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Purpose 3-iodothyronamine (3-T1AM), a decarboxylated and deiodinated thyroid hormone metabolite, leads at pharmacological doses to hypoinsulinemia, hyperglucagonemia and hyperglycemia in vivo. As the pancreatic Langerhans islets express thyroid hormone transmembrane transporters (THTT), we tested the hypothesis that not only plasma membrane-mediated 3-T1AM binding to and activation of G-protein coupled receptors, but also 3-T1AM metabolite(s) generated by 3-T1AM uptake and metabolism might decrease glucose-stimulated insulin secretion (GSIS). Methods Murine pancreatic β-cells MIN6 were characterized for gene expression of THTT, deiodinases and monoamine oxidases. 3-T1AM uptake and intracellular metabolism to the corresponding 3-iodothyroacetic acid were analysed by liquid-chromatography tandem mass spectrometry (LC-MS/MS) at different time points in cells as well as the conditioned medium. Mitochondrial activity, especially ATP-production, was monitored real-time after 3-T1AM application using Seahorse Bioanalyzer technique. Effect of 3-T1AM on GSIS into the culture medium was assayed by ELISA. Results MIN6 cells express classical THTT, proposed to transport 3-T1AM, as well as 3-T1AM metabolizing enzymes comparable to murine primary pancreatic islets. 3-T1AM accumulates in MIN6 cells and is metabolized by intracellular MaoB to 3-iodothyroacetic, which in turn is rapidly exported. 3-T1AM decreases mitochondrial ATP-production concentration dependently. GSIS is diminished by 3-T1AM treatment. Using LC-MS/MS, no further 3-T1AM metabolites except 3-iodothyroacetic were detectable. Conclusions This data provides a first link between cellular 3-T1AM uptake and regulation of mitochondrial energy metabolism in s-cells, resulting in reduced insulin secretion. We conclude that MIN6 is an appropriate cell model to study 3-T1AM-dependent (intra-)cellular biochemical mechanisms affecting insulin production in vitro.

This work describes the identification and characterization of an amine oxidase from Kocuria varians LTH 1540 (syn. Micrococcus varians) primarily acting on putrescine. Data from MALDI-TOF MS/MS and the identification of Δ(1)-pyrroline as degradation product from putrescine indicate that the enzyme is a flavin-dependent putrescine oxidase (PuO). Properties of partially purified enzyme have been determined. The enzyme oxidizes diamines, putrescine and cadaverine, and, to a lesser extent, polyamines, such as spermidine, but not monoamines. The kinetic constants (Km and Vmax) for the two major substrates were 94 ± 10 μM and 2.3 ± 0.1 μmol/min·mg for putrescine and 75 ± 5 μM and 0.15 ± 0.02 μmol/min·mg for cadaverine. Optimal temperature and pH were 45 °C and 8.5, respectively. Enzyme was stable until 50 °C. K. varians PuO is sensitive to human flavin-dependent amine oxidase inhibitors and carboxyl-modifying compounds. The new enzyme has been isolated from a bacterial starter used in the manufacture of fermented meat. One of the problems of fermented foods or beverages is the presence of toxic biogenic amines produced by bacteria. The importance of this works lies in the description of a new enzyme able to degrade two of the most abundant biogenic amines (putrescine and cadaverine), the use of which could be envisaged to diminish biogenic amines content in foods in the future.

In the last few decades, medicinal chemists have carried out extensive research on synthetic polyamines for use as anticancer drugs and multitarget-directed ligands in neurodegenerative diseases. The aim of this study was to evaluate the effect of some synthetic polyamines as inhibitors of two new potential targets, human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) and monoamine oxidases B (MAO B), enzymes involved in various multi-factorial diseases such as Alzheimer's disease. N,N'-Dibenzyl-dodecane-1,12-diamine (Bis-Bza-Diado), a newly synthesised compound, and ELP 12, a muscarinic cholinergic M(2) receptor antagonist, were found to behave as reversible and mixed non-competitive inhibitors of both amine oxidases (dissociation constants of about 100 microM). ELP 12 was found to be more selective for SSAO/VAP-1. Combining kinetic and structural approaches, the binding mode of ELP 12 to SSAO/VAP-1 was investigated. ELP 12 may bind at the entrance of the active site channel by ionic interactions with ASP446 and/or ASP180; one end of the polyamine may be accommodated inside the channel, reaching the TPQ cofactor area. The binding of ELP 12 induces rearrangement of the secondary structure of the enzyme and impedes substrate entry and/or product release and catalysis. These structural data reveal that the entrance and the first part of the SSAO/VAP-1 channel may be considered as a new target area, or a "secondary binding site", for modulators of human SSAO/VAP-1 activity. These results indicate ELP 12 and Bis-Bza-Diado as new "skeletons" for the development of novel SSAO/VAP-1 and MAO B inhibitors.

The ethylamine contents of tea shoots and made teas were derived with o-phthalaldehyde and 2-mercaptoethanol, and quantified by high performance liquid chromatography. The coefficient of variation of this method was 1.97% from eight analyses. The levels of ethylamine in tea shoots declined markedly during growth and senescence after plucking; they also declined in the extracts of fresh tea during the incubation at 37°C, but this decrease was completely inhibited by amine oxidase inhibitors. The content of ethylamine in high grade green teas was higher than in low grade teas, but was almost identical in high and low grade black tea. The mean contents of ethylamine in 22 green teas and 17 black teas were 6.76±3.07 μmol g−1 and 6.40±1.82 μmol g−1, respectively.

SynopsisDangerous and even fatal interactions can occur in man following combinations of antidepressants which include non-selective MAO inhibitors. To ascertain the causation, interactions reproducing the clinical phenomena have been elicited in animals with these combinations, and the mechanisms involved have been explored by various pharmacological strategies; 5-HT re-uptake inhibitors proved especially hazardous in combination. Interactions could, however, be avoided even with the 5-HT re-uptake inhibitors, by combination with relatively selective MAO A or B inhibitors, an approach with potential clinical value.

The metabolism of tryptophan by Taphrina deformans has been studied to confirm the reported ability of this organism to produce tryptamine. Such amine production was not observed, despite use of amine oxidase inhibitors at levels which should have resulted in the accumulation of tryptamine in the medium. It has been shown that the metabolites of tryptophan include indolepyruvic acid, indolelactic acid, tryptophol, and indoleacetic acid, and that the original report of tryptamine production must be reevaluated in light of the extraction procedures employed.

5-Hydroxytryptamine was not detected in animal cerebrospinal fluid after amine oxidase inhibitors, reserpine, or both. Both human and animal cerebrospinal fluid can produce a stimulating effect on the clam heart which is not due to 5-hydroxytryptamine. Cerebrospinal fluid also has the property of increasing the sensitivity of the clam heart to 5-hydroxytryptamine.

The newer monoamine oxidase inhibitors have clinical actions in hypertension and angina pectoris similar to those of iproniazid but appear to produce less frequent side effects. Some of the side effects suggest that in addition to amine oxidase inhibition, they may also have a ganglionic blocking action. The amine oxidase inhibitors are effective and useful in the clinical management of refractory cases of angina pectoris even though they may not alter the electrocardiogram significantly. Since the relief of chest pain also is accompanied frequently by a sense of well-being, cautioning the patient against over-exertion is advisable. Some of the amine oxidase inhibitors are also worthy of a trial in resistant cases of hypertension. However, they should be employed cautiously in these selected cases since their long term effects, even in moderate dosage, on liver and cardiac function are not known.

Storage and release of catecholamines in the isolated heart and the heart in vivo were investigated. The addition of DOPA to the perfusion fluid of a heart-lung preparation markedly increased the catecholamine concentration of the isolated heart. In vivo , the combination of iproniazid and DOPA had the same effect. Iproniazid alone failed to influence myocardial amine concentration. Nicotine raised the catecholamine concentration in heart muscle; electrically induced tachycardia failed to lower the catecholamine content of the heart in vivo ; reserpine caused a marked reduction. The reasons for the absence of a pharmacologic effect of the stored catecholamines are discussed.

Amnesia was induced by pretraining injections of cycloheximide (CYC) in a food motivated discrimination reversal task. Magnitude of amnesia varied as a function of the amount of training on both the initial discrimination and the reversal and also as a function of the length of intertrial interval used on both the reversal and the test. Memory spontaneously recovered 48 hr. following reversal training. Recovery from amnesia was induced by pretesting injections of d-amphetamine and 2 monoamine oxidase inhibitors, pargyline and catron. This enhanced performance was a true recovery of the memory and not a result of enhanced learning or increased arousal. Depletion of catecholamines by alpha-methyl-para-tyrosine, a tyrosine hydroxylase inhibitor, and diethyldithiocarbamate, a dopamine beta hydroxylase inhbitor, resulted in an amnesia quantitatively and qualitatively similar to amnesia induced by CYC. These data support the hypothesis that CYC-induced amnesia is mediated via central catecholamines.

The relative potencies of analogues of tryptamine and 5-hydroxytryptamine have been determined on the rat fundus preparation. This tissue had an amine oxidase activity, which, in the homogenate, was able to inactivate both tryptamine and 5-hydroxytryptamine to about the same degree. Amine oxidase inhibitors potentiated the action of tryptamine and many analogues on the isolated rat fundus preparation, but not the action of 5-hydroxytryptamine or of other hydroxytryptamines. This suggested that, in the isolated organ, the amine oxidase was unable to inactivate 5-hydroxytryptamine, but could inactivate tryptamine, 5-methoxytryptamine and many others. These results may be explained if it is supposed that tryptamine entered the cell, but because of the polar hydroxyl group 5-hydroxytryptamine did not. This hypothesis is supported by the oil/water partition coefficients. The structure/activity of the various tryptamine derivatives is discussed in the light of this assumption.

Concurrent observations were made on the rope-climbing performance and aromatic excretion pattern of male albino rats during drug treatment. Iproniazid, Niamid and Isoniazid were administered chronically and Reserpine was given in single doses, alone, and in combination with the Iproniazid. 1. Iproniazid and Niamid disturbed the climbing habit which later became re-established even though drug treatment was continued. Urinary concentrations of 5-hydroxyindoleacetic acid fell and of tryptamine rose immediately on giving the drugs, and tryptophane excretion gradually increased. 2. Isoniazid had little effect on climbing performance. 3. A study of T.M. 6 was abandoned when large sores developed at the site of injection. 4. Reserpine given alone disrupted climbing and potentiated excretion of 5-hydroxyindoleacetic acid, tryptophane and two unidentified Ehrlich positive materials. 5. When given on the second day of Iproniazid treatment, Reserpine also disrupted climbing and increased excretion of 5-hydroxyindoleacetic acid, tryptamine and tryptophane. When given on the 23rd day, the climbing performance was impaired but no change was observed in excretion pattern. 6. Some physiological and overall behaviour changes during the experiments are described.

Summary and conclusions(1) The multicellular system that controls chromatophores of Loligo pealii has been a useful tool for study of smooth muscle function in non-narcotized living animals. (2) Ac...

Monoamine oxidase is a complex enzyme system widely distributed in the body and is believed to be of primary importance in health and disease. Since the early work with iproniazid, a potent amine oxidase inhibitor, demonstrated that it stimulated the central nervous system, numerous related and unrelated compounds that inhibit this enzyme system have been investigated experimentally and clinically. Results have shown, however, that none of these drugs inhibits amine oxidase selectively. Hence it is unknown whether all clinical effects observed result from this or other pharmacologic actions. Pharmacologic Action The administration of monoamine oxidase inhibitors to experimental animals has been reported to result in increased amounts of serotonin, levarterenol, and related substances within the central nervous system. 1 The excitability which appears in animals is thought by some investigators to simulate the antidepressant action of these compounds in human patients. The drugs have also been reported to produce a