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PubMedDate not supplied

Catechol-O-methyltransferase activity in erythrocytes of children with autism.

1. The activity of the enzyme catechol-O-methyltransferase (COMT) was determined in the erythrocytes of normal and autistic children. 2. There was no difference in enzyme activity between the two groups, although in both the normal and autistic females the erythrocyte COMT activity showed considerable within-group variation. 3. When the erythrocyte homogenates were divided into particulate and soluble fractions, some differences were observed. The COMT activity in the soluble fraction was less in erythrocytes from autistic males than in those from control males, whereas that in autistic females was higher than in those from control females.

Autistic Disorder↗
PubMed1977

Monoamine oxidase and catechol-O-methyl transferase activity in Tetrahymena.

Tetrahymena pyriformis strain HSM was found to have monomine oxidase (MAO) and a catechol-3-methyl transferase-like (COMT) activity. As in mammalian tissues, the MAO activity is predominantly localized in the mitochondrial pellet and COMT in the cytosol. The COMT-like activity was present in amounts comparable to several mouse tissues and was inhibited by tropolone. MAO activity was much lower than in any of the mouse tissues tested, and its activity varied greatly from preparation to preparation. The substrate preference of Tetrahymena MAO was tryptamine greater than serotonin greater than dopamine, and activity increased with increasing pH from pH 6.5 to pH 7.8, as does that of mouse liver MAO. Teh Km of Tetrahymena MAO for tryptamine was approximately 4 micrometer, an order of magnitude lower than that of mouse liver MAO. Sensitivity of inhibition by MAO inhibitors was variable. In some preparations, no inhibition was observed. In others clear inhibition was obtained, harmine and clorgyline being among the most potent inhibitors.

Animals↗
PubMed1976

A comparative study of the role played by some inactivation pathways in the disposition of the transmitter in the rabbit aorta and the saphenous vein of the dog.

The aim of this study was to determine the relative importance of neuronal uptake, catechol-O-methyltransferase (COMT) and diffusion in the disposition of endogenous nor-adrenaline (NA) in the rabbit aorta and dog saphenous vein. Helical strips of dog saphenous vein and rabbit aorta were stimulated transmurally, relaxation occurring either in oil or in Krebs-Henseleit solution. The rate of inactivation of NA by various mechanisms was assessed from the decrease in the rate of relaxation after blockade of one or more of these processes. Cocaine was used to inhibit neuronal uptake and COMT was blocked with 3,4-dihydroxy-2-methyl propiophenone. Diffusion out of the tissue was prevented by replacing the Krebs-Henseleit solution in the muscle bath with mineral oil. Neuronal uptake was the primary mechanism of inactivation in the saphenous vein whereas diffusion and COMT appear to be more important in the aorta. The differences in the relative importance of the inactivation mechanisms (neuronal uptake, O-methyltransferase and diffusion) existing between these two vessels are attributed primarily to differing density and distribution of the adrenergic innervation.

Animals↗
PubMed1979

Influence of progressive starvation upon brain and adrenal monoaminergic activity in developing rats of two different ages.

Experiments show the influence of progressive starvation upon the synthetic and metabolic activity of monoaminergic function in the brain and the adrenal gland of young rats of two different ages. Brain and adrenal monoamine oxidase (MAO) showed a tendency to decline with the prolongation of the starvation interval. After 60 h of starvation, MAO activity was irreversibly decreased, even with 24 h of feeding, in the two age groups. Cerebral catechol-O-methyltransferase (COMT) activity was very slightly affected in response to the starvation in the older group, but the younger group showed an increased level of enzyme activity, and refeeding after 60 h of starvation of the young rats produced further increases. 60 h of starvation produced an increase in COMT activity of the adrenal gland of the older rats whereas the younger group did not show any marked change. Adrenal phenylethanolamine-N-methyltransferase (PNMT) declined after 24 and 48 h of starvation in the older rats, but the younger rats showed progressive increases after similar intervals of starvation. After 60 h of starvation, PNMT in the adrenal gland of the old rats increased significantly when compared to the control value, but the younger rats did not show any important change. Adrenal stores of adrenaline rose progressively up to 60 h of starvation in the old rats whereas the younger group responded in a contrary manner. Adrenal noradrenaline followed a similar pattern of evolution in both groups up to 60 h of starvation (when the results are expressed per milligram of adrenal protein), and refeeding had very little influence on the effects of starvation. The effects of starvation upon adrenal and cerebral MAO activity were verified with two different substrates. The results provide evidence that the metabolism of monoamines by oxidative deamination can be markedly affected by starvation, and this can be irreversible even after 24 h of feeding of starved rats. COMT activity augments when MAO activity declines.

Adrenal Glands↗
PubMed1976

Red blood cell catechol O-methyl transferase and response to imipramine in unipolar depressive women.

When baseline red blood cell catechol O-methyltransferase (COMT) was measured in 15 unipolar depressive women, the authors found a linear correlation between COMT and response to imipramine (best outcome occurring at low COMT). The results of this study were not related to such variables as intensity of depression, family history, or psychiatric history. The authors suggest that this assay may be useful either as a predictor of response to the drug or as a guide in choosing the optimum dose.

Adult↗
PubMed1978

Catechol-O-methyl transferase activity in patients with depressive illness and anxiety states.

Erythrocyte catechol-O-methyl transferase (COMT) activity was studied in 65 patients with depressive illness and anxiety states. A hypothesis that measurement of this enzyme might have some value as an aid to diagnosis and as an index of clinical recovery has not been confirmed. In patients with endogenous depression, agitated subjects had COMT levels significantly higher than normal (P less than .01) and retarded subjects had levels significantly lower than normal (P less than .02). These observations are congruent with some reports of high and low urinary MHPG excretion in patients with depression. Further data correlating COMT assays with catecholamine metabolites in depressed patients may reveal homogeneous biochemical subgroups which could serve as a guide to rational therapy.

Anxiety↗
PubMed1979

Catechol-O-methyltransferase activity and classification of depression.

Red blood cell catechol-O-methyltransferase (COMT) activity was compared across different depressive diagnoses. In a sample of 88 depressed inpatients, using defined criteria, no difference was found in respect of enzyme activity and the following categories: primary, secondary, delusional, nondelusional, endogenous, nonendogenous (neurotic), characterological depressions. COMT did not vary with age or sex. A significant increase in COMT activity was noted in agitated, depressed males, as compared to other groups.

Adult↗
PubMed2024

Associations between (pharmaco-)genetic markers and postoperative pain after inguinal hernia repair - a prospective study protocol.

BACKGROUND: Postoperative pain is a common complication following surgery, with severity and duration varying between patients. Chronic postoperative pain after inguinal hernia surgery has an incidence rate of approximately 10%. Risk factors for acute and chronic pain following hernia surgery include age, sex, psychosocial factors, and demographic background. Additionally, genetic polymorphisms in enzymes involved in pain mechanisms, as well as the metabolism of analgesics might influence pain perception, pain development, and response to pain medications. Key enzymes include the catechol-o-methyltransferase (COMT), the µ-opioid receptor 1 (OPRM1), and the cytochrome P450 2D6 (CYP2D6). CYP2D6 plays a crucial role in metabolizing analgesics such as tramadol, codeine, and oxycodone. It is also suspected to be involved in the synthesis of catecholamines and endogenous morphines suggesting a potential role in pathophysiology of pain. We hypothesize that the CYP2D6 activity influences the development of postoperative pain after hernia surgery. METHODS: This study is a prospective, observational, multicenter association study investigating adult patients scheduled for inguinal hernia surgery using a robotic-assisted (rTAPP) approach. Patients are enrolled during the preoperative surgical consultation. A buccal swab is collected for genetic testing at this time. Pain at the site of the hernia is assessed using the validated EuraHSQoL score preoperatively and at 2, 4, and 6 weeks postoperatively. Additionally, information on co-medication and details of the surgery will be collected. The planned number of participants is 350 patients. The primary objective is to analyze the association between different genotype-predicted CYP2D6 phenotypes and patient-reported pain intensity 6 weeks after surgery. Secondary objectives include the association between further genetic variants, such as the COMT rs4680 and OPRM1 rs1799971 genotype, and pain severity. Additionally, the potential of pharmacogenetic panel testing to optimize analgesic therapy in hernia surgery patients will be explored. DISCUSSION: The findings of this study are expected to provide valuable insights into identifying patients at higher risk for postoperative pain before surgery. This knowledge could pave the way for tailored interventions during and after surgery for these specific patients. TRIAL REGISTRATION: Deutsches Register Klinischer Studien https://www.drks.de/DRKS00034796 Registered on August 07, 2024.

Genetic Association Studies↗
PubMed1977

Monoamine metabolism in human brain.

Norepinephrine (NE), dopamine (DA), tyrosine hydroxylase (TH), catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) levels were measured in human brain tissue obtained at autopsy from a series of 39 patients dying of various medical and accidental causes. The nine following brain areas were studied: globus pallidus, thalamus, hypothalamus, hippocampus, substantia nigra, floor of the fourth ventricle, orbital cortex, caudate nucleus, and mammillary bodies. Enzyme activity correlated positively with age in all brain areas for MAO (with both benzylamine and tryptamine substrates) but no consistent pattern of correlation was found for COMT and TH. Mean MAO activity was significantly higher in women than men. There is increased brain MAO activity during late childhood and adolescence. These data are consistent with previous evidence suggesting that age and sex are important determinants of amine metabolism in the human central nervous system.

Adolescent↗
PubMed1978

The neuronal and extraneuronal uptake and metabolism of 3H-(-)-noradrenaline in the perfused rat heart.

1. Hearts were obtained from reserpine-pretreated rats and perfused with 0.95 micron 3H(-)-noradrenaline. The rate of removal of 3H-noradrenaline from the perfusion fluid was measured (from the arterio-venous difference) as well as the rate at which the 3H-metabolites appeared in the venous effluent. 2. When either 30micron corticosterone was added under steady-state conditions during perfusion with 3H-noradrenaline (to inhibit neuronal and extraneuronal uptake, respectively), each inhibitor reduced the removal of noradrenaline by about 50%; in the presence of both inhibitors removal was abolished. 3. Dihydroxymandelic acid (DOMA) was of neuronal, normetanephrine (NMN) of extraneuronal origin; dihydroxyphenylglycol (DOPEG) and the OMDA fraction (containing methoxyhydroxyphenylglycol-MOPEG-and methoxyhydroxymandelic acid-VMA) were formed both neuronally and extra-neuronally. 4. The extraneuronal metabolism of 3H-noradrenaline was in quick equilibrium with the 3H-noradrenaline in the perfusion fluid; most of the total formation of DOPEG, MOPEG and NMN was recovered from the venous effluent. 5. Extraneuronally formed DOPEG, MOPEG and NMN distributed in the tissue with half times corresponding to their half time for efflux. 6. Inhibition of monoamine oxidase (MAO) by pargyline increased the extraneuronal formation of NMN; MAO and catechol-O-methyl transferase (COMT) appear to be contained in the same extraneuronal compartment. 7. The extraneuronal accumulation of 3H-noradrenaline required 30 min or more to reach a steady state; inhibition of one or both enzymes slowed this process. Inhibition of MAO increased the extra-neuronal accumulation of 3H-noradrenaline; inhibition of COMT failed to do so, since the enzyme inhibitor (U-0521) was a weak inhibitor of extra-neuronal uptake. 8. The rate constants for the efflux of the metabolites of noradrenaline decreased in the order of MOPEG greater than DOPEG greater than NMN greater than DOMA greater than VMA.

Animals↗
PubMed1975

Relation between the amount of smooth muscle of venous tissue and the degree of supersensitivity to isoprenaline caused by inhibition of catechol-O-methyl transferase.

The relation between the smooth muscle cell mass of dog saphenous vein strips and the degree of supersensitivity to isoprenaline caused by U-0521 (3,4-dihydroxy-2-methyl propiophenone), an inhibitor of the catechol-O-methyl transferase (COMT), was studied. For the quantitative determination of smooth muscle mass, the thickness of the muscle layer as determined by light microscopy and the maximal shortening induced by supramaximal concentration of phenylephrine were used. After the strips had been contracted by 3x10-6M phenylephrine, a concentration which was able to produce an about 90% maximal contraction, dose-response curves to the relaxant effect of isoprenaline were determined in the absence and in the presence of U-0521 (10-4M). It was observed that U-0521 caused marked supersensitivity to the relaxant effect of isoprenaline (varying between 3 and 81 times), as well as an increase of the maximal relaxation caused by this amine (varying between 7 and 120%). The correlation between these data and the smooth muscle cell mass shows that there was a direct proportionality between these parameters. Oxytetracycline (10-4M), an inhibitor of binding of catecholamines to collagen, did not produce any enhancement of the effects of isoprenaline. It is concluded that COMT is related to smooth muscle cells in this tissue.

Animals↗
PubMed1979

An assay for human erythrocyte catechol-O-methyltransferase activity using a catechol estrogen as the substrate.

A radiometric assay for catechol-O-methyltransferase (COMT) activity in human erythrocytes is described that employs 2-hydroxy[3H]estrone, and non-radiolabeled S-adenosylmethionine (SAM) as the cosubstrates. The ease of separation of the product of the reaction, 2-methoxy[3H]estrone from 2-hydroxy[3H]estrone makes it possible to achieve low reaction blanks. The assay is very sensitive, and only 200 microliter of whole blood are used per determination. The assay is highly reproducible. The interassay variability (coefficient of variation) was 6.5% for 24 assays of COMT activity in red blood cells in blood obtained daily for 24 days from one person. In incubations conducted at 37 degrees C for 30 min, the catechol-O-methyltransferase activity was a linear function of enzyme concentration (equivalent to 11 to 180 microliter of packed red blood cells). Employing this assay, we evaluated the catalytic conversion of 2-hydroxyestrone to 2-methoxyestrone by catechol-O-methyltransferase from human red blood cells and found that the apparent Michaelis constant and the apparent maximal rate of reaction were 3 x 10(-7) M and 6.7 x 10(-9) mol . ml-1 erythrocytes . h-1, respectively. The catechol-O-methyltransferase activity measured in erythrocytes obtained from 100 healthy subjects (men and nonpregnant women) was 8.2 +/- 0.17 (mean +/- S.E.) nmol 2-methoxyestrone . ml-1 erythrocytes . h-1.

Carbon Radioisotopes↗
PubMed1975

Further study of the adrenoceptors of the saphenous vein of the dog: influence of factors which interfere with the concentrations of agonists at the receptor level.

In the present study the affinities of some sympathomimetic amines for alpha- and beta-adrenoceptors of the dog saphenous vein tissue were determined after all known factors interfering with the concentration of these agonists at the receptor level had been assessed and excluded. It was observed that in control experiments the relative potencies of sympathomimetic agonists for inducing contractions were: adrenaline (1.6) greater than noradrenaline (1.0) greater than phenylephrine (0.38) greater than isoprenaline (0.009). The elimination of neuronal uptake by cocaine, 4 X 10(-6) M, enhanced predominantly the effects of noradrenaline (by a factor of 7.5), whereas block of catechol-O-methyl transferase (COMT) by U-0521, 10(-4) M, only enhanced those of adrenaline (by a factor of 2.6) and block of beta-adrenoceptors by propranolol, 5 X 10(-7) M, enhanced those of isoprenaline (by a factor of 3) and adrenaline (by a factor of 1.8). Block of COMT enhanced the effects of adrenaline approximately as much as did the blockade of neuronal uptake; this seems to indicate that the affinity of adrenaline for extraneuronal and neuronal uptake processes is approximately the same. Regarding the relaxation-inducing capacity of sympathomimetic agents it was observed that isoprenaline, adrenaline and noradrenaline are full agonists, whereas phenylephrine was not able to produce relaxation amounting to more than 5% of the maximum. Denervation did not modify the relaxant effects of isoprenaline. After elimination of all known factors interfering with the concentration of the sympathomimetic agonists in the biophase, the ratios between the ED50's of each amine for alpha- and beta-adrenoceptors were: adrenaline = 34, noradrenaline = 109 and isoprenaline = 0.0041.

Animals↗
PubMed1975

Regional brain catechol-O-methyl transferase: age related differences in the mouse.

Activity levels of COMT were measured in the frontal cortex, hippocampus, hypothalamus and amygdala of two strains of male mice, C57BL/6J and DBA/2J, at various ages between 2 and 30 months. Determinations were made in mice housed under normal conditions and in mice exposed to a form of mild stress, an open-field apparatus, for 5 minutes. There were no major significant differences between the two strains as a function of age. However, after the open-field experience, C57BL/6J mice appeared significantly more responsive to the environment, as interpreted by increases in COMT, than DBA/2J mice. Interpretation is offered that C57BL/6J mice possess a more labile norepinephrine system, in spite of aging, than DBA/2J mice.

Age Factors↗
PubMed1977

Tissue levels of S-adenosylmethionine in aging rats.

The tissue levels of S-Adenosylmethionine (SAMe) in 30-mo.-old rats were measured, and a remarkable decrease was observed compared to adult rats. The synthesis of SAMe by the methionine-activating enzyme and its utilization by COMT were investigated in different tissues. The activity of the synthesizing enzyme was unchanged in the liver and brain of adult and senescent rats, while COMT activity appeared to be higher in the aging rats. Thus, the result indicates that the decrease of same in these organs of senescent rats is due to the increased utilization rather than the decreased synthesis of this methyl donor compound.

Adrenal Glands↗
PubMed1977

Effects of pharmacologic alterations of adrenergic mechanisms by cocaine, tropolone, aminophylline, and ketamine on epinephrine-induced arrhythmias during halothane-nitrous oxide anesthesia.

The purpose of this study was to examine the effects of pharmacologic alterations of adrenergic terminating mechanisms by cocaine, tropolone, aminophylline, and ketamine on the ability of epinephrine to induce arrhythmias during halothane-nitrous oxide anesthesia in dogs. Because the first three drugs inhibit intraneuronal uptake of catecholamines, extraneuronal catechol-O-methyl transferase (COMT), and phosphodiesterase, respectively, they might be expected to potentiate epinephrine-induced arrhythmias. To evaluate this possibility, the authors devised a technique for determining the minimal arrhythmic dosage of epinephrine that permitted graded assessment of changes in the sensitivity of the heart to epinephrine-induced arrhythmias. When the first three drugs were administered to the same dog in the order listed at intervals of 60 minutes, they sequentially increased the ability of epinephrine to induce arrhythmias. Ketamine, according to several investigators, also appears to block reuptake of catecholamines, and when studied was also found to enhance the arrhythmogenicity of epinephrine. The extent of enhancement was comparable to that seen with cocaine. These results indicate that drugs like cocaine and ketamine that interfere with intraneuronal uptake can facilitate the development of epinephrine-induced arrhythmias and that the successive pharmacologic interference of intraneuron uptake, COMT, and phosphodiesterase leads to a stepwise increase in the arrhythmogenicity of epinephrine.

Aminophylline↗
PubMed1979

Monoamine oxidase and catechol-o-methyltransferase activity in cultured fibroblasts from patients with maple syrup urine disease, Lesch-Nyhan syndrome and healthy controls.

Monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) activities have been measured in fibroblasts from nine healthy controls, three patients with maple syrup urine disease (MSUD) and six patients with Lesch-Nyhan syndrome. Both A and B types of MAO activity are found in these cell lines. In comparison to controls, the MAO activity is significantly reduced in cells from patients with Lesch-Nyhan syndrome. A different situation has been observed in the cell lines from MSUD patients: one showed a high MAO activity, another a significantly reduced activity, and the third was in the range of the normal controls. COMT activity is also present in these cells, but with a wide variation. No specific differences have been noted among the controls and the mutant cells.

Catechol O-Methyltransferase↗
PubMed1976

Decreased phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase activity in rabbit adrenal glands during pregnancy.

1 Phenylethanolamine-N-methyltransferase (PNMT) activity in adrenal gland was lower than the control values at day 24 of rabbit pregnancy and fell throughout the gestational period. 2 Catechol-O-methyltransferase (COMT) activity during pregnancy and parturition followed a similar pattern to PNMT. 3 Adrenaline content of the adrenal gland declined significantly during the last few days of pregnancy but at parturition showed a tendency to return towards normal. 4 The biochemical mechanisms which result in a decline in PNMT and COMT activities and adrenaline concentration appear to be the consequence of modifications in endocrine gland secretion during pregnancy.

Adrenal Glands↗