D. Kierska

Histamine in C3H/W mice carrying spontaneous tumors of the mammary gland

Adenocarcinoma mammae, a spontaneously growing mammary cancer in C3H/W mice, contrary to many transplanted tumors does not evoke any rise in histamine level either in the tumor or in distant tissues. On the other hand, the histamine level is reduced by 90% in the tumor in comparison with the healthy gland. This seems to be a consequence of the fall of histidine decarboxylase activity to below a detectable level. There is also a significant reduction in histamine N-methyltransferase activity to onefifth of the control level. The healthy mammary gland contains a high concentration of histamine and catabolizes it exclusively through the methylation pathway.

Histamine and its catabolism in tumour-bearing rat and mouse.

The hypothesls that fallure of histamine (Hi)-mediated inter and intracellulary cell-cell communication may be involved in the control of cellular growth has been tested in leukaemia-bearing mice and fibrosarcoma-bearing rats.In all examined tissues of mice bearing leukaemia L1210 cells and rats bearing methylcholanthrene fibrosarcoma histamine content was higher than in controls.Tissues of fibrosarcoma-bearing rats more intensively metabolized14C-Hi and oxidative pathway was predominat. Histamine metabolic activity as well as histamine catabolic pathways do not differ in leukaemic mice as compared with the controls.

Histamine concentration and metabolism in mouse mammary gland during the estrous cycle.

Results and discussion The results are presented in Table 1. Among the parameters studied histidine decarboxylase and histamine concentration changed during the estrous cycle. They were at their highest during the estrus and their lowest in diestrus. In contrast, neither histamine N-methyltransferase nor transglutaminase activity varied significantly according to the hormonal status

Phosphopyridoxal complexes with histamine and histidine. (3) The influence of presumed complex on activity of rat intestinal histaminase.

Histamine in high concentration inhibits the rat intestinal histaminase (diamine oxidase E.C. 1.4.3.6). The apparent Km is approximately 4.2×10−5 M. This inhibition can be reversed by an addition of PLP.It was also found that excess of PLP inhibits enzyme activity. It is competitive inhibition.Histamine and other amines which were associated with enzyme inhibition form spectrophotometricaly demonstrable complex with PLP. The possible mechanism of the inhibitory action of PLP and complex with histamine and other amines on rat intestinal histaminase activity are discussed.

Conditions for the formation of cyclic compounds between pyridoxal phosphate and 5-hydroxytryptamine or 5-hydroxytryptophan

Abstract5-Hydroxytryptamine (5HT) and 5-hydroxytryptophan (5HTP) form cyclic compounds (probably of the tetrahydro-β-carboline type) with pyridoxal phosphate (PLP). In the first step of reaction a Schiffs base is formed; during incubation it is transformed into a cyclic compound with a maximum absorption spectrum at 330 nm. The degree of cyclization depends on pH and substrate concentrations. One mole of 5HT or 5HTP reacts with one mole of coenzyme. The velocity of cyclization increased with an excess of either 5HT (5HTP) or PLP, without any change in the mole to mole ratio. The formation of cyclic compounds was confirmed by the use of isotopes, separation from substrates being achieved by high-voltage electrophoresis.

Phosphopyridoxal complexes with histamine and histidine. (4) The kinetics of complex formation between histidine and pyridoxal 5' -phosphate in the presence of bacterial histidine decarboxylase.

The dynamics of the complex formation between pyridoxal 5′-phosphate (PLP) and histidine in the presence of bacterial histidine decarboxylase was examined. Since PLP is able to form a cyclic product with histidine and histamine, the possibility of complex formation between PLP and histamine formed during a decarboxylation reaction was examined too. It was found that the cyclization reaction between PLP and histidine is equimolecular and the rate of cyclic product formation is not significantly influenced by the presence of enzyme. In the presence of bacterial histidine decarboxylase both the cyclization reaction and cyclic product formation were observed. Predominance of histamine or cyclic product formation was dependent on pH and substrate concentration. In the presence of histidine and enzymatic protein, histamine formed during the decarboxylation reaction was unable to form a cyclic product with PLP.

Phosphopyridoxal complexes with histamine and histidine (1) the kinetics of complex formation between pyridoxal 5′-phosphate and histamine

Amines and amino acids are able to form cyclic compounds with pyridoxal 5′-phosphate (PLP). The quantitative relationship between histamine and PLP in the cyclization reaction were examined. It was found that one mole of amine reacts with one mole of coenzyme. The velocity of complex formation increased with an excess of either histamine or PLP, without any change in molar ratios. The formation of cyclic compound was confirmed by the use of isotopic method. The separation of cyclic compound from histamine, but not from PLP, was achieved by paper chromatography.

In vivo formation of histamine phosphopyridoxal cyclic compounds

A possibility of in vivo formation of cyclic compounds between histamine (Hi) given i.p. and endogenous pyridoxal (PL) or pyridoxal 5′-phosphate (PLP) has been studied. Cyclic compounds of Hi with PL or PLP were found in all tissues examined. Although an increase in Hi levels in tissues enhances the formation of cyclic compounds, no simple relationship between the rate of formation and Hi concentration has been observed. The reaction seems to be limited by endogenous PLP. The cyclic products Hi-PL and HI-PLP were discovered in urine. It is suggested that the process of cyclic compound formation may reduce PLP resources, resulting in a modification of PLP-enzyme activities.

Decreased histamine content and metabolism in mammary cancer tissue from C3H mice.

Histamine (HA) level and its metabolism in adenocarcinoma mammae, spontaneously growing cancer in C3H mice, were examined in relation to the type of tumor, intensity of tumor vascularization and the presence or absence of a secretory function. Histamine concentration being in mammary gland one of the highest among mammalian organs (418 nmol/g) was decreased by 90% in tumor (34 nmol/g). Similarly, histidine decarboxylase (HDC) activity dropped from approximately 7.6 pmol/min/g in normal gland to an undetectable level in adenocarcinoma mammae. Of the two main HA degrading enzymes, namely, diamine oxidase and histamineN-methyl-transferase (HMT), only HMT could be detected in mammary gland, either healthy or neoplastic, and its activity was about 5-fold lower in tumor than in the control tissue (1 nmol/g/min vs. 5.2 nmol/g/min).The pattern of changes in histaminergic parameters evoked by the tumor was similar irrespective of the morphological type it represented, characteristics of its vascular bed or whether or not it showed secretory activity.

Causal relationship between a tumour growth and the changes in histamine metabolism in tissues of sarcoma-bearing rat

The relationship between malignancy and histamine metabolism in the liver and the small intestine has been examined in sarcoma-bearing Wistar rats two weeks after subcutaneous implantation of a transplantable methylcholanthrene sarcoma Sa1828 and on the 3, 7 and 14th days after tumour extirpation. Two weeks after tumour implantation, the histamine level was increased by 100% and 50% in the liver and the small intestine, respectively. On the 3rd day after extirpation of the tumour the level of histamine had returned to the control values and remained unchanged during the next 10 days. Neither of the histamine catabolizing enzymes, diamine oxidase with a putrescine as a substrate or histamine methyltransferase were influenced by the existing tumour or by its extirpation except on the 14th day where a high increase in diamine oxidase activity was found. Some changes in the distribution of histamine metabolites suggest an involvement of an oxidative pathway of histamine catabolism as well as the aldehyde catabolizing enzymes in tumour development.