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PubMed1987

Photosensitizing effects of Photofrin II on the site-selected mitochondrial enzymes adenylate kinase and monoamine oxidase.

The response to Photofrin II-induced photosensitization on the activities of mitochondrial monoamine oxidase (MAO) and adenylate kinase (AK) were studied in order to gain further insight into site specific effects. Utilizing intact mitochondria in vitro, both MAO, located on the cytoplasmic side of the outer mitochondrial membrane, and AK, located in the intermembrane space, were inhibited by exposure to Photofrin II plus light; inhibition was drug-dose and light-dose dependent. However, MAO activity was inhibited to a greater extent than AK; at 35 micrograms/ml of Photofrin II and 160 J/cm2, MAO activity was decreased by 80% whereas AK activity was inhibited by 30%. Higher doses of Photofrin II had no further effect on AK activity. Studies of photosensitization of AK in different mitochondrial preparations demonstrated that inhibition of activity was evident only when mitochondrial membranes containing sequestered porphyrins were present in the reaction mixture. Using an in vivo-in vitro protocol and sampling at 2 to 72 h after administration of 25 mg/kg of Photofrin II, photosensitization of MAO (30% inhibition) was seen at 2 h after drug treatment but inhibition of activity was not observed at later times. AK activity was unchanged over the entire time course. Compared to cytochrome c oxidase, located in the inner mitochondrial membrane and which displayed a sustained inhibition of activity, we suggest that inhibition of MAO or AK activities probably does not contribute to the tumor cytotoxicity under the usual conditions used for photodynamic therapy.

Adenylate Kinase↗

PubMedDate not supplied

[Monoamine oxidation in the mitochondrial fraction of bovine kidney catalyzed by monoamine oxidase type B].

Oxidative deamination of tyramine, serotonin and benzyl amine in bovine kidney mitochondria was inhibited by low concentrations of deprenil (but not clorgylline). These data and the patterns of the plots of residual enzymatic activity against concentration of the inhibitors as well as the "mixed substrates" experiments suggest occurrence in bovine kidney mitochondria of monoamine oxidase of the B type only, which has to be considered in studies on the nature of monoamine oxidases using bovine kidney mitochondria as a rich source of monoamine oxidase activity.

Animals↗

PubMed2004

Monoamine oxidases: certainties and uncertainties.

A great deal has been learned about the behaviour of monoamine oxidase in the 75 years since it was first discovered, but there is still a great deal left to understand. This review concentrates on the dynamic aspects of our knowledge of the interactions of MAO with substrates and inhibitors and how it may collaborate with other enzymes, with particular emphasis on aspects that remain to be clarified.

Animals↗

PubMed1977

[Several kinetic features of membrane-dependent monoamine oxidase].

The v versus (S) plots for the initial rates of serotonin oxidation, catalyzed by monoamine oxidase in fragments of the rat liver or bovine brain mitochondrial membrane, had complicated non-hyperbolic shape, suggesting kinetic manifestation of cooperation in binding the substrate by the enzyme. A possibility of interactions of different monoamine oxidase types via the conformational alterations in the bio-membrane itself is considered.

Animals↗

PubMed1978

Release of cryptic monoamine oxidase activity by growth of BHK-21 cells in D-chloramphenicol.

The activity of monoamine oxidase, a marker enzyme of the outer mitochondrial membrane, is stimulated in BHK cells grown in the presence of 100 microgram ml-1 D-chloramphenicol. The observed stimulation can be reversed by removal of the antibiotic. Addition of the non-ionic detergent Triton X-100, to cell homogenates results in an elevation of the enzyme activity similar to that produced by D-chloramphenicol treatment. The activation by chloramphenicol is apparently related to a release of cryptic monoamine oxidase activity.

Cells, Cultured↗

PubMed1982

A simple method for screening monoamine oxidase (MAO) inhibitory drugs for type preference.

A simple method is described for screening monoamine oxidase (MAO) inhibitors for preferential action on either type A or type B MAO. Kynuramine, a substrate for both types of MAO, was used and the sources of enzyme were rat heart (type A) and mouse heart (type B). The method clearly showed that clorgyline (a preferential type A inhibitor) preferentially inhibited rat heart MAO; whereas pargyline (a preferential type B inhibitor) preferentially inhibited mouse heart MAO. Pheniprazine, an inhibitor without type preference, was equally effective in the two tissues. The method was used to substantiate a report by others that amphetamine has preferential inhibitory action against type A MAO.

Animals↗

PubMed1997

Monoamine oxidase inhibitors and cardiac anesthesia revisited.

There are well-recognized adverse interactions between the monoamine oxidase inhibitors and anesthetic drugs, particularly narcotics. Patients having cardiopulmonary bypass procedures are commonly anesthetized using high-dose narcotic techniques. We describe an uneventful perioperative course in a parkinsonian patient who required urgent coronary artery bypass graft surgery while he was taking selegiline, a selective inhibitor of monoamine oxidase type B.

Aged↗

PubMed2003

Relationship between imidazoline(2) sites and monoamine oxidase.

I(2) site-selective compounds are known to interact with and inhibit monoamine oxidase (MAO), but it remains unclear as to whether this interaction occurs through an allosteric or competitive interaction. This study used the new selective, irreversible I(2) ligand BU99006, to clarify the relationship between MAO and the I(2) binding sites (I(2)-BS). Results demonstrate that irreversible binding of BU99006 to rat brain membranes does not inhibit the enzyme or interfere with its interaction with other imidazoline enzyme inhibitors. This finding suggests that the I(2) sites that react with BU99006 are not those implicated in MAO inhibition and points to the existence of at least two distinct I(2) binding proteins.

Animals↗

PubMed1987

Inhibition of type A monoamine oxidase by 1-methyl-4-phenylpyridine.

1-Methyl-4-phenylpyridine (MPP+) is now confirmed to be one of the oxidative products of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by type B monoamine oxidase (MAO-B) and is considered to cause a parkinsonism-like syndrome. We studied the effect of MPP+ on type A monoamine oxidase (MAO-A) activity in mitochondria prepared from various sources. By kinetic analysis, MPP+ was found to inhibit MAO-A in competition with the substrate, kynuramine. The Ki value of MAO-A with MPP+ in human brain synaptosomal mitochondria (1.3 microM) was much lower than the Ki values of MAO-A in other organs. Among the MAO-A samples, MAO-A in intrasynaptosomal mitochondria from human brain was the most sensitive to MPP+. The Ki value of MAO-A with MPP+ in striatum (1.6 microM and 2.0 microM for MAO-A prepared from putamen and from caudate) was similar to the Ki value of MAO-A in synaptosomes from cortex. The difference in the Ki values of MPP+ for MAO-A from various sources was considered to be due to the difference in lipid components of mitochondria. The possible significance of the inhibition of MAO-A was discussed in terms of the etiology of parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

Modeling of substrate-binding region of the active site of monoamine oxidase A.

The mold of the substrate-binding region of the active site of monoamine oxidase A (MAO A) was designed using data of the enzyme interaction with reversible competitive inhibitors and the analysis of their three-dimensional structures. The superposition of ligands in biologically active conformations allowed determination of the shape and dimension of the active site cavity accommodating these compounds. The correctness of this approach was validated by the analysis of HIV protease interaction with its inhibitors using three-dimensional structures of HIV protease-inhibitor complexes. The mold of the substrate/inhibitor-binding site can be used for searching for new ligands in molecular databases and the development of a new generation of MAO inhibitors using lead structures that have not been employed for this purpose yet.

Binding Sites↗

PubMed1998

Function of endogenous monoamine oxidase inhibitors (tribulin).

Recent research on tribulin [low molecular weight endogenous inhibitory activity of monoamine oxidase (MAO)] has confirmed that its level is increased in both human urine and rat tissues by stress or anxiety, and by anxiogenic drugs. However tribulin is now known to contain several different molecules. The raised inhibitory activity in rat tissues is selective for MAO-A. There is a parallel decrease in MAO-A activity ex vivo, suggesting a possible functional effect. Increase in endogenous MAO I may competitively inhibit the binding of irreversible MAO I drugs, and may also help to mediate some mood altering effects of other drugs, or procedures such as ECT. In human urine both MAO-A I and MAO-B I have been found to be increased in mild stress. Similar findings have been made with human saliva. Selective inhibitors of MAO-A have been identified from human urine, and pig brain, but it is not yet clear to what extent they account for the MAO-A I activity increased in stress. Isatin is an endogenous selective inhibitor of MAO-B (K1 approximately 3 microM). It has a distinct distribution in rat brain, with highest concentration in the hippocampus of 0.1 microgram/g. Its level is increased by pentylene tetrazole, and isatin is itself anxiogenic in rodent models. Its administration also increases monoamine levels in the brain. It is a potent antagonist of the ANP receptor, and it may act to link the control of monoamine function and natriuresis.

Animals↗

PubMed1990

Isoelectric analysis of 3H-pargyline-labelled monoamine oxidase in rat and carp.

1. After selective binding of [3H]pargyline to either monoamine oxidase (MAO) A or MAO B in the rat liver, MAO B alone in the rat brain and MAO in carp brain and liver, molecular weight and isoelectric points (pI) of these MAO were determined by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis and isoelectric focusing and results obtained were compared. 2. For all tissues tested, SDS-polyacrylamide gel electrophoresis of [3H]pargyline-bound samples revealed a labelled protein band of an apparent mol. wt of 60,000 da. 3. Estimation of radioactivity of [3H]pargyline bound after isoelectric focusing revealed a single protein band with acidic pI values of about 5.5 for rat brain and liver MAO B. 4. Moreover, the pI values of about 7.5 were obtained for carp brain and liver MAO. This basic value was also found for MAO A in the rat liver MAO A.

Animals↗

PubMed1989

Tetrahydroaminoacridine inhibits human and rat brain monoamine oxidase.

The inhibitory effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on monoamine oxidase (MAO; EC 1.4.3.4) enzyme activities in human hippocampal and rat striatal homogenates have been studied. The activities of MAO-A and MAO-B were estimated radiochemically, in-vitro, in human hippocampus and rat striatum in the presence of various concentrations of THA with [2-14C]hydroxytryptamine binoxalate (100 microM) and beta-[ethyl-14C]phenylethylamine hydrochloride (20 microM) as substrates for the respective enzyme form. THA was found to inhibit both MAO-A and MAO-B activities reversibly and competitively, with inhibition constants (Ki) of 12.5 microM and greater than 500 microM respectively, of the rat striatal enzymes. From this it can be extrapolated that at therapeutic tissue concentrations of THA (10(-8) to 10(-6) M), more than 20% of the MAO-A activity should be inhibited. Thus it is possible that inhibition of MAO may be involved in the therapeutic action of THA in Alzheimer's disease.

Aged↗

PubMed1989

Monoamine oxidase activity and triiodothyronine biosynthesis in human cultured thyroid cells.

1. The proposal that monoamine oxidase (MAO) is a source of peroxide in thyroid hormone biosynthesis has been examined by use of isolated cultured human thyroid cells which retain the ability to secrete triiodothyronine (T3) in response to thyroid stimulating hormone (TSH). 2. The results demonstrated the presence of MAO A and B in human thyroid cells which oxidized 5-hydroxytryptamine and 2-phenylethylamine, respectively, and were selectively inhibited by the MAO inhibitors clorgyline and (-)-deprenyl. 3. Addition of propylthiouracil to the culture system induced a 61% reduction in TSH-stimulated T3 secretion, indicating that the bulk of such secretion apparently derives from de novo iodothyronine synthesis. 4. The MAO A and B substrate, tyramine, was ineffective in stimulating T3 secretion. 5. The selective MAO inhibitors, clorgyline and (-)-deprenyl, alone and in combination, and in the presence and absence of tyramine, failed to inhibit basal as well as TSH-stimulated T3 secretion in cultured human thyrocytes. 6. It is therefore apparent that even though thyroid MAO A and B enzyme reactions result in the generation of H2O2, this H2O2 does not seem to play a significant role in T3 biosynthesis.

Cells, Cultured↗

PubMed1987

Binding of [3H]Ro 16-6491, a reversible inhibitor of monoamine oxidase type B, to human brain mitochondria and platelet membranes.

The reversible inhibitor of monoamine oxidase type B (MAO-B) [3H]Ro 16-6491 binds specifically and with high affinity to a single population of binding sites in human frontal cortex crude mitochondria and platelet membranes. In both tissues binding equilibrium was reached after 1 h incubation at 20 degrees C. Dissociation of bound radioactivity was relatively fast at 20 degrees C (t1/2 = 90-120 min) whereas at 0 degrees C [3H]Ro 16-6491 showed the characteristics of a slowly dissociating ligand. Inhibitors and substrates of MAO-B inhibited binding of [3H]Ro 16-6491, whereas MAO-A blockers were much less potent. Ro 16-6491 was also a substrate for MAO-B and a stable unidentified intermediate of the oxidation of Ro 16-6491 possessing high affinity for the enzyme may account for the marked MAO-B inhibitory effect of the drug. According to this hypothesis Ro 16-6491 would behave as a mechanism-based reversible inhibitor. In conclusion, [3H]Ro 16-6491 binds selectively to MAO-B and represents an excellent new radioligand probe for studying the regional tissue distribution of this enzyme in normal and pathological conditions.

Benzamides↗

PubMed2005

Monoamine oxidase B (MAO-B) inhibition by active principles from Uncaria rhynchophylla.

Attenuation of monoamine oxidase B (MAO-B) activity may provide protection against oxidative neurodegeneration. For this reason, inhibition of MAO-B activity is used as part of the treatment of Parkinson's and Alzheimer's patients. The hook of Uncaria rhynchophylla (Miq.) Jacks. (Rubiaceae) is a traditional Chinese herbal drug that is generally used to treat convulsive disorders. In this study, the fractionation and purification of Uncaria rhynchophylla extracts using a bioguided assay isolated two known compounds, (+)-catechin and (-)-epicatechin. The compounds inhibited MAO-B, as measured by an assay of rat brain MAO-B separated by electrophoresis on a 7.5% native polyacrylamide gel. The IC(50) values of (+)-catechin and (-)-epicatechin were 88.6 and 58.9 microM, respectively, and inhibition occurred in a dose-dependent manner, as measured by the fluorescence method. The Lineweaver-Burk plot revealed K(i) values for (+)-catechin and (-)-epicatechin of 74 and 21 microM, respectively. This suggests that these two compounds, isolated here for the first time from Uncaria rhynchophylla, might be able to protect against neurodegeneration in vitro, and, therefore, the molecular mechanism deserves further study. This finding may also increase interest in the health benefits of Uncaria rhynchophylla.

Animals↗

PubMed2006

A bioluminescent assay for monoamine oxidase activity.

This article describes a novel two-step homogeneous bioluminescent assay for monoamine oxidase (MAO) that is simple, sensitive, and amenable to high-throughput screening. In the first step, MAO reacts with an aminopropylether analog of methyl ester luciferin. In the second step, a luciferin detection reagent inactivates MAO and converts the product of the first step into a luminescent signal. The amount of light produced is proportional to the amount of MAO and the time of incubation in the first step, but the luminescent signal is stable in the second step with a half-life greater than 5h. The assay has high precision, is more sensitive than current fluorescent methods, and can accurately measure the binding constants of known substrates and inhibitors. An automated screen of the Sigma-RBI Library of Pharmacologically Active Compounds (LOPAC(1280)) revealed a surprisingly high percentage of MAO inhibitors (16%) with a low false hit rate (0.9%). This implies that a significant number of compounds interact with the MAO enzymes and suggests that it is important to include MAO assays in drug metabolism studies. Other advantages of this bioluminescent assay over comparable fluorescent assays are discussed.

Animals↗

PubMed2002

Monoamine oxidase A and B activities in embryonic chick hepatocytes: differential regulation by retinoic acid.

Monoamine oxidases (MAOs) A and B are two isoenzymes involved in the degradation of many biological amines in the nervous system and in peripheral organs. In the present work hepatocytes isolated from 14-day-old chick embryos were used as a model system to determine whether retinoic acid (RA) is capable of modulating the activity of the two MAO forms. RA is a retinoid that, by binding with nuclear receptors, interferes with the expression of specific genes in many differentiation processes. Enzymic activity was measured with a radiochemical method using serotonin and beta-phenylethylamine as preferential substrates for MAO A and MAO B, respectively. The specific activity of the two forms was measured in hepatocytes cultured for 24, 48 and 72 h in the presence and the absence of serum. RA stimulated MAO B but not MAO A activity, in a dose- and time-dependent way, and only in the presence of serum. Maximum stimulation (about 3.5-fold) was obtained after treatment with 5 microM RA for 72 h. Kinetic analysis of MAO B activity showed an increase in V(max) in treated hepatocytes (5 microM RA for 72 h) with no change in K(m). In conclusion, the present work shows that RA selectively elicits MAO B activity in cultured chick embryonic hepatocytes, this stimulation requires the presence of some factors present in the serum and is probably due to an increase in the number of enzyme molecules.

Animals↗