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PubMed1996

Association study between schizophrenia and monoamine oxidase A and B DNA polymorphisms.

Monoamine oxidases (MAO) A and B, which are encoded by two distinct genes located on the human X chromosome, are both involved in the oxidative metabolism of dopamine. Decreased levels of platelet MAO-B activity has been reported in patients with schizophrenia and genetic variation in MAO activity had been proposed as a significant factor in the etiology of this disease. We carried out an association study using two intragenic polymorphisms within the MAO-A and MAO-B genes in 110 schizophrenic patients and 87 control subjects. For each polymorphic marker, no significant difference in allelic frequencies was observed between patients and controls. Nevertheless, a trend toward an association between allele 1 of the MAO-B gene and paranoid schizophrenia was found. Our results do not support the hypothesis that inherited variants of MAO genes might play a major role in a genetic predisposition to schizophrenia. Since several previous reports found a low MAO-B platelet activity in patients with paranoid schizophrenia, the identification of polymorphisms related to enzyme activity would be useful.

Adolescent↗

PubMed1998

Substrate regulation of monoamine oxidases.

The rate of oxidation by monoamine oxidase (MAO) of a particular amine in a given cell depends on the levels of MAO-A and MAO-B expressed in the mitochondrial outer membranes, on the amine concentration and the oxygen concentration. Its disposal will be slowed by the presence of competing amines or endogenous inhibitors. However, substrate binding alters the properties of MAO and influences catalytic turnover. (a) It increases the redox potential of the flavin making possible the transfer of electrons from the higher potential amine. (b) It accelerates the reactivity of the covalently bound flavin with oxygen, effectively increasing the Vm (particularly for MAO-B). (c) It bypasses the generation of free oxidised enzyme in the reaction cycle so that, at high amine concentrations, only the affinity of a substrate or inhibitor for the reduced enzyme (particularly for MAO-A) is important. These changes are induced only by substrate, not by the few stable products available nor by inhibitors suggesting a very specific interaction between a substrate ligand and the enzyme. The altered properties are very different for MAO-A and MAO-B even with the same substrate. Elucidation of the mechanisms involved must await structural information from physical studies, molecular modelling and mutational analysis.

Amines↗

PubMed1993

Serotonin uptake inhibition by the monoamine oxidase inhibitor brofaromine.

The selective, reversible monoamine oxidase (MAO) A inhibitor brofaromine inhibits serotonin (5-HT) uptake in animal models in vitro and in vivo. We investigated whether such an effect can be demonstrated at clinical doses in humans by treating three groups of six volunteers with either placebo, 15 mg phenelzine three times a day, or 75 mg brofaromine twice a day in a 2-week experiment. As an indirect, although relevant parameter, binding of 3H-paroxetine to the 5-HT uptake sites on blood platelets was assessed. Moreover, whole-blood 5-HT as a measure of platelet 5-HT, and serum homovanillic acid (HVA) to tentatively estimate MAO inhibition, were determined. Brofaromine reduced 3H-paroxetine binding to platelets compared with placebo by 20%-25% throughout the treatment period, significance being reached on the last treatment day. In contrast, phenelzine tended to increase 3H-paroxetine binding. Both drugs increased whole-blood 5-HT to approximately 140%-150%. Brofaromine moderately and on some days significantly decreased serum HVA, whereas phenelzine only tended to do so. Our results suggest that brofaromine at the clinically used dosage of 150 mg/day does indeed inhibit 5-HT uptake, as evidenced by measurements of 3H-paroxetine binding to platelets.

Adult↗

PubMed1996

Influence of C terminus on monoamine oxidase A and B catalytic activity.

Monoamine oxidase (MAO) A and B play important roles in the metabolism of neurotransmitters and dietary amines. The domains important for enzyme specificities were studied by construction of chimeric MAOA/B enzymes. Exchange of the N-terminal 45 amino acids of MAOA with the N-terminal 36 residues of MAOB (chimeric enzymes B36A and A45B) resulted in the same substrate and inhibitor sensitivities as the wild-type MAOA or B. Thus, the N terminus may not be responsible for MAOA or B enzyme specificities. When MAOB C-terminal residues 393-520 were replaced with MAOA C-terminal residues 402-527 (chimeric B393A) catalytic activity was not detectable. Chimeric B393A consists of eight residues with different charges, three less proline residues (458, 476, and 490), and one additional proline at 518 compared with wild-type MAOB. These differences may have induced conformational changes and affected MAOB catalytic activity. Thus, the C terminus of MAOB is critical for maintaining MAOB in an active form. It is interesting that when the C terminus of MAOA was switched with MAOB (chimeric A402B), little effect was observed on MAOA catalytic activity. This new information is valuable for further studies of the structure and function relationship of this important enzyme.

Amino Acid Sequence↗

PubMed1987

[Electrophoretic properties of mitochondrial monoamine oxidase in monkey liver].

Monkey liver monoamine oxidase (MAO) was predominantly the B-form enzyme from the observed differences in substrate specificities and differences in sensitivities to MAO inhibitors. It is known that a MAO inhibitor, pargyline, binds to MAO irreversibly in the molar ratio of 1:1. 3H-pargyline was used as a marker to determine the existence of MAO. The molecular weight of MAO in monkey liver mitochondria was investigated by SDS-polyacrylamide gel electrophoresis after solubilization of 3H-pargyline binding mitochondria with 6% sodium dodecyl sulphate (SDS). The subunit molecular weight was found to be 60,000. The molecular weight determined from the electrophoretic mobility on several concentrations of gels by disc gel electrophoresis in the absence of SDS was found to be 120,000. These results indicate that monkey liver mitochondrial MAO exists as a dimer. Isoelectric focusing of the enzyme after solubilization with 0.1% Triton X-100 and 0.75% Triton X-100 and 0.75% Lubrol showed that it had a pI value near 6.5. Similar pI values were obtained for enzyme preparations solubilized with 0.75% Triton X-100 after treatment with phospholipase A or methylethylketone. These results suggest that the pI value of MAO in monkey liver mitochondria does not depend on the properties of detergents used to solubilize the enzyme preparation.

Animals↗

PubMed1981

Studies on beta-phenylethylamine deamination by human placental monoamine oxidase.

Kinetical properties of human placental monoamine oxidase (MAO) were investigated in studies on inhibitors and mixed substrates. MAO activity was determined by a radioisotopic assay. Lineweaver-Burk plots were linear at higher and lower concentrations of PEA, whereas at intermediate substrate concentrations, a downward curving plot was obtained. The Km values of the low- and high-affinity sites for PEA deamination were estimated. Studies with mixed substrates showed that 5-HT was a competitive inhibitor and tyramine a mixed-type inhibitor of deamination at high concentrations of PEA, whereas both were non-competitive inhibitors at lower concentrations of PEA. After pre-incubation of human placental mitochondrial preparations with deprenyl, Lineweaver-Burk plots were completely linear, and the Km value was the same as that obtained at low concentrations of PEA in the absence of deprenyl. Tyramine and 5-HT were competitive inhibitors of PEA deamination by deprenyl-treated MAO. From these results it is concluded that there are two kinds of MAO with high- and low-affinity sites for PEA in mitochondria of human placenta, corresponding to type B and A Mao, and that tyramine, 5-HT and PEA share a substrate-binding site on type A Mao, while tyramine and 5-HT bind to a site on type B MAO that is different from the PEA binding site.

Deamination↗

PubMed2006

Effects of prenatal methylmercury exposure on brain monoamine oxidase activity and neurobehaviour of rats.

Monoamine oxidase (MAO) regulates levels of dopamine, serotonin, and noradrenaline in the nervous tissue and is required for proper neuronal development. The purpose of this study was to determine if oral exposure of adult female rats to methylmercury (MeHg) at 0.5 or 1 mg/kg/day before and during pregnancy would affect MAO activity in various brain regions of the offspring. Offspring neurobehaviour performance was also assessed. The brain MAO activity of female offspring was reduced at both MeHg doses with significantly lower values noted in the brainstem region. No significant MeHg dose effects on MAO activity were observed in the male offspring. Neurobehavioural evaluations indicated that MeHg exposure altered auditory startle in the female offspring. Rat whole embryos (gestational day 13.5) cultured with 750 microg/L MeHg in vitro significantly decreased total MAO activity by 15%. In conclusion, this study demonstrated that exposure to MeHg in rats before and/or during gestation resulted in a reduction of MAO activity in the developing embryo and brainstem of the female offspring with accompanying changes in auditory startle response. Evaluation of MAO activity may serve as an indicator for neurotoxicity following developmental exposure to MeHg and should be further investigated.

Acoustic Stimulation↗

PubMed1994

Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. The inhibition of monoamine oxidase B (MAO-B) by lazabemide was measured in platelets collected from 35 young (19-36 years) and 40 older (60-78 years) healthy volunteers after single (100-300 mg) and multiple (100-350 mg twice daily) oral doses respectively. 2. The relationship of the effect with plasma concentrations of the MAO-B inhibitor was defined by a sigmoid Imax-model using either a parametric or semi-parametric method for predicting plasma drug concentrations. Population parameter estimates were obtained by the expectation maximization method and a standard two-stage method. 3. At the lowest dose platelet MAO-B activity was almost completely inhibited for around 20 h. No time delay between plasma drug concentration and resulting inhibition of platelet MAO-B occurred. Low concentrations of the inhibitor produced 50% of maximum inhibition (IC50, estimates for population mean +/- s.d.: 0.48 +/- 0.89 microgram l-1 for young and 1.5 +/- 2.3 micrograms l-1 for elderly subjects). The maximum extent of enzyme inhibition attributable to lazabemide (Imax) was 94 +/- 5.1% and 96 +/- 4.5% in the young and older populations. There was no correlation between age and either Imax or IC50. 4. Model parameters describing the interaction of lazabemide with the enzyme did not change over the treatment period of 7 days.

Adult↗

PubMed2000

Association analysis between mood disorder and monoamine oxidase gene.

To ascertain whether mood disorders, including bipolar and unipolar, are genetically associated with the monoamine oxidase A (MAOA) or monoamine oxidase B (MAOB) gene in the Chinese population, 132 cases of mood disorder and 88 normal controls were genotyped for the MAOA(CA)n, MAOB(GT)n, and MAOB(TG)n loci by the method of amplification fragment length polymorphism. Among 132 cases with mood disorder, eight alleles (size: 112-126 bp) of locus MAOA(CA)n, 12 alleles (size: 168-198 bp) of locus MAOB(GT)n, and nine alleles (size: 195-213 bp) of locus MAOB(TG)n were observed. Comparison of the allele frequency of the three loci showed no difference between mood disorder cases and normal controls on average. When each group was stratified into several subgroups, significant differences were found. On the MAOA(CA)n locus, the frequency of 116 bp allele was higher in the female bipolar disorder cases (0.2581) compared with that in the female unipolar disorder patients (0.1154) (Z=2.15, p<0. 05). On the MAOB(GT)n locus, the frequency of 180 bp allele was higher in bipolar disorder patients (0.1579) than that in normal controls (0.0678) (Z=2.05, p<0.05). The frequency of this allele was even higher in female bipolar disorder patients (0.1719) than that in female normal controls (0.0541). On the MAOB(TG)n locus, the frequency of 205 bp allele was higher in female bipolar disorder patients (0.6406) than that in female normal controls (0.4375) (Z=2. 17, p<0.05). For the unipolar disorder patients, the frequency of this allele was higher in female cases (0.5222) than that in male cases (0.1818) (Z=3.49, p<0.05). As for association studies, significant association between bipolar disorder and MAOB gene was detected. For the 180 bp allele of MAOB(GT)n, the relative risk (RR) of biploar versus normal control was 2.58 (p<0.05), and the RR of female bipolar disorder versus female normal control was 3.63 (p<0. 05). For the 205 bp allele of MAOB(TG)n, the RR of female bipolar disorder versus female normal control was 2.29 (p<0.05). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:12-14, 2000.

Alleles↗

PubMed1997

Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease.

Monoamine oxidase B (MAO-B) is an enzyme that has relevance for Parkinson disease (PD) because of its roles in catabolizing dopamine and potentially activating exogenous neurotoxicants. A polymorphism of the gene encoding MAO-B has been identified as a single base change (A or G) in intron 13 of the X chromosome. The A allele was previously associated with an approximately twofold risk of PD. The present study compared A and G allele frequencies between newly diagnosed idiopathic PD cases and a control group free of neurodegenerative diseases. All study subjects were Caucasian. Cases were 37 men and 25 women, age 37-80 years; controls were 50 men and 29 women, age 45-82 years. MAO-B genotype was determined by the allele-specific polymerase chain reaction on DNA extracted from peripheral lymphocytes. In complete contrast to previous studies, elevated risks were detected with the G allele. The age-adjusted odds ratio for the G allele in males was 1.87 ((95% confidence interval) 0.78-4.47). Among females the age-adjusted odds ratios were 5.00 ((95% confidence interval) 1.13-22.1) for the GA genotype and 5.60 ((95% confidence interval) 1.01-30.9) for the GG genotype. These findings, although of limited statistical precision, suggest that the G allele of this MAO-B polymorphism may relate to PD risk.

Adult↗

PubMed1989

Deuterium isotope effect of phenelzine on the inhibition of rat liver mitochondrial monoamine oxidase activity.

Phenelzine is a suicide monoamine oxidase (MAO) inhibitor with antidepressant properties. The present study compares the inhibition of rat liver mitochondrial MAO by phenelzine and 1,1-dideuterated phenelzine and the metabolism of these drugs by that enzyme. Phenylacetaldehyde, which was measured by a high performance liquid chromatographic procedure, was found to be the major metabolite of phenelzine after incubation with MAO. The time-courses of aldehyde formation were non-linear due to the time-dependent inhibition of MAO. The reaction rate was reduced substantially when the hydrogen atom in the 1-carbon position was replaced by deuterium. The VH/VD value was 3.1, indicating a primary isotope effect. Such a substitution of deuterium in the phenelzine molecule did not affect significantly the initial reversible inhibition of MAO, which was determined by comparison of their Ki values. The irreversible inhibition, as estimated from IC50 values, however, was potentiated substantially by deuteration. These results support the notion that the irreversible inhibition of MAO activity by phenelzine proceeds via a phenylethyldiazene intermediate, which reacts with the enzyme to form a covalent adduct. An alternative pathway involving hydrogen abstraction from carbon-1 of phenelzine or via rearrangement of the diazine on the enzyme surface could occur to form a phenylethylidene hydrazine intermediate which would subsequently be hydrolyzed to phenylacetaldehyde. The reduction in the rate of phenylethylidene hydrazine formation due to the isotope effect could lead to the accumulation of phenylethyldiazene intermediate and thus potentiate the inhibition of MAO activity.

Acetaldehyde↗

PubMed2004

Monoamine oxidase expression during development and aging.

Monoamine oxidase (MAO) isoenzymes play a major role in regulating the concentration of several bioactive amines, including serotonin and catecholamines. Both in the nervous system and in peripheral organs, MAOs can potentially modulate all the processes involving these bioactive amines. In the present article, we review some of the most significant articles published so far on changes in MAOs during development and aging. The data available on development refer mainly to the mammal brain at fetal and post-fetal stages. Very little work has been done on studying MAO ontogenesis during early development, that is, at stages prior to organogenesis, and what has been done refers to non-mammal vertebrates such as fish, amphibians and birds. MAO A and MAO B changes have been measured as values of enzymatic activity, as amount of protein or, more rarely, as amount of mRNAs. A knowledge of MAO developmental changes not only provides a basis for the investigation of factors regulating MAO expression, but can also contribute to a better understanding of the possible trophic and/or morphogenetic role of monoaminergic neurotransmitters in the developing brain. Transgenic mice lacking MAO A and rodents treated with MAO inhibitors during gestation have been very useful in this second case. The investigations of changes in MAO A and MAO B during aging in the literature refer mostly to humans, mice and rats. Interest in studies on aging is stimulated, among other things, by the observation that age-related diseases leading to neurodegenerative phenomena could be accompanied by changes in MAO activity.

Aging↗

PubMed1980

Golden hamster pancreatic islets: a tissue rich in monoamine oxidase.

We compared the steady state monoamine oxidase (MAO) activity of collagenase-isolated pancreatic islets of the golden hamster with the steady state MAO activity of liver, kidney, median eminence, pituitary, acinar pancreas, and cerebral cortex. The MAO activity of the islets (5384 +/- 412 pmol/mg protein . min) was 3-fold greater than the activity of the next highest tissue (liver) and 12.5 times greater than the activity of the acinar pancreas. This high MAO activity was not due to collagenase exposure. The islet MAO was mainly of the so-called type B, although there was also some type A activity in this tissue. By assaying the formation of new islet MAO after the irreversible activation of MAO by the MAO inhibitor pargyline, we found that the t 1/2 of islet MAO (5.9 days with 95% confidence limits of 4.1-10.5 days) did not differ from the t 1/2 of MAO in tissues with lower steady state MAO activities. This suggested that the high steady state MAO activity in golden hamster islets is due to a high rate of synthesis rather than to a lower rate of degradation. Although rats, Chinese hamsters, guinea pigs, mice, and rabbits had substantial MAO activity in their pancreatic islets, their levels, at most, were only 16% that of the golden hamster. When the MAO activity of golden hamster islets was inhibited by the administration of pargyline plus clorgyline, there was a 3-fold increase in islet serotonin concentration, with no increase in islet norepinephrine concentration, suggesting that islet MAO activity plays a role in regulating islet serotonin concentration.

Animals↗

PubMed2003

Inflammation and inducible nitric oxide synthase have no effect on monoamine oxidase activity in glioma cells.

Heightened monoamine oxidase (MAO) and inducible nitric oxide synthase (iNOS) activity can contribute to oxidative stress, the formation of active neurotoxins, and associated neurodegenerative diseases of the brain. Although these enzymes co-exist within astrocytes, there has been little research examining the correlation between the two during inflammation. In this study, C6 glioma cells were stimulated with lipopolysaccharide (LPS):Escherichia coli 0111:B4 (6 micro g/mL):rat interferon-gamma (IFN-gamma) (100U/mL). In LPS/IFN-gamma-treated cells, the MAO substrates dopamine (DA) and tyramine caused a concentration-dependent attenuation of NO(2)(-) and NO(3)(-). In contrast, treatment with an MAO-A inhibitor (clorgyline) or an MAO-B inhibitor ((-)-deprenyl) did not reverse these effects. MAO activity was inhibited effectively by clorgyline and deprenyl; however, neither MAO inhibitor had an effect on NO(2)(-) in stimulated cells. Inversely, increasing concentrations of LPS/IFN-gamma resulted in heightened iNOS protein expression and NO(2)(-); however, these events did not correlate with any distinctive change in MAO enzyme activity. Moreover, a selective iNOS inhibitor, N(6)-(1-iminoethyl)-L-lysine, in LPS/IFN-gamma-stimulated cells caused a concentration-dependent attenuation of NO(2)(-) with no effects on MAO activity or iNOS protein expression. The attenuating effects of DA on iNOS were blocked completely by ICI 118-551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride], indicating a role for the beta(2)-adrenergic receptor. In conclusion, these data indicate that activity or expression of iNOS does not influence MAO activity in activated rat glioma cells. Moreover, DA exerts an inhibitory effect on glial iNOS through a receptor-mediated cascade.

Analysis of Variance↗

PubMed1992

Promoter organization and activity of human monoamine oxidase (MAO) A and B genes.

Monoamine oxidase A and B (MAO A and B) play important roles in the metabolism of biogenic and dietary amines and are encoded by two genes derived from a common ancestral gene. The promoter regions for human MAO A and B genes have been characterized using a series of 5' flanking sequences linked to a human growth hormone reporter gene. When these constructs were transfected into NIH3T3, SHSY-5Y, and COS7 cells, the maximal promoter activity for MAO A was found in a 0.14 kilobase (kb) PvuII/DraII fragment (A0.14) and in a 0.15 kb PstI/NaeI fragment (B0.15) for MAO B. Both fragments are GC-rich, contain potential Sp1 binding sites, and are in the region where the MAO A and B 5' flanking sequences share the highest identity (approximately 60%). However, the organization of the transcription elements is distinctly different between these two promoters. Fragment A0.14 consists of three Sp1 elements, all in reversed orientations, and lacks a TATA box. Two of the Sp1 sites are located within the downstream 90 base pair (bp) direct repeat, and the third is located at the 3' end of the upstream 90 bp direct repeat. Fragment B0.15 contains an Sp1-CACCC-Sp1-TATA structure; deletion of any of these elements reduced promoter activity. Additional Sp1 sites, CACCC elements, CCAAT boxes, and direct repeats (four 30 bp direct repeats in MAO A and two 29 bp direct repeats in MAO B) are found in farther-upstream sequences of both genes (1.27 kb for MAO A and mostly in 0.2 kb for MAO B). Inclusion of these sequences decreased promoter activity. The different promoter organization of MAO A and B genes provides the basis for their different tissue- and cell-specific expression.

3T3 Cells↗

PubMed1984

On-line radiochemical assay for monoamine oxidase utilizing high-performance liquid chromatography.

A fast and sensitive assay for the determination of monoamine oxidase activity was developed. The method is based on the separation and quantitation of 14C-labeled assay products by high-performance liquid chromatography, which is interfaced directly into a flow-through radioactivity detector. This allows on-line quantitation of the radioactive compounds with picomole sensitivity. The method makes possible the complete separation and detection of the deaminated products of monoamine oxidase A and B substrates benzylamine and 5-hydroxytryptamine, respectively. This assay has been applied to the measurement of monoamine oxidase A and B activities in rat brain.

Animals↗

PubMed1981

Platelet monoamine oxidase activity in Down's syndrome.

The activity of platelet monoamine oxidase in Down's syndrome cases was significantly lower than that of controls. This difference was found for both males and females, and with tyramine, tryptamine and beta-phenethylamine as substrate. The Km values of the monoamine oxidase towards tryptamine as substrate from controls and Down's syndrome patients were similar.

Adolescent↗

PubMed1993

Type B monoamine oxidase and neurotoxins.

The biochemical process underlying Parkinson's disease is dopamine cell death of the nigrostriatal system. The age-dependent cell death is now proposed to be elicited by the formation of free hydroxy radicals which are formed from hydrogen peroxide, a product of oxidation of dopamine by monoamine oxidase, especially type B. The potent neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, was found to induce cell death by an energy crisis or oxidative stress in dopamine neurons. Other endogenous mammalian neurotoxins, monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. N-methylated isoquinolines were found to be oxidized by monoamine oxidase, and hydroxy radicals were found to be produced by this reaction. In addition, by incubation with the N-methylated isoquinolines, ATP was depleted from a dopaminergic cell model, clonal rat pheochromocytoma PC12h cells. ATP depletion could be protected by pretreatment of the cells with monoamine oxidase inhibitors. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1-methyl-1,2,3,4-tetrahydroisoquinoline and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were found to inhibit the activity of monoamine oxidase, indicating that they may be neuroprotective agents in the brain. The involvement of monoamine oxidase is discussed in relation to the pathogenesis of Parkinson's disease.

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