Editorial: New look at monoamine oxidase inhibitors.
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Adult↗
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Monoamine oxidases A and B are differentially regulated by glucocorticoids and "aging" in human skin fibroblasts.
Two forms of monoamine oxidase (MAO A and MAO B) exist which, although similar in a number of properties, can be distinguished on the basis of their substrate specificity, inhibitor sensitivity, kinetic parameters, and protein structure. These properties were used to study the molecular mechanism(s) by which glucocorticoid hormones and "aging," known to alter MAO activity in vivo, regulated the expression of MAO A and MAO B in cultured human skin fibroblasts. The addition of dexamethasone or hydrocortisone to cultures resulted in a dose- and time-dependent increase in total MAO activity, whereas the removal of hormone from cultures resulted in a time-dependent decrease in activity toward control levels. The response to dexamethasone was affected by culture conditions such as serum concentration, feeding frequency, and cellular "age." Cellular aging, in the absence of hormone, also resulted in increased levels of total MAO activity. The effects of hormones and aging on total MAO activity appeared to be selective for MAO A. The 6- to 14-fold increases in total activity were paralleled by similar increases in the activity and amount of active MAO A but less than 2- to 3-fold increases in the activity and amount of MAO B. Altered synthesis or degradation of the active enzyme appeared to account for the effects of hormones, aging, and various culture conditions on MAO activity. Inhibitor sensitivity, substrate affinity, electrophoretic mobility, and molecular turnover number of either form of the enzyme were not altered during dexamethasone treatment or during cellular aging. However, rates of active MAO synthesis were affected by hormone treatment and feeding frequency, rates of active MAO degradation by serum concentration, and rates of active MAO synthesis or degradation by aging. In summary, we have shown that glucocorticoids and cellular aging selectively affect the amount of MAO A at the level of active enzyme synthesis or degradation. Further, our finding that the expression of the two forms of MAO in human fibroblasts can be independently regulated supports the growing evidence that MAO A and MAO B are separate molecular entities.
Adult↗
Selectivity of 4-methoxyphenethylamine derivatives as inhibitors of monoamine oxidase.
It has been established that the oxidative deamination of tyramine by monoamine xodase is inhibited by (+/-)-4-methoxy-beta-hydroxyphenethylamine and its N-methylated derivatives. This particular series of compounds does not inhibit the action of monoamine oxidase when tryptamine is used as the substrate. In contrast, 4-methoxyphenethylamine and its N-methylated homologs inhibit the monoamine oxidase-catalyzed deamination of both tyramine and tryptamine.
Animals↗
Direct measurement of monoamine oxidase inhibition in humans.
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Humans↗
cDNA cloning of two splice variants of a human copper-containing monoamine oxidase pseudogene containing a dimeric Alu repeat sequence.
Two alternatively spliced transcripts, psiHLAO1 and psiHLAO2, of a copper-containing monoamine oxidase pseudogene have been isolated from a human-liver cDNA library. The larger psiHLAO1 cDNA (2073bp) contains a 5'-flanking segment of 134bp, followed by an apparent open reading frame (ORF) of 1725bp. The deduced amino acid sequence of this ORF (574 residues) shares 81.0% similarity with the 763-residue monoamine oxidase from human placenta (HPAO) (the N-terminal 533 residues of psiHLAO1 share 86.7% similarity with HPAO). The psiHLAO1 ORF is interrupted by an in-frame stop codon corresponding to amino acid 225 and terminates within a type S(a) dimeric Alu repeat sequence. psiHLAO2 appears to be an alternatively spliced variant of psiHLAO1 that has 413 bases of psiHLAO1 excised according to the 'GT-AG' rule. The slightly longer 3' end of the psiHLAO2 transcript shows that the Alu repeat is followed by an 11-bp poly(A) tract that, in turn, is followed by an AT-rich (81%) sequence of 105bp. A reverse transcriptase-polymerase chain reaction (RT-PCR) protocol was used to confirm that both psiHLAO1 and psiHLAO2 are transcribed in human liver and placenta. A search of the expressed sequence tag (EST) database indicates that, like HPAO, psiHLAO derives also from the region 17q21 of the human genome.
Alternative Splicing↗
On the reported inhibition of monoamine oxidase by an agent with sedative properties.
1-Benzyl-2-methyl-5-methoxytryptamine has been reported, on the basis of indirect evidence, to inhibit monoamine oxidase. More direct experiments, however, demonstrate that the drug is devoid of the ability to block monoamine oxidase in brain in vitro or in vivo.
Brain↗
Identification of A and B forms of monoamine oxidase in the iris-ciliary body, superior cervical ganglion, and pineal gland of albino rabbits.
The properties of monoamine oxidase activity in homogenates of the iris-ciliary body, superior cervical ganglion, and pineal gland of albino rabbits have been studied. Inhibition curves using specific inhibitors support the concept of A and B enzyme forms, with the following ratios of A/B activity: iris-ciliary body, 40/60; superior cervical ganglion, 90/10; pineal gland, 13/87. Experiments on enzymes from animals with superior cervical ganglionectomy indicate that both A and B forms in the iris-ciliary body have a predominantly extraneuronal location. No significant differences in activity were observed between iris-ciliary body preparations from normal and denervated animals with substrates specific for A or B forms, or with substrates deaminated by both A and B forms. With tryptamine as substrate the iris enzyme can be inhibited by a variety of common monoamine oxidase inhibitors. Topical application of the inhibitor pargyline lowers intraocular pressure in the normal rabbit eye but not in the sympathetically denervated eye. This observation and in vitro data suggest that the mechanism of action of pargyline is through the adrenergic system and not dependent upon intrinsic activity.
Animals↗
Monoamine oxidase and the enzymes of ethanol metabolism in rats after administration of tetrahydroisoquinolines.
A mixture of tetrahydroisoquinolines, synthesized by the method of Osswald et al. (1975), was injected intraperitoneally at a dose of 2 mg/kg into rats. After 3 hours, the activity of ethanol-metabolizing enzymes (alcohol dehydrogenase and the microsomal ethanol oxidizing system) and acetaldehyde-metabolizing enzymes (NAD- and NADP-dependent aldehyde dehydrogenases) in liver sub-cellular fractions, as well as the activity of monoamine oxidase with noradrenaline, tyyramine, benzylamine and serotonin as substrates, were investigated in various brain areas. There was observed a decrease in the activity of the microsomal ethanol-oxidizing system and the NAD-dependent mitochondrial aldehyde dehydrogenase with low Km for acetaldehyde, the activity of the other enzymes investigated being invariable. The inhibition of the activity of monoamine oxidase with noradrenaline as a substrate was revealed in the caudate nucleus, cerebellum, truncus cerebri, and cerebral cortex, while only in the cerebral cortex was there revealed an inhibition of monoamine oxidase with the other substrates. The data obtained indicate that tetrahydroisoquinoline alkaloids not only disturb biogenic amine metabolism, but also affect ethanol and acetaldehyde metabolism in animals.
Alcohol Oxidoreductases↗
Escherichia coli K-12 copper-containing monoamine oxidase: investigation of the copper binding ligands by site-directed mutagenesis, elemental analysis and topa quinone formation.
Copper-containing monoamine oxidase (EC 1.4.3.6) from Escherichia coli is a periplasmic enzyme containing topa quinone in addition to divalent copper as a cofactor. The amino acid sequence of E. coli monoamine oxidase was compared to several cloned amine oxidase genes and five well-conserved histidine residues were found. Site-directed mutagenesis studies were performed to determine which histidine residue serves as the binding ligand to the copper. Enzyme activity, absorption spectrum, and atomic absorption spectrophotometry of the mutant enzymes indicated that histidines 470, 554, and 556 are the copper binding ligands. The absorption spectra of phenylhydrazine derivatives suggested that copper is necessary for topa quinone formation.
Amino Acid Sequence↗
Relationship between monoamine oxidase (MAO) A specific activity and proportion of human skin fibroblasts which express the enzyme in culture.
Total deficiency of monoamine oxidase A (MAO-A) in affected males of a single, human kindred appears to be associated with mild mental retardation and significant behavioral anomalies. Though total MAO-A deficiency appears to be rare, the extent and significance of individual variation in monoamine oxidase A activity in human populations is unclear. Since MAO-A activity is undetectable in blood cells, most systematic surveys of individual variation MAO-A activity have compared enzyme activity in human fibroblasts cultured from skin biopsies. Surprisingly, MAO-A activity in skin fibroblast cultures from unrelated donors ranges over 100-fold. It has been suggested that this extreme variation in fibroblast MAO-A activity between donors reflects individual, genetic variation in the regulation of MAO-A in fibroblasts. I have found from studies with immunofluorescence microscopy and flow cytometry that the proportion of MAO-A+ cells in fibroblast cultures is (a) highly variable between cultures, (b) a reproducible characteristic of each culture and (c) the primary factor responsible for variation in MAO-A specific activity in whole cell, skin fibroblast homogenates. It has been shown previously that MAO-A activity of a skin fibroblast culture is relatively constant with continued passage prior to cellular senescence. Therefore, these new data raise the possibility that MAO-A expression is confined to a functionally distinct subset of human skin fibroblasts.
Cells, Cultured↗
(R)(+)-N-propargyl-1-aminoindan (rasagiline) and derivatives: highly selective and potent inhibitors of monoamine oxidase B.
(+)-N-Propargyl-1-aminoindan (rasagiline) and a series of derivatives have been synthesized and screened for monoamine oxidase inhibitory activity. Rasagiline and several analogues were found be highly selective and potent inhibitors of the B form of the enzyme in contrast to the levorotatory enantiomer which was not active. The results indicate that rasagiline has potential for the treatment of Parkinson's Disease. This compound is currently under development for that indication.
Animals↗
The therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, in Parkinson's disease.
In this open study, the therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, was tested in 20 patients with Parkinson's disease who developed levodopa-induced motor response complications. Moclobemide as adjunct therapy reduced "off" time duration for 27%, without an overall motor and functional improvement during their "on" periods. Since it was well tolerated, moclobemide may be specially indicated in elderly or depressed fluctuating parkinsonian patients.
Antiparkinson Agents↗
Monoamine oxidase in bovine thyroid tissue.
Two functional forms of monoamine oxidase (MAO) defined as MAO A and MAO B have been described in several tissues. In this study the characteristics of MAO present in a particulate subcellular fraction of bovine thyroid tissue were investigated. The selective inhibitors of MAO, clorgyline (A form) and deprenyl (B form) were used. The monoamines 5-hydroxytryptamine (5-HT) (preferred of the A form), tyramine (both forms) and beta-phenylethylamine (PEA) (B Form) were used as substrates. MAO activity towards 5-HT was markedly inhibited by clorgyline. Tyramine oxidation was very sensitive to clorgyline and the curve obtained was in accordance with the presence of a high proportion of the A form. MAO activity towards PEA was also markedly inhibited by clorgyline. Deprenyl was not able to induce modifications in the MAO activity except when it was used at very high concentrations. According to these results the bovine thyroid tissue contains predominantly the A form of MAO. In this tissue PEA was deaminated by the A form of the enzyme.
Animals↗
Regional cerebral cortical activation in monoamine oxidase A-deficient mice: differential effects of chronic versus acute elevations in serotonin and norepinephrine.
Mice deficient in monoamine oxidase A have previously been shown to demonstrate a chronic elevation of serotonin and norepinephrine in the brain. Using the autoradiographic [14C]iodo-antipyrine method, we examined cerebral cortical blood flow in conscious, restrained four- to five-month-old knock-out and wild-type animals following the intraperitoneal administration of either saline or D-fenfluramine. Knock-out animals administered saline, compared to their wild-type counterparts, demonstrated a significantly higher regional cortical blood flow in somatosensory and barrel field neocortex, an area which previous histological studies have shown to be characterized by abnormal serotonergic projection fibers and absent barrel formation. Regional cortical blood flow was significantly lower in knock-out than in wild-type mice in the entorhinal and midline motor cortex, with non-significant decreases noted in the olfactory, piriform and retrosplenial cortices and the amygdala. We compared the above findings to those obtained in response to D-fenfluramine which, in conjunction with its metabolite D-norfenfluramine, results in acute elevations of brain levels of serotonin and norepinephrine. Administration of D-fenfluramine (21. 2mg/kg) resulted in changes in regional cortical perfusion in most brain regions of both knock-out and wild-type mice that were opposite to the genotypic differences seen in perfusion in response to saline. Fenfluramine significantly increased regional cortical blood flow in the allocortex (olfactory, piriform, entorhinal) and the amygdala, and significantly decreased regional cortical blood flow in the somatosensory, barrel field, midline motor and retrosplenial cortices. Changes in regional perfusion in response to fenfluramine were topographically equivalent in knock-out and wild-type mice, although in knock-out mice such changes were of greater magnitude. Our study suggests that the effects on regional cortical blood flow of a lifelong absence of monoamine oxidase A, and the consequent chronic increase in serotonin and norepinephrine, differ from those attributable to acute increases in these neurotransmitters following fenfluramine administration. Such a differential response may reflect neurodevelopmental abnormalities and/or effects of a chronic physiological adaptation on the regulation of cortical activation.
Animals↗
Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes.
Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, we demonstrate the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7. The dihydroisoquinolinium ion was shown to react with cyanide and borohydride, but not glutathione. These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity.
Cytochrome P-450 Enzyme System↗
Different sensitivity of mitochondrial and cytosolic monoamine oxidases to in vivo but not in vitro inhibition by specific irreversible inhibitors.
The sensitivity of mitochondrial and cytosolic monoamine oxidase (MAO) activities to inhibition by specific irreversible inhibitors was investigated. There were no significant differences in the sensitivity of MAO A and MAO B activities of these fractions to selective inhibitors. However, in vivo administration of pargyline caused a much more potent inhibition of cytosolic MAO than the mitochondrial enzymes. This suggests that cytosolic MAO activity does not represent an artifact (e.g. a product of proteolytic degradation) appearing after tissue homogenisation. The higher sensitivity of cytosolic MAO to inhibitors also points to different routes for pargyline to inhibit MAO in these subcellular fractions.
Animals↗
[Determination of monoamine oxidase activity in a coupled reaction with alcohol dehydrogenase].
A simple kinetic method is developed for estimation of the monoamine oxidase (MAO) activity in solubilized mitochondria and purified preparations of MAO from rat liver tissue. The method is based on the property of alcohol dehydrogenase (from horse liver tissue) to catalyze the reduction of fatty-aromatic aldehydes (products of the MAO reaction) to appropriate alcohols in presence of NADH2 excess. The rate of the coupled reaction was evaluated spectrophotometrically by a decrease of the optic density at 340 nm. The optimal conditions were ascertained for coupling of these two reactions. Application of several amines was shown to be possible for estimation of the MAO activity by the kinetic method developed.
Alcohol Oxidoreductases↗
Translational neuroimaging: positron emission tomography studies of monoamine oxidase.
Positron emission tomography (PET) using radiotracers with high molecular specificity is an important scientific tool in studies of monoamine oxidase (MAO), an important enzyme in the regulation of the neurotransmitters dopamine, norepinephrine, and serotonin as well as the dietary amine, tyramine. MAO occurs in two different subtypes, MAO A and MAO B, which have different substrate and inhibitor specificity and which are different gene products. The highly variable subtype distribution with different species makes human studies of special value. MAO A and B can be imaged in the human brain and certain peripheral organs using PET and carbon-11 (half-life 20.4 minutes) labeled mechanism-based irreversible inhibitors, clorgyline and L -deprenyl, respectively. In this article we introduce MAO and describe the development of these radiotracers and their translation from preclinical studies to the investigation of variables affecting MAO in the human brain and peripheral organs.
Aging↗