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PubMed1984

Characteristics of mitochondrial and synaptosomal monoamine oxidase in monkey brain.

Enzymic properties of monoamine oxidase (MAO) from monkey brain were studied. High MAO activity was observed in the mesencephalon and dienecephalon of the brain. Highest activity in every region of the brain was found with tyramine as a substrate. Monkey brain mitochondrial MAO showed a different substrate specificity and different Km and Vmax values than the enzyme from mice, rats, guinea pigs and rabbits. The pH activity curves were all bell-shaped, but the pH optima were remarkably different with the various substrates used. The activities of various substrates at pH 7.2 were compared with those at the pH optimum. At the pH optima, the activity was about 1.2-fold higher with tyramine and dopamine, 2-fold higher with beta-phenylethylamine (beta-PEA) and 3-fold higher with serotonin (5-HT) and benzylamine. These results were almost similar when synaptosomes from monkey brain were used. MAO activities with 5-HT and beta-PEA were strongly inhibited by much lower concentrations of clorgyline and deprenyl, respectively. Plateau-shaped inhibition curves by these inhibitors were obtained with tyramine as the substrate. These results indicate that both the A- and B-form of MAO appear to be uniformly distributed in monkey brain, and the A-form of MAO represents approximately 35% and 50% of the total MAO activity in mitochondria and synaptosomes, respectively.

Animals↗
PubMed1996

Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide.

Irreversible, nonselective monoamine oxidase (MAO) inhibitors have been reported adversely to interact with indirectly acting sympathomimetic amines present in many cough and cold medicines. This study investigated the safety and tolerability of concomitant administration to 12 healthy subjects of both genders (aged 19-36 years) of ephedrine and moclobemide, a reversible MAO-A inhibitor. A 2-day, randomized, crossover administration of placebo or ephedrine (two doses of 50 mg with a 4-h interval) was followed by 9 days open-label dosing with moclobemide, 300 mg b.i.d.. On the last 2 days of moclobemide dosing, the randomized crossover treatment of ephedrine and placebo was repeated. No subject was withdrawn from the study for tolerability reasons. Moclobemide treatment, however, increased the incidence of adverse events elicited by ephedrine, particularly palpitations and headache. The pharmacodynamic interaction between the two drugs was quantified by calculation of the area under the effect-time course (AUE) for systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR). The difference in AUE between monotreatment with ephedrine and placebo was statistically significant for all three vital signs. Moclobemide potentiated the effect of ephedrine by a median factor of 3.2 for SBP, 3.8 for DBP, and 0.6 for HR. Ephedrine had no significant influence on the plasma concentrations of moclobemide or its metabolites. In conclusion, the combined use of moclobemide and high doses of sympathomimetic drugs should be approached with caution.

Adrenergic Agents↗
PubMed2001

A bootstrapped commingling analysis of platelet monoamine oxidase activity levels corrected for cigarette smoking.

Monoamine oxidase (MAO) activity levels have been suggested as a possible biological marker for alcohol dependence and abuse, as well as for schizophrenia and other psychiatric conditions. Using platelet MAO activities in the Collaborative Study on the Genetics of Alcoholism data set, we applied bootstrapping methods as a novel way to test for admixture in families. This bootstrapping involved resampling in family units and hypothesis testing of the resampled datasets for commingling in the distribution of MAO activity levels. Prior to commingling analysis, we used linear models to find covariates of greatest effect on MAO activity levels. While an alcoholism diagnosis was significant in men (n = 1151, P < 0.0001) and women (n = 1254, P = 0.0003), the effect lost significance after controlling for cigarette smoking, indicating alcoholism and smoking behavior to be highly confounded. When smoking histories were compared, former smokers had levels (mean = 7.1) closer to those who never smoked (mean = 7.0) than to current smokers (mean = 5.4). Furthermore, current daily smoking and time since smoking cessation were significantly related to MAO levels, indicating smoking probably has a direct effect on MAO levels, rather than the reverse. These results suggest that studies using MAO levels as a biological marker should consider smoking as an important covariate. Finally, admixture was found in MAO levels controlled for smoking and sex, possibly indicating a major genetic locus; this confirms previous evidence for admixture.

Biomarkers↗
PubMed1994

Risk-benefit assessment of newer versus older monoamine oxidase (MAO) inhibitors.

The first generation of monoamine oxidase (MAO) inhibitors fell into disuse because of poor efficacy in major depression with melancholia and/or endogenous depression, and because of poor tolerability (drug interactions and the 'cheese' effect). New MAO inhibitors, reversible inhibitors of MAO-A (RIMAs), are able to induce a reversible and specific inhibition of MAO-A. Consequently, the inhibition of MAO is quicker and the dose-response relationship improved, such that dosage adjustment is easier. Also, no carry-over effect once treatment is terminated is observed. The frequency and severity of drug interactions with RIMAs is reduced, although coadministration with pethidine (meperidine) or dextromethorphan should still be avoided. No specific subgroup of patients with depression has shown a better or worse response to RIMAs. The presence of melancholia in major depression, or the existence of endogenous depression, are not predictive of reduced efficacy compared with tricyclic antidepressant (TCA) reference compounds. Dysthymic patients have shown a good response to both RIMAs and TCAs independent of the co-existence of a major depressive episode. Older MAO inhibitors are more effective than TCAs in the treatment of atypical depression, and further studies are needed to confirm if this is true for RIMAs. Long term studies to evaluate the effects of RIMAs on disease recurrence are also required. RIMAs are better tolerated than older MAO inhibitors, including use in subgroups particularly at risk of adverse effects such as the elderly. Overall, RIMAs appear to represent therapeutic progress in the treatment of depression in terms of both efficacy and tolerability.

Depression↗
PubMed1987

Monoamine oxidase in rat and bovine endocrine tissues.

Monoamine oxidase (MAO) was characterized in tissue homogenates from rat pancreatic islets, rat neurohypophysis and adenohypophysis, and rat and bovine adrenal medulla and adrenal cortex. Phenylethylamine was preferentially deaminated by rat pancreatic islet and bovine adrenal medulla MAO and with slight preference by rat neurohypophysis MAO, whereas 5-hydroxytryptamine was preferentially deaminated by MAO from all other endocrine tissues. Tyramine was a good substrate for all tissues. Clorgyline, a selective inhibitor of MAO-A, preferentially inhibited deamination of 5-hydroxytryptamine by all tissue homogenates, whereas deprenyl, a selective inhibitor of MAO-B, preferentially inhibited deamination of phenylethylamine. Km values for 5-hydroxytryptamine and tyramine were higher by one to two decimal powers than for phenylethylamine in homogenates from all endocrine tissues. Km values were significantly lower for 5-hydroxytryptamine and significantly higher for phenylethylamine in rat and bovine adrenal cortex than in adrenal medulla. According to these results, the contributions of MAO-B to total enzyme activity were 70% for rat pancreatic islets, 45% for rat neurohypophysis, 15% for rat adenohypophysis, 20% for rat adrenal medulla, 10% for rat adrenal cortex, 60% for bovine adrenal medulla, and 20% for bovine adrenal cortex. PC 12 cells also contained predominantly MAO-A (90%); however, an increased Km for phenylethylamine and a sensitivity of deamination of this MAO-B substrate to inhibition by clorgyline are indicators of abnormal behavior of MAO in this clonal rat pheochromocytoma cell line.

Adrenal Cortex↗
PubMed1996

Inactivation of cytochrome P4502B1 by the monoamine oxidase inhibitors R-(-)-deprenyl and clorgyline.

The monoamine oxidase inhibitors R-(-)-deprenyl (deprenyl) and clorgyline inactivated the 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity of purified cytochrome P4502B1 (P4502B1) in a reconstituted system containing P4502B1, NADPH-cytochrome P450 oxidoreductase, and L-alpha-phosphatidylcholine dilauroyl as the lipid. The inactivation was time- and concentration-dependent. The inactivation required NADPH, demonstrated saturation kinetics, and no lag time for inactivation was observed. The inactivation was not affected by the presence of an excess exogenous nucleophile, such as glutathione. Deprenyl exhibited a KI (concentration of inactivator required for half-maximal inactivation) of 1.05 microM, and clorgyline had a KI of 1.5 microM. The maximum rate of inactivation of the enzyme at saturating levels of inactivator (kinactivation) was 0.23 min-1 for deprenyl and 0.28 min-1 for clorgyline. The partition ratio for deprenyl and clorgyline was between 2 and 3. Studies on the isozyme specificity of these compounds in microsomes from rats pretreated with specific inducers demonstrate that the inactivation was relatively specific for the major phenobarbital-inducible isozyme, P4502B1, because significant inactivation of P4501A1 and P4502E1 was not observed. When the purified P4502B1 in the reconstituted system was incubated with either inactivator in the presence of NADPH, there was approximately a 60-70% loss in spectrally detectable P450 over 5 min at a 1:21 ratio of P450 to inactivator. However, at this ratio of enzyme to inactivator, there was > 90% loss of the O-deethylase activity. This loss in enzyme activity was irreversible, and the protein did not regain activity after dialysis or extensive washing to remove excess inactivator.

Animals↗
PubMed1995

Characterization of a dinucleotide-binding site in monoamine oxidase B by site-directed mutagenesis.

Monoamine oxidase B (MAO B), an integral protein of the outer mitochondrial membrane, catalyzes the oxidative deamination of neuroactive and vasoactive amines. The oxidation step is coupled to the reduction of an obligatory FAD cofactor. In this study, we have examined the role of one amino acid (Glu34) in human MAO B that is thought to play a crucial role in binding to the 2'-hydroxy group of ribose in the AMP moiety of FAD. Glu34 is located within a region of the MAO B molecule of high sequence identity to the dinucleotide-binding site in other flavoproteins. In MAO B, this region is postulated to consist of a beta 1-sheet-alpha-helix-beta 2-sheet motif which culminates with a Glu at the C-terminal end of the second beta-sheet. We used site-directed mutagenesis to convert Glu at position 34 to Asp, Gln, and Ala. The wild-type and mutant cDNAs were then transiently transfected into COS-7 cells and assayed for MAO B activity. All three variants exhibited a dramatic decrease in the enzymatic activity as compared to wild-type MAO B, and only the Asp variant retained any detectable activity. Our studies indicate that the Glu34 residue in human MAO B is essential for catalysis. Whether Glu34 is responsible only for alignment of the FAD for participation in the oxidation/reduction cycle or also for the initial binding of FAD to the apoenzyme remains to be determined.

Amino Acid Sequence↗
PubMedDate not supplied

[Monoamine oxidase inhibitors and pressor response to dietary amines].

Because gastro-intestinal monoamine oxidase (MAO) effectively prevents dietary pressor amines, typically tyramine, from entering the tissues, a marked hypertensive response (the "cheese reaction") can occur when subjects treated with antidepressant MAO inhibitors ingest foods or beverages rich in such amines. Although tyramine is a substrate for both MAO-A and -B, it is only inhibitors of the former enzyme, which are also the effective antidepressants, that give rise to the cheese reaction. This has be shown to be owing to MAO-A being the major form of MAO in intestine and stomach. Selective inhibition of that form of the enzyme results in substantial amounts of unchanged tyramine passing through the intestine. The development of reversible inhibitors of monoamine oxidase-A (RIMAs) has reduced this hypertensive response since rising tyramine concentrations can displace the inhibitor from the enzyme and thus allow some metabolism to occur. This has led to the development of MAO-inhibitory antidepressants that may, apparently, be used without dietary restriction. However, reversibility of the inhibitory process is not sufficient and the analysis of inhibitory behaviour presented here indicates that such safety will only be obtained with inhibitors that are competitive with respect to the amine substrates. Noncompetitive inhibitors might be expected to offer no safety advantage in this respect, whereas uncompetitive could actually exacerbate the pressor response.

Blood Pressure↗
PubMed1982

The activity of monoamine oxidases A and B in gamma-irradiated rabbit brains.

The activities of monoamine oxidases A and B towards 5-hydroxytryptamine and beta-phenethylamine, respectively, were compared in the left and right caudatus, hippocampus, parietal cortex, cerebellum and frontal cortex 6 months after gamma-irradiation (single dose of 23 Gy) of either the right hemisphere or of the whole rabbit brain (in which case, a dose of l6 Gy). No difference in monoamine oxidase A or B activities were found in any of the brain regions.

Animals↗
PubMed1982

Effect of dietary trans fatty acids on cholinesterase and monoamine oxidase activities in different organs of rats.

The effect of trans fatty acids and essential fatty acid deficiency upon the activities of cholinesterase and monoamine oxidase in livers, hearts, brains and lungs of rats was studied. This study was performed using three groups of male albino rats. Two out of these three groups were fed essential fatty acid low diets containing 10% hydrogenated coconut oil (HCNO) or margarine stock (MS, partially hydrogenated soybean oil) while the third group was fed an adequate supply of essential fatty acids through a diet containing 10% corn oil (CO). In the group of rats fed HCNO the activities of cholinesterase and monoamine oxidase in their livers, hearts, brains and lungs were not significantly different from those of the control group fed CO. In the group of rats fed MS, the activity of cholinesterase was significantly decreased in the livers, hearts and brains, but not affected in the lungs, while the activity of monoamine oxidase was significantly decreased in the livers and hearts but not affected in the brains and lungs as compared to the control group fed CO. The levels of serum total lipids, total cholesterol and triglycerides were elevated in both groups of rats fed HCNO or MS than in the group fed CO, but this elevation was more highly significant in the group fed MS than in the group fed HCNO.

Animals↗
PubMed1985

Photoinactivation of B-type monoamine oxidase by a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine metabolite.

The reaction of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with monoamine oxidase from a variety of tissues including rat and monkey brain, bovine liver, and human placenta and platelets was found to yield, as a primary product, a reactive photosensitive substance with an absorbance maximum at 345 nm which is not the cation 1-methyl-4-phenylpyridinium ion previously reported as a monoamine oxidase-MPTP metabolite in vivo and in vitro. Our results suggest that the 1-methyl-4-phenyl-pyridinium ion is probably only generated in subsequent nonenzymatic transformations of this reactive monoamine oxidase metabolite. This substance was found to specifically inactivate the B-form of monoamine oxidase by a photo-induced mechanism and to react directly with NADPH and dopamine. Properties of the metabolite and potential significance of its reactions to MPTP neurotoxicity are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Moclobemide: a reversible inhibitor of monoamine oxidase type A.

The search for the ideal antidepressant continues. Moclobemide, the first reversible inhibitor of monoamine oxidase type A to enter widespread clinical use, has a number of advantages over traditional monoamine oxidase inhibitors and represents a valuable addition to the antidepressant armamentarium.

Benzamides↗
PubMed1984

Some properties of monoamine oxidase in carp heart.

Studies using clorgyline, deprenyl and semicarbazide as inhibitors showed that carp heart homogenate contained a new type of monoamine oxidase (MAO) and a clorgyline- and deprenyl-resistant amine oxidase (CRAO). The deamination of monoamines by carp heart MAO proceeded in two steps by a double-displacement (ping-pong) mechanism. The Km values of the MAO for oxygen (K0 values) with tyramine, 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (PEA) as substrates were identical (59 microM).

Animals↗
PubMed2001

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release.

OBJECTIVE AND DESIGN: It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAO(A) and MAO(B) in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites. RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAO(A) and MAO(B), their respective target enzymes, with IC(50) values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAO(A) and MAO(B) with IC(50) values for each enzyme in the moderate to high micromolar range. For MAO(A), the IC(50) for phentermine was estimated to be 143 microM, that for S(+)-fenfluramine, 265 microM and that for sertraline, 31 microM. For MAO(B), example IC(50)s were as follows: phentermine (285 microM), S(+)-fenfluramine (800 microM) and paroxetine (16 microM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility. CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine. Instead, the lack of potency of these drugs as MAO inhibitors is contrasted with their powerful ability either to inhibit the uptake of one or more monoamines (fluoxetine, paroxetine, sertraline, sibutramine's active metabolites) or to evoke the release of one or more monoamines (S(+)-fenfluramine, S(+)-norfenfluramine, phentermine). These differences in mode of action may be linked to the adverse cardiovascular events experienced with some of the releasing agents.

Animals↗
PubMed1996

Effect of physicochemical parameters on the retention of some monoamine oxidase inhibitory drugs on a porous graphitized carbon column.

The retention of sixteen monoamine oxidase inhibitory drugs (proparlgylamine derivatives) was determined on a porous graphitized carbon (PGC) column using ethanol-water mixtures as eluents. The HPLC retention characteristics of drugs were correlated with their physicochemical properties using stepwise regression analysis and principal component (PC) analysis. The dimensions of the matrices for PC loadings and variables was reduced using a non-linear mapping technique, varimax rotation and cluster analysis. It has been established that the drugs can be well separated on the PGC column in ethanol-water eluents. Calculations proved that the retention behavior of monoamine oxidase drugs on PGC column is of mixed character: both steric and electronic parameters influence the retention.

Chromatography, High Pressure Liquid↗
PubMed1990

Catalytically active monoamine oxidase type A from human liver expressed in Saccharomyces cerevisiae contains covalent FAD.

Monoamine oxidase type A from human liver cDNA was expressed in Saccharomyces cerevisiae. This enzyme's properties with respect to Km and Ki values for kynuramine and amphetamine, respectively, were similar to values for human placental enzyme. As expected, clorgyline inhibited the yeast enzyme at lower concentrations than deprenyl. Interestingly, the FAD cofactor was covalently attached and fluorescence properties of the enzyme bound prosthetic group indicate that it is attached to a cysteine residue, the same linkage observed in other monoamine oxidases. The yield of expressed enzyme is about 15 mg/l of culture with an A600 of 15. It is suggested that covalent flavin attachment proceeds by an autoflavination mechanism.

Base Sequence↗
PubMed1984

Effect of 6-aminonicotinamide on monoamine oxidase and Na+K+ATPase activity in different regions of rat brain.

The monoamine oxidase activity in the cerebral hemispheres decreased significantly after 2, 4, 8 and 16 hr of 6-amino-nicotinamide (35 mg/kg body weight, i.p.) administration. In the cerebellum, the MAO activity was not affected significantly. In the brain stem, however, a significant increase was observed after 2 hr of drug administration followed by a gradual decrease at later time intervals. The Na+K+ATPase activity in the cerebral hemispheres was increased significantly at 2 and 4 hr of 6-aminonicotinamide administration. This was followed by a gradual decrease at later time intervals. In the cerebellum, like monoamine oxidase, the Na+K+ATPase did not change significantly. The brain stem showed a decrease at 2 hr of drug administration, followed by a significant increase at 4 hr and then a gradual decrease to near control values.

6-Aminonicotinamide↗
PubMed1977

[Properties of mitochondrial monoamine oxidase isolated from rabbit brain and liver].

The effect of pO2 on the monoamine oxidase activity of mitochondria from rabbit brain and liver was investigated using the substrates tyramine, dopamine, tryptamine and serotonin. The effect of the second substrate (oxygen) was dependent upon the concentration of the first substrate (the amine). At amine concentrations below 50 micronM, the reaction rate as measured by a radiometric assay, was not affected by variations in the pO2. It was found that both phenazine methosulfate (PMS) and chlorpromazine (CPZ) are reversible inhibitors of monoamine oxidase, the former was a potent inhibitor (Ki=3X10(-6) M) and the latter relatively weak (Ki=5X10(-4) M). Inhibition by both compounds was non-competitive with respect to the amine substrate. Imipramine was a weak inhibitor of purified MAO from beef kidney and of the MAO activity of mitochrondria from brain and liver. Using tyramine or dopamine as the substrate (0.5-1.0 mM), inhibition ranging from 6-30% was observed at 5X10(-4) M imipramine. With tryptamine or serotonin (0.5-1.0 mM) as the substrate in the presence of 5X10(-4) M imipramine the drug seemed to have no net effect on MAO activity since the average value in the presence of imipramine for a number of experiences was the same as the average for control experiments. For p-iodo-phenyl-3-p-nitrophenyl tetrazolium chloride, a Ki of 43X10(-6) M was found using dopamine as the substrate and oxygen as the gas phase.

Animals↗