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Imidazoleacetic acid, a product of the action of histaminase (E.C. 1.4.3.6) on histamine, inhibits specific release of histaminase from human peripheral blood granulocytes with an inhibition constant between 5 X 10(-9)M and 1 X 10(-8)M. Hence, modulation of enzyme release is indirectly mediated by the activity of the enzyme.
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High histaminase [amine:oxygen oxidoreductase (deaminating) (pyridoxal-containing), EC 1.4.3.6] activity is found in certain human tumors and in the placenta of most mammals. The present study explores the relationship of tumor histaminase to histaminases found in placenta and other human, pig, and rat tissues. The electrophoretic mobility and Michaelis constants for the deamination of histimine and putrescine were identical for histaminases from human placenta and from medullary thyroid carcinoma. An antibody was raised in rabbits against human placental histaminase that was highly purified by a new affinity procedure. In separate studies, using inhibitory concentrations of antibody and a second antibody precipitation technique, identical patterns of immunoreactivity were found for histaminases from human placenta, kidney, medullary thyroid carcinoma, and small cell lung carcinoma; human intestinal histaminase crossreacted well but less strongly than did enzymes from these other tissues. Histaminases from pig kidney, pig intestine, and rat intestine showed no crossreaction; histaminases from rat thymus and adrenal gland showed minimal crossreactivity. The findings suggest that placental histaminase activity is not a unique product of a fetal or trophoblastic genome. The presence of histaminase in malignancies does not appear to be an example of ectopic tumor production of a placental trophoblastic protein.
The present study describes the use of affinity chromatography to achieve a high degree of purification of histaminase (diamine oxidase, EC 1.4.3.6) from plasma of women in the third trimester of pregnancy. The procedure is based upon the binding of histaminase to cadaverine, a diamine substrate for the enzyme, which is coupled to Sepharose. Contaminant proteins were removed by high concentrations of NaCl (up to 1.0M), and the histaminase was then eluted from the column with a buffer containing 300--400 units/ml of sodium heparin. The purification technique has the following characteristics: (1) in optimal experiments, 3000-fold purification of enzyme was obtained; (2) the yield of enzyme was as great as 25%; (3) the binding of histaminase to the amine groups of the cadaverine appears to represent a true "affinity" phenomenon since enzyme bound to DEAE-cellulose under neutral pH conditions was eluted at much lower concentrations of NaCl (less than 0.4 M). The enzyme purified by the present procedure has the following properties: (1) disc gel polyacrylamide electrophoresis showed two protein bands for 1000--3000-fold pure histaminase; the major band may represent a contaminant protein, while the minor band corresponded to the position of histaminase activity; (2) a 90 000 molecular weight subunit for the plasma histaminase was identified on calibrated sodium dodecyl sulfate gels; this value agrees well with previous estimations for the subunit size of human placental histaminase; (3) the purified enzyme behaved as classical histaminase (diamine oxidase) in that it was totally inhibited by low concentrations of aminoguanidine, but was less inhibited by semicarbazide and by inhibitors of monoamine oxidase, and the enzyme was active against histamine and putrescine, but not against the monoamines benzylamine and tryptamine. Also, the enzyme was strongly inhibited by NaCl.
Histaminase has been shown to be associated with several types of human cancer. In the present study, we examined the activity of histaminase and its relationship with Regan isoenzyme of alkaline phosphatase in ascitic fluids obtained from patients with ovarian and several other types of cancer. We have found that about 44% of the ovarian cancer patients had elevated levels of histaminase in the ascitic fluid, whereas a less frequent incidence was observed in fluids obtained from other types of cancer. There was concurrence in the elevation of histaminase activity with the appearance of Regan isoenzyme in most of the samples examined. Of the 10 patients who showed elevated histaminase, 9 had high Regan isoenzyme activity; whereas in 9 patients with normal levels of histaminase, all except 1 had low or moderate levels of Regan isoenzyme activity. These results, therefore, confirm the observation of an association of histaminase with human cancer and suggest the possibility for the utilization of histaminase, in conjunction with Regan isoenzyme and cancer-associated proteins, for cancer diagnosis and clinical evaluation of tumor progression and regression during therapy.
The distribution of calcitonin, L-dopa decarboxylase, and histaminase is studied in sectioned total thyroid glands from patients with different stages of familial medullary thyroid carcinoma. In 5 glands with gross carcinoma and in 3 with early microscopic carcinoma the distribution of all three parameters positively correlates (p less than .01 for each correlation). In contrast, in 6 glands with C-cell hyperplasia only the distribution of calcitonin and L-dopa decarboxylase correlates (r = 0.64, p less than .01) while those for histaminase vs. calcitonin (r = .17, p = N.S.) and histaminase vs. dopa decarboxylase (r = .03, p = N.S.) do not. In the glands with microscopic carcinoma the peak levels of histaminase occur in the areas of disease as defined by immunohistochemical staining of calcitonin; mean histaminase activity is the only one of the three parameters measured that distinguishes between C-cell hyperplasia and microscopic carcinoma (p less than .005). Immunohistochemical staining of histaminase shows positive cells in glands with gross and microscopic carcinoma, but in none of the glands with hyperplasia alone. Histaminase is thus found in high amounts in some malignant C-cells only and may be a useful marker to distinguish between hyperplasia and malignancy in thyroids with early C-cell proliferative disorders.
Plasma histaminase activity has been estimated in 79 patients with squamous cell carcinoma of the cervix. The mean plasma histaminase value is significantly higher in patients than in controls (P less than 0.001). The plasma histaminase activity falls significantly following radiotherapy (P less than 0.001). Pretreatment plasma histaminase values do not show any correlation with clinical stages and the posttreatment values decline significantly but remain higher in clinical stages III and IV than in stages I and II. The increased plasma histaminase activity also reflects the degree of differentiation within the tumor. Further it is noted that the plasma histaminase value is inversely proportional to the radiation response. It is suggested that estimation of plasma histaminase activity can serve as an important marker in assessing the treatment response and monitoring the course of treatment.
Histaminase (EC-1.4.3.6), one of the two catabolic enzymes for histamine, is contained in human granulocytes. Opsonized zymosan or the calcium ionophore A-23187 induce a dose-dependent release of histaminase from human granulocytes in vitro. Release is completed within 30 min, is temperature dependent, and requires divalent cations. Opsonized zymosan-induced histaminase release was maximal in the presence of both calcium and magnesium, whereas ionophore release was magnesium independent. The total cellular content of histaminase could be released by both opsonized zymosan and ionophore. In contrast, only 25% of the cellular beta glucuronidase, a lysosomal enzyme, was released after maximal stimulation with opsonized zymosan; there was minimal release of beta glucuronidase with ionophore. Zymosan- and ionophore-induced histaminase release was inhibited by agents that are presumed to interfere with cell metabolism and disrupt microtubules. Human granulocytes therefore may modulate the effect of histamine by releasing histaminase at a site of inflammation. Studies of granulocyte histaminase release in vitro may also provide a new model to explore granulocyte function and secretion.
The release of histaminase activity in plasma after small intravenous of heparin was studied in 85 normal subjects and patients. In normal subjects, plasma histaminase activity (basal level, 1.7+/-0.1 U/ml, mean +/-SEM) increased 1.6+/-0.2 U/ml after 10 U of heparin/kg, 8.5+/-2.4 U/ml after 20 U/kg, and 33+/-4.9 U/ml after 75 U/kg. The extent of the increase varied widely among individuals but in a particular individual the response was constant and dose-dependent. Histaminase activity rose to peak levels within 7-15 min and then declined exponentially with a half-life of 40-120 min. This pattern of response was also observed in two patients with the histaminase-producing tumor, medullary carcinoma of the thyroid. A significantly reduced response was observed, however, in 14 patients with type I hyperlipoproteinemia, a disorder in which high plasma triglyceride levels are associated with low postheparin plasma lipolytic activity. After 10 U heparin/kg, plasma histamine activity increased 0.5+/-0.2 U/ml, and after 75 U heparin/kg, 10.9+/-5.6 U/ml. In contrast, in 27 patients with other types of hyperlipoproteinemia in whom postheparin lipolytic activity was normal, the increase (2.4+/-0.6 U/ml) in plasma histaminase activity after 10 U heparin/kg was not significantly different from that of normal subjects. The reduced response of the plasma histaminase activity to heparin in patients with type I hyperlipoproteinemia did not appear to be due to the presence of lipemia or to an inhibitor of the enzyme in plasma. These findings suggest that many patients with type I hyperlipoproteinemia may have deficient release of both lipolytic and histaminase activities into plasma after heparin administration.
We have demonstrated by tissue assay and immunohistochemical techniques that tumor cells appear to be the source of the increased histaminase activity found in 60% of ascitic fluids from patients with ovarian carcinoma. The histaminase activity in 64% of tumor tissues studied was greater than 100 U/g of tissue, a value higher than that for normal tissues other than kidney and intestine. The presence of elevated ascitic fluid histaminase activity (greater than 3.5 U/ml) correlates with the presence of high histaminase activity in tumor tissue. Histaminase activity is higher in ascitic fluid from the patients than it is in their plasma, probably reflecting the direct entry of histaminase into the peritoneal cavity.
A sensitive isotopic assay was employed to follow the changes in plasma histaminase activity during pregnancy in patients who become pregnant following spontaneous and induced ovulation. Values in nonpregnant women ranged from 0.2 to 2.7 pmoles of histamine deaminated per milliliter of plasma per hour. In pregnant women, plasma histaminase activity began to increase 9 to 28 days following the presumed day of ovulation and then rose exponentially with a doubling time of 4 to 5 days. Peak values, 1,500 pmoles per milliliter per hour, were reached during the third trimester of pregnancy. The data suggested that the increase in histaminase activity actually started at about the same time in all patients, although the early rise in enzyme activity was not apparent in women who had high histaminase activity before pregnancy. Plasma histaminase did not rise in patients with spontaneous abortion, blighted ovum with hydatidiform degeneration, or choriocarcinoma. The high levels of chorionic gonadotropin and low levels of histaminase activity seen in patients with trophoblastic neoplasia suggest that these tests may be of value in the diagnosis of trophoblastic neoplasia early in pregnancy.
To help resolve the current uncertainty as to whether assays for plasma histamine are measuring non-histamine compounds as well, we compared the effects of prior incubation with histaminase and buffer on measurements in (1) normal plasma, (2) buffer and normal plasma to which several amounts of exogenous histamine had been added, and (3) plasma obtained after inhalation-induced asthma or form the site of a local heat urticaria challenge. As measured by the radioenzymatic technique, low (1 to 4 ng/ml) levels of histamine-like material were present in normal plasma after incubation with either histaminase or buffer. In contrast, histaminase (but not buffer) incubation markedly reduced measured histamine in all other specimens. Exogenous histamine in buffer was reduced almost 100% by histaminase, whereas the degree of reduction in plasma specimens varied directly with the starting histamine level. Therefore it appears that low levels of histaminase-resistant material reacting in histamine assays is present in normal plasma. The use of histaminase incubation appears to be helpful in differentiating this from true histamine release in allergic reactions.
Grass pea seedling histaminase (a copper-diamine oxidase) was found to exert a significant cardioprotection against post-ischaemic reperfusion damage. Electrocardiogram (ECG) recordings from the rats subjected in vivo to ischaemia and reperfusion showed ventricular tachycardia (VT) and ventricular fibrillations (VF) occurring in 9 out of 12 untreated rats whereas no ventricular arrhythmias were found under histaminase (80U/kg body weight) treatment (n=16 rats). Computer-assisted morphometry of the ischaemic reperfused hearts stained with nitroblue tetrazolium showed the extension of damaged myocardium (area at risk and infarct size) significantly reduced in rats treated with histaminase, in comparison with the non-treated rats, whereas no protection was found with the semicarbazide inactivated histaminase. Biochemical markers of ischaemia-reperfusion myocardial tissue damage: malonyldialdehyde (MDA), tissue calcium concentration, myeloperoxidase (MPO), and apoptosis indicator caspase-3 were significantly elevated in untreated post-ischaemic reperfused rats, but significantly reduced under histaminase protection. In conclusion, plant histaminase appears to protect hearts from ischaemia-reperfusion injury by more than one mechanism, essentially involving histamine oxidation, and possibly as reactive oxygen species scavenger, presenting good perspectives for a novel therapeutic approach in treatment of ischaemic heart pathology.
Histaminase (diamine oxidase) is an enzyme associated with pregnancy and with a number of human cancers. In pregnancy, the enzyme is produced by the decidual cells of the placenta. Histaminase of the placenta is biochemically and immunologically identical to that of cancer, Based on this, a radioimmunoassay procedure for histaminase has been developed. The high affinity monospecific antiserum for the assay was obtained from rabbits by injecting with homogeneous histaminase purified from placenta by affinity chromatography. Radioactive labeling of histaminase was carried out by iodination with 125I using chloramine T as the oxidizing agent. The iodination yielded [125I]-histamine of high specific radioactivity (20 microCi/microgram protein) with no apparent affect on the immunologic affinity. For separating the antibody-antigen complex from the unbound antigen, a second antibody bound to polyacrylamide beads was most effective at high antiserum dilutions. The assay had a working range of 0.3 to 80 microgram/ml and a minimal detectable quantity of 0.15 ng/ml. Compared to the enzymatic assay with [14C] putrescine as substrate, the radioimmunoassay procedure is about 70 times more sensitive. Measurements of histamine in placental extracts and malignant effusions using both radioimmunoassay and enzyme assay demonstrated that the two methods were highly correlated, thus providing evidence for the specificity of the radioimmunoassay. This procedure will be useful in future studies of histaminase as a biochemical marker for human cancer and for the elucidation of the significance of this enzyme is pregnancy and in neoplasia.
The interaction of opsonized particles with human granulocytes promotes a number of important biologic functions, including phagocytosis, superoxide generation, and release of a variety of enzymes, including histaminase. We have previously determined that histaminase release occurs via a C3-dependent process. Although fluid-phase C3b dimers can mediate release, the relative effects of particle-bound C3b and C3bi and of IgG have not been examined. In this report we demonstrate that particle-bound C3 deposited on activators of the alternative C pathway effected histaminase release in the absence of IgG. Particle-bound C3bi and C3b were both effective as mediators of histaminase release. The extent of release varied as a function of the activating surface on which C3 was deposited (zymosan C3b was considerably more potent than C3b bound to rabbit erythrocytes, which was slightly more potent than C3b bound to neuraminidase-treated sheep erythrocytes). In contrast, C3b or C3bi deposited on nonactivating surfaces (such as sheep erythrocytes) at inputs of up to 2,000,000 molecules per granulocyte failed to induce histaminase release unless IgG was also present. The ability of C3b bound to particles that serve as activators of the alternative pathway to induce histaminase release is apparently not the result of decreased susceptibility of C3b to proteolysis or to an increased binding affinity to the C3b receptor, but may relate to the interaction of other surface structures on activating particles with the PMN membrane.
Tissue samples from 125 cases of a variety of human malignancies and benign conditions were examined for the presence of histaminase by the immunoperoxidase method on conventional pathological specimens. Histaminase was found diffusely in the cytoplasm of cancer cells of primary and metastatic tumors of lung, thyroid gland, pancreas, stomach, esophagus, ovary and pharynx. Histaminase-positive cases were also found in carcinoids, dysgerminomas and in melanoma. The incidence of positive histaminase staining in epithelial malignancies overall was 28/84, and those in sarcoma as well as in benign conditions were 1/22 and 0/19, respectively, excluding placental decidual cells and eosinophils intermingled in the tissues. No significant difference in the incidence of histaminase was found by histological type or by degree of cellular differentiation. The present results thus provided another direct evidence for the production of histaminase by many kinds of tumor cells.
The release of histaminase, a diamine oxidase of the human neutrophil, is initiated by soluble secretagogues. Histaminase is simultaneously inactivated by the reactive oxygen intermediates generated by the respiratory burst. Thus, quantitative assessment of histaminase release relative to other granule markers is best achieved in the presence of superoxide dismutase and catalase. Human neutrophils activated with secretagogues preferential for the specific granule, such as calcium ionophore A23187 in a limited concentration, phorbol myristate acetate (PMA), formyl-methionyl-leucylphenylalanine (fMLP), and concanavalin A, release vitamin B12-binding protein, lysozyme, and histaminase but not beta glucuronidase. PMA activation in the presence of cytochalasin B augments the release of lysozyme and initiates the release of beta glucuronidase through recruitment of the azurophilic granule but has no incremental effect on the release of vitamin B12-binding protein and histaminase observed with PMA alone. Subcellular fractionation of resting neutrophils by sucrose density gradient centrifugation to separate specific granules from two classes of azurophilic granules selectively distributes vitamin B12-binding protein and histaminase to the specific granule fractions.