Amine oxidases. XI. Inhibition of monoamine oxidase by 1-isonicotinyl-2-isopropylhydrazine.
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Amines↗
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Switching monoamine oxidase inhibitors.
Substituting one monoamine oxidase inhibitor for another is recommended only after a drug-free interval to avoid hypertensive emergencies. The evidence and mechanism firmly supporting this caution is lacking. We report a case where monoamine oxidase inhibitors were substituted without apparent adverse consequences.
Adult↗
[Modification of mitochondrial monoamine oxidase activity by certain amine inhibitors].
Monoamine oxidase inhibitors /trans-2-phenylcyclopropylamine, pyrazidol, phenharmane/ belonging to the category of primary or secondary amines, in the molecule of which/ after dehydration/ formation of an azomethine bond is possible, modified the activity of membrane bound bovine brain monoamine oxidases inhibiting the deamination of serotonin and, at the same time, causing appearance of or significant increase in cadaverine--or histamine--deaminating properties. This modification was not caused either by primary amines /amphetamine, GABA/ which are not potent monoamine oxidase inhibitors or by the amines possessing strong monoamine oxidase inhibiting properties/pargylline, deprenyl, harmine/ but devoid of the potential property of forming an azomethine bond. In vivo trans-2-phenylcyclopropylamine, pyrazidol or phenharmane /contrary to amphetamine/ did modify the monoamine oxidase activity in brain of mice inducing the deamination of histamine and decreasing its tissue concentration.
Amphetamine↗
[A behavioral and neurochemical study on the mechanism of the anxiolytic effect of monoamine oxidase inhibitors].
The author examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety, induced by conditioned fear stress. The selective serotonin1A receptor agonist inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), Ro 41-1049 (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduces anxiety or fear, while inhibition of monoamine oxidase A or B alone fails to reduce anxiety or fear. In vivo microdialysis studies showed that the irreversible monoamine oxidase A inhibitor clorgyline and the irreversible monoamine oxidase B inhibitor selegiline induced a mild increase and no increase in extracellular serotonin, respectively. Interestingly, the combined treatment with clorgyline and selegiline resulted in much larger increases in extracellular serotonin in the medial prefrontal cortex than did either monoamine oxidase inhibitor alone. Our previous studies have indicated that facilitation of 5-HT neurotransmission decreases conditioned freezing, i.e., anxiety or fear. The results of these in vivo microdialysis studies may account for the results of this study that the simultaneous blockade of both monoamine oxidase A and B reduced conditioned freezing, whereas blockade of either monoamine oxidase alone failed.
Animals↗
Monoamine oxidase A mediates iodotyrosine formation induced by monoamines in bovine thyroid particulate fraction.
Monoamines are able to increase the thyroid iodine organification in vitro. A predominance of the A form of monoamine oxidase (MAO) has been previously demonstrated to exist in bovine thyroid tissue. In the present study we have investigated the form of MAO that could be involved in the iodotyrosine formation induced by tyramine, 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PEA) in a bovine thyroid subcellular fraction. The relative capacity of these monoamines to generate H2O2 and to incorporate iodine into tyrosine has also been studied. The MAO A inhibitor clorgyline (10(-9) M) produced a strong inhibition on the iodotyrosine formation induced by tyramine, 5-HT and PEA. In contrast, only a slight reduction was observed with deprenyl as MAO B inhibitor. Among the three monoamines, tyramine produced the highest H2O2 generation and iodotyrosine formation. The lowest Km value obtained was for 5-HT and the highest for PEA. Regarding the Vmax, the lowest value was for 5-HT and the highest for tyramine. The amount of iodine incorporated to tyrosine was not equivalent to the H2O2 generated by the monoamines nor to that exogenously added. Our results indicate that in bovine thyroid tissue mainly the A form of MAO is involved in the monoamine metabolism.
Animals↗
Some properties of human platelet monoamine oxidase in iron-deficiency anaemia.
1. Monoamine oxidase activity in platelets prepared from the blood of patients with iron-deficiency anaemia was significantly lowered when compared with that in platelets from normal subjects. 2. The Km values of the platelet enzyme for the substrates dopamine, 5-hydroxytryptamine, phenylethylamine and kynuramine were similar for the platelet enzyme from iron-deficient and normal groups. 3. Heat-in-activation studies showed that the platelet monoamine oxidase from iron-deficient subjects was more labile to this treatment, when compared with the platelet enzyme from normal subjects. 4. The sensitivity of platelet monoamine oxidase to the inhibitors, clorgyline and deprenil, was increased in iron-deficiency anaemia. 5. Binding studies with the 14C-binding irreversible monoamine oxidase inhibitor, deprenil, showed that the amount of enzyme capable of binding this inhibitor was lowered by 48% in platelets from iron-deficient patients when compared with platelets from normal subjects. 6. The results show that there is a lowered amount of active enzyme in platelets from iron-deficient subjects. It is suggested that iron is necessary either for the synthesis of monoamine oxidase apoenzyme or is a cofactor for an enzyme which attaches flavin-adenine dinucleotide covalently to the monoamine oxidase apoenzyme.
Adult↗
Assay of platelet monoamine oxidase in whole blood.
Monoamine oxidase (MAO; EC 1.4.3.4.) was measured in whole blood with kynuramine as the substrate. Optimal circumstances were determined. By use of selective inhibitors, gradient centrifugation, dilution of samples and removal of thrombocytes from whole blood it was shown that this assay of MAO in whole blood is in fact a determination of platelet MAO. No reversible endogenous inhibitors are present in the blood. Because preparation of platelet-rich plasma may lead to considerable losses of specific subpopulations with relatively low or high enzyme activities, the advantage of using whole blood is that the MAO activity is determined in the whole platelet population.
Blood Platelets↗
Selective inhibitors of monoamine oxidase. 2. Arylamide SAR.
Monoamine oxidase (MAO) exists in two forms distinguishable by substrate specificity. Inhibition of MAO A is believed to be responsible for the antidepressant activity of MAO inhibitors. A group of N-arylacetamides are highly specific inhibitors of MAO A, some with IC50 values in the 10-100 nM range. The requirements for high activity and specificity include a nearly linear tricyclic aromatic portion but a larger and a smaller central ring component. The amide group, which is best acetamido, is optimally placed para to the smaller central group. The size and shape of the aromatic moiety appear to be the major influence on activity and specificity for MAO A.
Acetamides↗
Gonadal influences on the inhibition of monoamine oxidase type B activity.
Monoamine oxidase type B (MAO-B) was similarly active in the hypothalamus of 60-day-old male and female Charles River rats. A single, 2 mg/kg IP injection of deprenyl, however, resulted in a significantly greater inhibition of hypothalamic MAO-B in normal males than in normal females. Repeated administration of estrogen (estradiol valerate) to intact males postnatally, a treatment which disrupts the masculinization process, although not provoking true "feminization," decreased the inhibition of MAO-B, thus abolishing the sex-specific difference. The intensity of deprenyl-provoked hypothermia and ptosis in males exceeded that of females; neonatal and postnatal estrogenization of males resulted in diminution of these effects. Androgen administration to neonate females did little affect the biochemical and in vivo parameters of MAO inhibition. It is concluded that sex-specific, biochemical differences in MAO-B inhibition may have pharmacological correlates, and both facets of MAO inhibition are sensitive to neonatal exposure to estrogen.
Animals↗
Developmental changes in the activity and substrate specificities of mouse brain monoamine oxidase.
Developmental changes in monoamine oxidase (MAO) activity in the mouse brain were investigated with the substrates beta-phenylethylamine (PEA), tryptamine, and 5-hydroxytryptamine (5-HT). In the newborn brain, MAO activity towards PEA was found to be much lower than the adult and to be inhibited by clorgyline in a double-sigmoidal fashion. The inhibition curve shifted to a single-sigmoidal pattern with age. MAO activity towards 5-HT as substrate was inhibited by 90% and in a single-sigmoidal manner by clorgyline throughout the postnatal life. Lineweaver-Burk plots with PEA as substrate presented two linear lines (apparent Km: 28.6 and 4.1 microM) for the newborn and one line (apparent Km: 11.4 microM) for the adult, respectively. The plot with high Km value for the newborn brain disappeared in a clorgyline-treated preparation. These findings suggest that age-dependent alterations in the ratio of MAO-A/MAO-B activity affect the substrate specificity of the enzyme.
Animals↗
[Properties of intestinal monoamine oxidase in the rat].
Monoamine oxidase (MAO) activity (substrate: tyramine) has been studied in rat intestinal wall mitochondrial fractions identified by monitoring succinate dehydrogenase and cytochrome oxidase activities. The MAO activity, which was not due to contamination with mitochondria, has been also found in nuclear and microsomal (+hyaloplasm) fractions. Deamination of tyramine, serotonin and dopamine by rat intestinal mitochondrial MOA obeyed the Michaelis--Mentern kinetics. The Vmax values were the highest for deamination of tyramine, the lowest--for norepinephrine. The lowest Km value was recorded in the systems with 2-phenylethylamine. Data on the inhibitory effect of low concentrations of deprenyl suggest that 50% of the total tyramine deaminating activity in rat intestinal mitochondria was due to presence of MAO type B. Low concentrations of chlorgyline inhibited the deamination of tyramine in these systems by 20-30% suggesting a possibility of presence in the rat intestinal mitochondria of a tyramine deaminating activity distinct from MAO type A. Pyrazidol or harmine, which are selective inhibitors of the MAO type A, caused only partial (30-40%) inhibition of MAO activity (substrate: tyramine) in rat intestinal mitochondria. Controlled heating experiments indicated higher thermostability of MAO type B (substrate: 2-phenylethylamine) as compared with MAO type A (substrate: serotonin) in rat intestinal mitochondria. The data obtained suggest that rat intestinal mitochondria, contrary to human intestinal mucosa (cf. ref. 2), contain about 50% of MAO type B, which is comparatively thermostable and does not resemble in this respect the MAO type B in many other biological sources.
Animals↗
Orientation of oxazolidinones in the active site of monoamine oxidase.
Oxazolidinone inhibitors of monoamine oxidase (MAO) and oxazolidinone antibacterials are two distinct classes of drug, often with linear structures and overlapping activities for some derivatives. By synthesizing novel dimerised derivatives with identical substitution of the two C-5 side chains, we have obtained experimental evidence for the orientation of oxazolidinones in the active site of MAO A. Two types of spectral changes, either increasing the absorbance at 510 nm or decreasing it at 495 nm depending on the group nearest to the flavin cofactor, were seen on ligand binding to MAO A. Side chain derivatives with amine substituents are very poor substrates so that it was possible to examine the spectral change due to binding of a substrate before reduction of the flavin occurred. Binding of these amino derivative substrates to MAO A induced a spectral change characterized by a strong decrease in absorbance at 495 nm. These substrates reduced the enzyme fully without any trace of a semiquinone intermediate. Only oxazolidinone inhibitors with a bromo-imidazole substituent increased the yield of semiquinone intermediate obtained during chemical reduction. In accord with the experimental data, results of docking experiments showed that binding of the oxazolidinone ring in the aromatic cage close to the flavin was favored and that the nitrogen of the derivatives that were substrates was within van der Waals distance of N-5 of the flavin.
Binding Sites↗
Monoamine oxidase activities towards biogenic monoamines in several regions of rat brain.
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Animals↗
On the functions of monoamine oxidase, the emotions, and adaptation to stress.
Monoamine oxidase is an iron containing enzyme that exists as 2 isozymes, A and B, that have different affinities for various amines as substrates. The activity of monoamine oxidase helps to maintain neuron firing rates throughout the body within homeostatic limits. It does this by metabolizing in the liver bioactive amines absorbed into the bloodstream from food, by metabolizing in the endothelial cells of cerebral vascular microvessels, as part of the blood brain barrier, bioactive amines in the bloodstream, and by metabolizing in the cytoplasm of neurons, molecules of biogenic amine neurotransmitters that are not enclosed in vesicles. Part of the biochemical activity of monoamine oxidase generates hydroxyl radicals, very toxic members of the oxygen free radical group, that may be involved in neurodegenerative disorders such as Parkinson's disease. Inhibiting monoamine oxidase with selegiline (1-deprenyl) seems to have neuroprotective actions but this may be due to inducing the release of neuronal growth factors rather than by preventing the formation of free radicals. Other drugs that inhibit monoamine oxidase are used to treat patients with atypical depression, panic attacks or post traumatic stress syndrome. It is hypothesized that the emotions act as positive or negative reinforcers of behavior patterns that increase the probability of survival of the organism. The original releasing stimuli for the emotions are related to the basic survival reflexes of the hypothalamus but the emotional response can be easily conditioned to formerly neutral stimuli by association. In the absence of the original releasing stimuli, these learned emotions increase the frequency of survival oriented behavior and decrease the frequency of behavior that jeopardizes survival. The emotional disorders are conditions in which the brain's reinforcement system is inoperative, the person loses contact with reality and the person's behavior bears no relationship to survival. Aversive stimulation evokes a negative emotional response that motivates the organism to escape from the aversive stimulation, and to avoid it, and any conditioned stimuli associated it, in the future. When the aversive stimulation and to avoid it, and any conditioned stimuli When the aversive stimulation is inescapable or unavoidable, the organism experiences stress. When the stressful aversive situation is not lethal, survival does not depend on escape but rather on conservation of energy. With repeated exposure, the negative emotional response to the aversive stimulation extinguishes, the organism adapts to the situation and takes on a passive, energy saving behavior pattern.(ABSTRACT TRUNCATED AT 400 WORDS)
Adaptation, Psychological↗
Inhibition of rat fat cell lipolysis by monoamine oxidase and semicarbazide-sensitive amine oxidase substrates.
It has been demonstrated that amine oxidase substrates stimulate glucose transport in cardiomyocytes and adipocytes, promote adipogenesis in pre-adipose cell lines and lower blood glucose in diabetic rats. These insulin-like effects are dependent on amine oxidation by semicarbazide-sensitive amine oxidase or by monoamine oxidase. The present study aimed to investigate whether amine oxidase substrates also exhibit another insulin-like property, the inhibition of lipolysis. We therefore tested the influence of tyramine and benzylamine on lipolytic activity in rat adipocytes. These amines did not modify basal lipolysis but dose-dependently counteracted the stimulation induced by lipolytic agents. The response to 10 nM isoprenaline was totally inhibited by tyramine 1 mM. The blockade produced by inhibition of amine oxidase activity or by 1 mM glutathione suggested that the generation of oxidative species, which occurs during amine oxidation, was involved in tyramine antilipolytic effect. Among the products resulting from amine oxidation, only hydrogen peroxide was antilipolytic in a manner that was potentiated by vanadate, as for tyramine or benzylamine. Antilipolytic responses to tyramine and to insulin were sensitive to wortmannin. These data suggest that inhibition of lipolysis is a novel insulin-like effect of amine oxidase substrates which is mediated by hydrogen peroxide generated during amine oxidation.
Adipocytes↗
Kinetic mechanism of monoamine oxidase A.
Steady-state kinetic data for monoamine oxidase A in crude extracts suggest an exclusively ping-pong mechanism, in contrast to those for monoamine oxidase B, which indicate alternate mechanisms involving either a binary or ternary complex. In this study, with use of purified monoamine oxidase A, steady-state data for the inhibition by D-amphetamine of the oxidation of primary amines indicate the possibility of a ternary complex mechanism for monoamine oxidase A also. Stopped-flow studies demonstrate that the rate of reoxidation of reduced enzyme is enhanced by substrates but not by the product, 1-methyl-4-phenylpyridinium. Thus, for the A enzyme, the ternary complex with substrate, but not product, is reoxidized at a faster rate than the free, reduced enzyme. For both the A and B forms of monoamine oxidase, the mechanism is determined by competition between alternate pathways on the basis of the relative rate constants and dissociation constants.
1-Methyl-4-phenylpyridinium↗
Monoamine oxidase inhibitor toxicity.
Monoamine oxidase inhibitor (MAOI) drugs are used in the treatment of depressive and anxiety disorders in adults. MAOIs are also used in high doses for the treatment of lymphomas and of central nervous system (CNS) tumors in children. Toxic effects resulted when procarbazine, a drug of this class, was used in treating a child with a CNS tumor. Psychotic reaction in the child may have been triggered by any of several factors, but arguments are for an organic cause. The implication of the MAOI procarbazine must be seriously considered. The case highlights potential serious problems associated with MAOIs and the interaction of this agent with other drugs.
Brain Neoplasms↗
Ubiquitin is involved in the in vitro insertion of monoamine oxidase B into mitochondrial outer membranes.
Monoamine oxidase B that has been synthesized by a reticulocyte lysate charged with bovine liver RNA will insert in a proteinase K-resistant form into isolated outer membranes from rat liver mitochondria. It appears that ubiquitin, a 76-amino acid polypeptide which is enzymatically conjugated to proteins, may be involved in the insertion process. Depletion of endogenous ubiquitin from the reticulocyte lysate with purified antibodies against this polypeptide inhibits the insertion of monoamine oxidase B, and this inhibition is relieved if ubiquitin is restored. On the other hand, a mutant form of ubiquitin which is unable to conjugate with proteins will not support insertion. Conjugation with ubiquitin is an ATP-dependent process. Not only does enzymatic depletion of ATP from the lysate prevent the insertion of monoamine oxidase, but ubiquitin will not restore insertion unless ATP is also present. These data indicate that the formation of a ubiquitin conjugate is involved in the insertion of newly synthesized monoamine oxidase B into the outer membranes.
Adenosine Triphosphate↗