increased in patients with the multiple type of cerebral infarction. Thus, we postulate that plasma BzAO metabolism is involved in cerebrovascular disease, and that plasma BzAO level varies with the type of cerebral infarction.

Decreased plasma benzylamine oxidase in a subgroup of schizophrenia.

Plasma benzylamine oxidase (BzAO) activity was analysed in a group of 40 schizophrenic patients and compared with that of healthy controls. Although plasma BzAO was significantly decreased in schizophrenics as a whole, when patients were divided into type I (favourable course) and type II (poor course) it was found that the reduced BzAO activity was only observed in type I. Several clinical features were associated with a low BzAO level. The clinical and biological significance of the identification of a biochemical alteration in a subgroup of schizophrenic patients is discussed, and we suggest that the possibility of BzAO being a marker for prognosis in schizophrenia should be further investigated.

Relation of blood serotonin and benzylamine oxidase to clinical symptoms and prognosis in Parkinson's disease.

In 21 parkinsonian patients, we investigated the contents of blood serotonin (5HT) and benzylamine oxidase (BzAO) before and during L-dopa therapy. Then, we studied the patients prospectively, and evaluated the relationship between 5HT and BzAO and the clinical characteristics. The levels of blood 5HT and BzAO varied not only with the treatment, but also with the duration and clinical type of the disease. We postulated that in certain types of Parkinson's disease, the generalized defect of 5HT and enzyme metabolism might primarily exist, and might influence the efficacy of L-dopa therapy and the prognosis of the disease.

[Changes in the amine oxidase activity of human serum during different types of anesthesia and hyperbaric oxygenation]. / Izmenenie aktivnosti aminoksidaz syvorotki krovi cheloveka pri nekotorykh vidakh anestezii i pri giperbaricheskoo oksigenatsii.

Some types of anesthesia, used usually in labor anesthesia (sodium hydroxybutyrate, lexir) or in abdominal delivery (neuroleptanesthesia, cetalar narcosis, electroanesthesia) did not affect distinctly the activity of amine oxidases in blood sera of women in labor and of fetus. In some groups of women in labor the neonates were found, blood serum of which exhibited high activity of diamine oxidase, not observed in normal state. A slight decrease in deamination of benzylamine (20%) and 4-nitrobenzylamine (30%) was observed in patients with gynecological diseases within 2 and 3 days after operations. If intestinal paresis developed in the patients within the postoperational period deamination of these substrates was decreased by 75-80% in blood sera. After 2-4 courses of hyperbaric oxygenation a slight but statistically distinct decrease (by 22-25%) in the rate of deamination of benzylamine and 4-nitrobenzylamine was found in blood sera of the patients.

Pyridoxamine as inhibitor of the blood plasma benzylamine oxidase and other copper-containing amine oxidases.

Pyridoxamine inhibits rabbit and pig plasma benzylamine oxidase (BAO), the diamine oxidase of pig kidney and the lysyloxidase of pig aorta in-vitro. In-vivo in the rabbit, the inhibitory activity of pyridoxamine on plasma BAO is antagonized by an increase in the level of this enzyme that is dependent on an increase in rate of synthesis, there being no variation in the degradation rate constant.

Reaction of pig plasma benzylamine oxidase with beta-aminopropionitrile.

Beta-aminopropionitrile (BAPN) is an inhibitor of pig plasma benzylamine oxidase. BAPN is oxidized by benzylamine oxidase. Inhibition develops in a time-dependent fashion upon incubation of BAPN with the enzyme in the absence of substrate. The product of oxidation of BAPN by benzylamine oxidase, cyanacetaldehyde, was identified and prepared by synthesis. It is an irreversible inhibitor of the enzyme.

Inhibitory effect of drugs used in the treatment of Parkinson's disease on plasma monoamine oxidase activity.

The plasma amine oxidase (benzylamine oxidase, BzAO) of patients with Parkinson's disease is sometimes decreased in activity, when compared to normal controls. This is the result of therapy with DOPA decarboxylase inhibitors. The Authors suggest that complications due to prolonged therapy with these drugs may be, at least in part, the result of an interference with BzAO capacity to catabolize circulating amines.

Benzylamine oxidase activity in spontaneously hypertensive rats.

Benzylamine oxidase (BzAO) activity was assayed in aorta, atria and serum from 20 week old spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) control rats. Atrial BzAO activity was reduced by 50% in SH rats compared with WKY control. Aorta and serum BzAO activity did not differ significantly between the two groups. Thus, BzAO activity of serum and cardiovascular tissues appears unrelated to pressure-induced changes in connective tissue production.

Spermidine cytotoxicity in vitro: effect of serum and oxygen tension.

Plasma amine oxidase activities (benzylamine oxidase and spermine oxidase) were determined in the sera of a number of species of various ages. Benzylamine oxidase (BZO) activity, measured spectrophotometrically, was present in bovine, equine, and ovine species examined. Generally its activity in serum increased with the age of the animal. Spermine oxidase activity (SPO) was estimated by a bioassay of in vitro toxicity and did not necessarily correlate with BZO. Cytotoxicity in the presence of spermidine was found only in the sera of the ruminant species examined. Serum activity tended to rise with animal age; however, great variability was found in perinatal bovine sera. The 50% lethal dose (LD50) of spermidine in the presence of 5% serum and 4 X 10(4) NS1 cells/ml was in the micromolar range. Aminoguanidine, a known inhibitor of SPO, could prevent the cytotoxic effects of exogenously added spermidine in vitro. In contrast, raising the ambient oxygen tension in the incubation environment to 95% lowered the LD50 dose of spermidine required for cytotoxicity. The results suggest that a cell line of hematogenous origin is susceptible to the cytotoxic effects of the products of oxidative deamination of spermidine by SPO, an enzyme present in perinatal bovine sera, and that these cytotoxic effects are potentiated in the presence of an oxygen-enriched environment in vitro.