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PubMed1980

Inherited levels of A and B types of monoamine oxidase activity.

In establishing the role of inherited variations in levels of monoamine oxidase (MAO) activity in neuropsychiatric diseases, it is important to measure levels of both A and B types of activity as they appear to be under separate genetic control. Levels of A and B types of activity can be evaluated in fibroblasts and platelets, respectively. A number of genes could be involved in determining levels of activity, including those coding for the catalytic and noncatalytic subunits of the enzyme, as well as those coding for enzymes involved in covalent attachment of the flavin cofactor, other processing steps, degradation of MAO, and lipid metabolism. Different genes may be critical in controlling activity levels in various cell types depending on differential expression of the genome. In order to establish the molecular basis of variation in activity, techniques should be employed to assess the structure and conformation of the enzyme, as well as the number of enzyme molecules and their interaction with other cellular components. Only by understanding the genetic and environmental factors controlling levels of A and B types of MAO activity can we hope to evaluate and manipulate the role of MAO in human neurophysiology.

Blood Platelets↗
PubMed1999

Genome screen for platelet monoamine oxidase (MAO) activity.

To identify loci involved in the control of platelet monoamine oxidase B (MAO-B) activity, a genomewide linkage screen was performed using 291 markers in 148 nuclear families containing a total of 1,008 nonindependent sib-pairs. Participants were genotyped and their platelet MAO-B activity levels were measured as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Sib-pair analysis using Haseman-Elston regression was carried out with two programs. Two-point analysis on all pairs with SIBPAL indicated three markers with p-values below 0.01: D6S1018 (p = 0.0004), D2S1328 (p = 0.008), and D2S408 (p = 0.003). MAPMAKER/SIBS multipoint analyses using independent pairs(N = 409) gave maximal lod scores of 2. 0 on chromosome 6 and 1.1 and 1.4 for the two regions on chromosome 2. These results are consistent with linkage, but do not provide definitive evidence. We are currently creating a denser map in these regions and have begun genotyping a second sample in COGA.

Blood Platelets↗
PubMed1976

Monoamine oxidase activity in blood platelets in alcoholism.

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets was applied in 50 alcoholic patients. The assay is the direct measurement of serotonin oxidation by MAO employing a double microcolumn technique on Sephadex G-10 and Amberlite CG-50 for separating 5-HIAA formed, which is measured fluorimetrically. Rebound of MAO activity levels after withdrawal of alcohol was observed to be more pronounced in the patients with delirium tremens than those who exhibited no outstanding abstinent symptomatology. MAO activity levels measured in the 1st week of alcohol withdrawal were 3.49 +/- 1.15 (Mean +/- S.D) nmol/mg protein/hour in the alcoholic patients with delirium tremens, a value significantly lower than that in the subjects without (p less than 0.01) and that in the male normal subjects (p less than 0.001). Four weeks after withdrawal of alcohol, the reduced MAO activity levels in the alcoholic population were restored to normal levels. These data demonstrate that physical dependency for alcohol occurred evidently in the alcoholic patients examined. Delirium tremens and other psychotic symptoms in alcoholism may be manifested as impaired serotonin metabolism in the brain, which may be due to MAO inhibition caused by excessive alcohol intake.

Adult↗
PubMed1981

Platelet monoamine oxidase. I: Effect of temperature, anticoagulant, and centrifugation technique.

Platelet yield and monoamine oxidase (MAO) activity per platelet in platelets obtained by the method of Corash, which isolates essentially all platelets from whole blood, and by a single differential centrifugation of whole blood, were compared. Platelets recovered by one spin in a swinging bucket rotor appeared to be a homogeneous population containing a reliable representation of the platelet population obtained by the Corash method since the MAO specific activity yielded by the two methods was not significantly different. The effect of the anticoagulant, temperature, and type of rotor on platelet recovery from blood and MAO activity/platelet were also studied. The MAO and plasma amine oxidaze (PAO) activities obtained from blood anticoagulated with ethylenediaminetetracetate (EDTA) were significantly greater than those found when acid-citrate-dextrose was the anticoagulant. Blood centrifuged in a swinging bucket rotor at room temperature yielded 80-90% of total platelets as compared to the 45-65% recovered with a fixed-angle rotor at 0-4 C. The most efficient method of platelet isolation was found to be a 2 1/2-min room-temperature spin at 600 X g with a swinging bucket rotor using EDTA as anticoagulant.

Adult↗
PubMed1988

Monoamine oxidases of the human brain and liver.

The two molecular forms of monoamine oxidase (MAO), MAO-A and MAO-B, were determined quantitatively in discrete regions of the human brain at autopsy, and in cerebral microvessels, choroid plexus and liver samples from the same subjects. MAO was assessed by specific[3H] pargyline binding, which is stoichiometric and irreversible, and by measuring the rate of oxidation of several MAO substrates. Basal ganglia structures (caudate, putamen, globus pallidus and substantia nigra) and hippocampus had about twice the levels of MAO that were present in the cerebral cortex and cerebellum. Cerebral microvessels, which constitute the blood-brain barrier, had minimal MAO, while the choroid plexus, which constitutes the blood-cerebrospinal fluid barrier, and the liver had higher MAO levels than any brain region. The vast majority of MAO (80-95%) in these tissues was of the B type, except in microvessels, where total MAO activity was low. Specific [3H]pargyline binding correlated well with the oxidation rates for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and benzylamine in all tissues. Both specific [3H]pargyline binding and the rate of oxidation of MAO substrates increased with age.

Adult↗
PubMed2002

Increased baroreceptor response in mice deficient in monoamine oxidase A and B.

The recent development of mice doubly deficient for monoamine oxidase A and B (MAO-A/B, respectively) has raised questions about the impact of these mutations on cardiovascular function, in so far as these animals demonstrate increased tissue levels of the vasoactive amines serotonin, norepinephrine, dopamine, and phenylethylamine. We recorded femoral arterial pressures and electrocardiograms in adult MAO-A/B-deficient mice during halothane-nitrous oxide anesthesia as well as 30 min postoperatively. During both anesthesia and recovery, systolic, diastolic, and mean arterial pressures were 10-15 mmHg lower in MAO-A/B-deficient mice compared with normal controls (P < 0.01). Mutants also showed a greater baroreceptor-mediated reduction in heart rate in response to hypertension after intravenous pulses of phenylephrine or angiotensin II. Tachycardia elicited in response to hypotension after nitroprusside was greater in mutants than in controls. Heart rate responsiveness to changes in arterial pressure was abolished after administration of glycopyrrolate, with no differences in this phenomenon noted between genotypes. These data suggest that prevention of hypertension may occur in chronic states of catecholaminergic/indoleaminergic excess by increased gain of the baroreflex.

Adrenergic beta-Antagonists↗
PubMed1989

Modification of vesicular dopamine and norepinephrine by monoamine oxidase inhibitors.

The possible effects of inhibitors of the two forms of monoamine oxidase (types A and B) on dopamine (DA) and norepinephrine (NE) accumulation and metabolism in the cytoplasmic and microsomal (vesicular) fractions of the rat brain have been examined. It was found that, while L-DOPA treatment raised only cytoplasmic DA without affecting vesicular DA and NE, clorgyline and pargyline treatments caused significant increases in DA and NE concentrations in both cytoplasmic and vesicular fractions. The DA increase in the synaptic vesicles (200-600%) was much more pronounced than that (150%) in the cytoplasm. In contrast, deprenyl treatment increased vesicular DA only slightly without any effect on either vesicular or cytoplasmic NE. L-DOPA administration to rats pretreated with clorgyline and pargyline, but not with deprenyl, further increased cytoplasmic and vesicular DA and NE concentrations. However, excessive increases in vesicular DA lowered vesicular NE. Reserpine drastically reduced vesicular and cytoplasmic DA and NE, and L-DOPA administration to the reserpine-treated rats caused a DA increase only in the cytoplasmic fraction without affecting vesicular DA or NE. The effect of reserpine was abolished by pargyline treatment, which suggests that pargyline may interact with the reserpine-sensitive vesicular uptake. There was a significant correlation between vesicular DA and NE increase.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Conformational changes in monoamine oxidase A in response to ligand binding or reduction.

The structure of monoamine oxidase B revealed three aromatic amino acid residues within contact distance of the flavin cofactor and a large number of aromatic residues in the substrate binding site. Circular dichroism (CD) spectroscopy can detect alterations in the environment of aromatic residues as a result of ligand binding or redox changes. CD spectra of MAO A indicate that a small inhibitor such d-amphetamine perturbs the aromatic residues very little, but binding of the larger pirlindole (2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole hydrochloride) causes spectral changes consistent with the alteration of the environment of tyrosine and tryptophan residues in particular. Reduction of the flavin cofactor induces large enhancement of the CD signals in the aromatic region (260-310 nm). When covalent modification of the flavin by clorgyline accompanies reduction, the perturbation is even greater. In contrast to the static picture offered by crystallography, this study reveals changes in the aromatic cage on ligand binding and suggests that reduction of the cofactor substantially alters the environment of aromatic residues presumably near the flavin. In addition, the covalently modified reduced MAO A shows significant differences from the substrate-reduced enzyme.

Circular Dichroism↗
PubMed1986

Monoamine oxidase activity in the term human placenta.

Using a radioenzymatic assay, placental monoamine oxidase (MAO) activity was measured at term after delivery in normal and high-risk pregnancies where decreases in placental blood flow previously were shown. MAO activity in placentas of healthy controls after spontaneous labor was similar to that after elective cesarean section not in labor (mean +/- SE, 133 +/- 18 versus 100 +/- 15 nmol/min/mg protein, respectively). Compared to controls, there was a significant reduction in placental MAO activity in high-risk pregnancies (chronic hypertension, toxemia, and diabetes mellitus), 71 +/- 14, 69 +/- 22, and 69 +/- 7, respectively (P less than 0.05). These differences also were maintained when data were expressed per total placental weight. Effects of antihypertensive drugs on MAO activity in healthy placental tissue were assessed. In homogenates, both hydralazine and magnesium sulfate reduced enzyme activity, while in explants this was not observed. The effects of certain metabolites (which are elevated in plasma of diabetic patients) on healthy homogenates also were studied. Only butyrate reduced enzyme activity. In conclusion, placental MAO activity in vitro is low in term high-risk pregnancies. This may reduce local metabolic inactivation of catecholamines and serotonin and consequently lead to a decrease in blood flow. Such a direct relationship must be confirmed in further studies.

Antihypertensive Agents↗
PubMed2003

Monoamine oxidase inhibitory properties of optical isomers and N-substituted derivatives of 4-methylthioamphetamine.

(+/-)-4-Methylthioamphetamine (MTA) was resolved into its enantiomers, and a series of N-alkyl derivatives of the parent compound, as well as its alpha-ethyl analogue, were prepared. The monoamine oxidase (MAO) inhibitory properties of these substances were evaluated in vitro, using a crude rat brain mitochondrial suspension as the source of enzyme. All compounds produced a selective, reversible and concentration-related inhibition of MAO-A. (+)-MTA proved to be the most potent inhibitor studied, while all the other derivatives were less active than the parent compound, with (-)-MTA being about 18 times less potent than the (+) isomer. The analysis of structure-activity relationships indicates that the introduction of alkyl substituents on the amino group of MTA leads to a reduction in the potency of the derivatives as MAO-A inhibitors, an effect which increases with the size of the substituent.

Amphetamines↗
PubMed1998

Detection and analysis of four polymorphic markers at the human monoamine oxidase (MAO) gene in Japanese controls and patients with Parkinson's disease.

Monoamine oxidase (MAO), which exists in two forms (MAOA and MAOB), plays an important role in the oxidative metabolism of neurotransmitters such as dopamine, and has been implicated in the etiology of Parkinson's disease (PD). Individual variations in the activity of these enzymes appear to be genetically determined, and these genetic variations appear to be predominantly mediated by the MAO locus. Here, we detected and analyzed four polymorphic markers in the MAO gene using a polymerase chain reaction method in 228 Japanese controls (102 males and 126 females) and 68 patients with PD (30 males and 38 females). Although the analysis of the MAOA marker demonstrated no overall association between its alleles and PD, a significant difference in the frequency of one particular MAOA allele between controls and patients with PD was found. Moreover, in a comparison of the distribution of the full haplotypes at the MAOA locus, there was a significant difference in the frequency of one particular haplotype between male controls and patients with PD. In the MAOB polymorphism, there was no difference in the distribution of alleles between them. These findings support the hypothesis that the MAOA gene may affect the susceptibility of individuals to PD among MAOA polymorphic loci.

Adult↗
PubMed2005

Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response.

Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of biogenic amines, may be implicated in the pathogenesis of major depressive disorder (MDD) and be related to the therapeutic effects of antidepressants. To elucidate a genetic predisposition of MDD, we studied a variable-number-tandem-repeat (VNTR) polymorphism in the promoter region of the MAOA gene in a Chinese population of 230 MDD patients and 217 controls. We also examined the association of this polymorphism and antidepressant therapeutic response in the MDD patients who underwent a 4-week fluoxetine treatment. Our results showed a significantly increased frequency of 4-repeat (4R) allele in MDD patients, especially in the female population. Furthermore, MDD female patients who were 3R homozygotes had a significantly better response to 4-week fluoxetine treatment when compared to 4R carriers (p=0.024), but there was a nonsignificant difference found in male patients (p=0.081). Since the 4R allele transcribed 2-10 times more efficiently than those with 3R allele, our findings suggest that the MAOA-uVNTR may be involved in the pathogenesis of MDD and the antidepressant therapeutic mechanisms in Chinese population, and that there may be a gender effect in this association.

Adolescent↗
PubMed1981

Gene for monoamine oxidase type A assigned to the human X chromosome.

Inherited variations in monoamine oxidase (MAO) activity are thought to affect human behavior and expression of disease. The present study has established the chromosomal location of one of the structural genes coding for this enzyme. Mapping was carried out by somatic cell hybridization between normal human skin fibroblasts and mouse neuroblastoma cells. Selective media for growth of cells with or without hypoxanthine phosphoribosyltransferase (HPRT) activity were used to obtain hybrid lines which had retained or lost the human X chromosome, respectively. Cytogenetic techniques, isozyme analysis, and limited proteolysis and peptide mapping of [3H]pargyline-labeled MAO were used to characterize hybrid lines. With one exception, only lines containing the human X chromosome and human forms of two X-linked enzymes (phosphoglycerate kinase and glucose-6-phosphate dehydrogenase) expressed the human form of the flavin polypeptide of type A MAO. The exceptional hybrid line contained a putative translocation of part of the human X chromosome, since it expressed human forms of both MAO and phosphoglycerate kinase but neither the human form of glucose-6-phosphate dehydrogenase nor HPRT activity. This evidence indicates that the structural gene for the flavin polypeptide of MAO-A is on the human X chromosome. This represents the first chromosomal assignment of a human gene coding for an enzyme of neurotransmitter metabolism. This information will help to elucidate the structure of MAO and modes of its inheritance in the human population.

Animals↗
PubMed1989

The influence of monoamine oxidase activity on the release of noradrenaline by tyramine.

The influence of monoamine oxidase (MAO) activity on the kinetic characteristics of noradrenaline (NA) release evoked by tyramine has been examined. Dog splenic artery strips were incubated with [3H]NA after inhibition of catechol-O-methyl-transferase (COMT) and of extraneuronal uptake. In some experiments MAO was also inhibited. The strips were then perifused for 200 min. Some strips were exposed to tyramine (1.5, 40 and 3240 mumols L-1) from the 100th to the 200th min of perifusion. In control experiments (i.e. in the absence of tyramine) most of the [3H]NA accumulated in the strips (83% of tissue activity) and did not contribute to the efflux. The value of this "bound fraction" (the NA located at a site(s) from which it could not be displaced by a simple concentration gradient) was the same whether or not MAO was inhibited. At all concentrations, tyramine mobilized only one NA compartment. Increasing the concentration of tyramine resulted in a decrease of the "bound fraction", which became negligible for the highest concentration of tyramine used (3240 mumols L-1), regardless of MAO being inhibited or not. However, for the lower concentrations of tyramine, MAO inhibition resulted in an increase in the amine's releasing effect. The formation of 3,4-dihydroxy-phenylglycol (DOPEG) increased with increase of tyramine from the 1.5 to 40 mumols L-1 concentration, but not beyond. The ratio NA/DOPEG increased for all concentrations of tyramine. Thus, it was not possible to exclude an inhibitory effect of tyramine on MAO activity with the highest concentration used.

Animals↗
PubMed1993

Glucose modulation of islet monoamine oxidase activity in lean and obese hyperglycemic mice.

Islet beta-cell monoamines are known to influence the insulin-releasing mechanisms. These amines are localized in the insulin-secretory granules and are inactivated by the enzyme monoamine oxidase (MAO), a hydrogen peroxide (H2O2)-generating enzyme. The activity of islet MAO may consequently be of importance for insulin secretion. In the present investigation, we studied the relation between islet MAO activity and plasma levels of insulin and glucose in obese (ob/ob) hyperglycemic mice and their lean littermates. In addition, the effect of glucose on the MAO activity of in vitro-cultured islets was studied. MAO activity was assayed with serotonin, dopamine (DA), and beta-phenylethylamine (PEA) as substrates. After an overnight fast in adult (age, 6 months) lean mice, islet MAO activity was increased by 35% to 70%. Plasma levels of glucose and insulin were markedly decreased as expected. However, fasting in adult obese mice either did not affect islet MAO activity (PEA and DA) or induced a slight decrease (serotonin) of approximately 25% (P < .05). Plasma glucose levels in adult obese mice were not significantly affected by the overnight fast. However, a correlation analysis based on individual adult obese mice (fed and fasted) showed a negative correlation between plasma glucose concentration and islet MAO activity with PEA (r = -.65, P < .02) and DA (r = -.66, P < .02), respectively. Further, a positive correlation (r = +.58, P < .05) was found between glucose level and islet MAO activity when using serotonin as substrate. There was no difference in islet MAO activity with PEA and DA as substrates in fed obese versus fed lean mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Monoamine oxidases and alcoholism: studies in unrelated alcoholics, normal controls and alcoholic families.

Monoamine oxidases (A and B) are of great interest in connection with alcoholism. Low MAO activity has been found in the brains and the platelets of alcoholics and their relatives supporting the hypothesis that low MAO activity is a biological marker for vulnerability to misuse. In order to determine the role of the MAO genes in alcoholism we have measured MAO-B activity and typed two simple sequence repeats (one in the MAO-A gene and one in the MAO-B gene) in a sample of 133 unrelated alcoholics, 300 subjects from 30 two- and three-generation pedigrees ascertained through an alcoholic proband, and 92 normal controls. The unrelated alcoholic group did not differ in MAO-B activity from normal controls nor were there significant differences between subtypes. We did, however, find significant differences between alcoholic males and females (t = 2.836, p = .005), a difference that was not present in controls. A two-way analysis of variance of MAO-B activity as a function of the allelic variation of each marker locus and diagnosis among male subjects was performed. There was no evidence for mean differences in activity levels for different alleles. The distribution of MAO-A and MAO-B "alleles" in the alcoholic sample differed from that of the control sample. Affected sib pair linkage analysis of MAO genes and alcoholism showed no evidence for an excess of concordant affected sib pairs suggesting that this region of the X-chromosome does not harbor a susceptibility locus.

Adult↗
PubMed1994

Longitudinal observations of monoamine oxidase B in alcoholics: differentiation of marker characteristics.

The marker characteristics of monoamine oxidase B (MAO B) in human platelets were investigated in a clinical study of 59 alcoholics (diagnosed according to the criteria of ICD-10) observed over a period of 6 months. Demographic and family history were obtained by a structured interview, including the substance abuse section of CIDI (Composite International Diagnostic Interview). The patient's personality was assessed by Cloninger's Tridimensional Personality Questionnaire (TPQ). Blood samples were first drawn during chronic intoxication (day of admission to the hospital for detoxication), after short-term abstinence (8 days later), medium-term (3 months later), and long-term abstinence (6 months later). A group of 22 matched healthy nonalcoholics served as controls studied under sober conditions and during acute intoxication (4 hr after ingestion of 1 g ethanol/kg body weight). All platelet samples were investigated with 6 kynuramine concentrations as substrate (fluorometric assay) in the absence and presence of 200 mM ethanol (ETOH) in vitro. MAO B activity was significantly reduced in alcoholics during chronic intoxication (Vmax: 2.70 +/- 0.15 nmol/mg protein) compared with sober (Vmax: 3.25 +/- 0.23 nmol/min/mg protein) and acutely intoxicated controls that turned to normal during abstinence. However, MAO B activity obtained during medium- and long-term abstinence was significantly lowered in patients with high novelty-seeking and impulsiveness scores in the TPQ, a history of suicide attempts, or an alcoholic mother. The affinity of MAO B (Km values) was unchanged in alcoholics at any time investigated. Addition of ETOH in vitro reduced the affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗