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PubMed1977

Solubilization and partial purification of particulate catechol-O-methyltransferase from rat liver.

Particulate catechol-O-methyltransferase (COMT) from rat liver has been solubilized by acetone treatment and partially purified. Results from the present study demonstrate that the solubilized, partially purified enzyme is similar to the cytosol COMT with respect to molecular weight, pH profile, sensitivity toward inhibitors, Mg2+ requirement, and substrate affinities. However, a comparison of the crude particulate COMT and the solubilized enzyme shows that there is a significant difference in their affinity for catechol substrates. This finding suggests that membrane protein and (or) lipid components may play an important role in catecholamine metabolism. The relationship of particulate COMT to [3H]norepinephrine binding was investigated. No correlation between the COMT and [3H]norepinephrine binding activities was observed in vitro.

Animals↗
PubMed1978

Human biochemical genetics of plasma dopamine-beta-hydroxylase and erythrocyte catechol-o-methyltransferase.

The purpose of the studies reviewed here was to investigate the role of inheritance in the regulation of human plasma dopamine-beta-hydroxylase (DBH) and human erythrocyte (RBC) catechol-O-methyltransferase (COMT) activities. DBH is a catecholamine biosynthetic enzyme and COMT is catecholamine metabolic enzyme. It has been suggested that the level of the activities of these enzymes in human blood might reflect the function or status of the adrenergic nervous system. Both enzyme activities were measured in blood samples from large, randomly selected populations of children, adolescents, and adults, and in the blood of first-degree relatives of subjects with either very low plasma DBH activity (less than 50 U/ml) or very low RBC COMT activity (less than 8U/ml). A radioimmunoassay for human plasma DBH was also used in these studies. The results of sibship and pedigree analyses of data from families of probands with very low enzyme activities were compatible with the autosomal recessive inheritance of an allele for very low plasma DBH activity that results in a decrease in DBH protein in plasma, and the autosomal recessive inheritance of an allele for low erythrocyte COMT activity.

Catechol O-Methyltransferase↗
PubMed1977

Effect of estradiol and testosterone on catechol-O-methyl transferase activity of rat superior cervical ganglion, pineal gland, anterior hypophysis and hypothalamus.

The effect of estradiol and testosterone on the activity of catechol-O- methyl transferase (COMT) of the superior cervical ganglion, pineal gland, anterior hypophysis and hypothalamus were examined in castrated rats. In female rats a single injection of 2 mug of estradiol caused a significant 25% increase of hypothalamic COMT, whereas after 3 daily injections no differences in enzyme activity were observed between hormone- and vehicle-injected controls. In male rats testosterone propionate (0.5 mg) increased hypothalamic COMT by 53%; this effect was not detectable in animals treated with the androgen for 3 days. COMT activity of the superior cervical ganglion, pineal gland and anterior hypophysis did not exhibit significant changes after any of the hormone schedules used.

Animals↗
PubMed1979

Catechol-O-methyltransferase activity in erythrocytes of women taking oral contraceptive steroids.

We have measured catechol-O-methyltransferase (COMT) activity in erythrocytes (red blood cells, RBCs) obtained from 64 women taking oral contraceptives steroids and compared these values with those found in RBCs obtained from 73 women using nonsteroidal contraceptives. The COMT activity in the RBCs of women taking oral contraceptives steroids and of women not taking contraceptive steroids was 9.1 +/- 0.28 (mean and standard error) and 8.8 +/- 0.26 nmoles 2-methoxyestrone X ml-1 RBC X hr-1, respectively. This difference in the COMT activity in RBCs from these two groups of women was not statistically significant. This finding differs from that of others who found that COMT activity in RBCs of women taking oral contraceptive steroids was greater than that of women not taking such drugs.

Adult↗
PubMed1978

Studies on the monoamine oxidase and catechol-O-methyltransferase of the rat cerebral microvessels.

The rat cerebral microvessels were isolated and assayed both for monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT) activities. Cerebral microvessels and brain filtrate were found to contain both forms (A & B) of MAO. On a per mg protein basis, the cerebral microvessels contained the greatest activity of MAO and COMT than that of brain filtrate and mesenteric artery. Chemical sympathectomy using 6-hydroxydopamine neither decreased total MAO activity, nor the A form of the enzyme, nor did it have any effect on COMT activity in the brain microvessels. These results suggest that COMT and both forms of MAO in the rat brain microvessels are extraneuronal in origin.

Animals↗
PubMed2026

Environmentally relevant concentrations of DCOIT impaired lifespan and healthspan in Caenorhabditis elegans.

DCOIT (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one) is an antifouling biocide widely used as an alternative to organotin compounds. While previous studies had focused on its effects on energy production, endocrine disruption, and lipid metabolism, its impact on aging and underlying mechanisms remained unclear. Here, we demonstrated that environmentally relevant concentrations of DCOIT (37, 370 and 3700 ng/L) significantly impaired both lifespan and healthspan in Caenorhabditis elegans. RNA-seq and validation assays revealed that DCOIT upregulated comt-4, a key gene in dopamine metabolism, leading to dopamine depletion and subsequent induction of oxidative stress. This redox imbalance critically contributed to accelerated aging phenotypes. Importantly, both genetic (comt-4 RNAi) and pharmacological (opicapone) interventions restored dopamine levels, alleviated oxidative stress, and reversed DCOIT-induced aging deficits. Our study established the comt-4/dopamine/oxidative stress axis as a central mechanism in DCOIT toxicity, suggesting dopamine modulation as a potential countermeasure against environmental toxicant-induced aging.

Animals↗
PubMed1978

Activities of types A and B MAO and catechol-o-methyltransferase in blood cells and skin fibroblasts of normal and chronic schizophrenic subjects.

We assayed activities of monoamine oxidase (MAO) type B in blood platelets and type A (and B) in fibroblasts cultured from punch biopsy specimens of skin, as well as of catechol-O-methyltransferase (COMT) in erythrocytes and fibroblasts. Fibroblasts contained moderate amounts of both forms of MAO (types A and B) found in human brain and large amounts of COMT activity. Activities of both enzymes correlated poorly between fibroblasts and blood cells. Comparing carefully diagnosed chronic schizophrenics with age-matched normal young men, we found no difference in these biochemical variables, nor could we distinguish patients with paranoid symptoms. In contrast, we confirmed markedly lower MAO activities in platelet samples from chronic patients provided by colleagues at the National Institute of Mental Health. Results concerning MAO and COMT activities are now sufficiently inconsistently characteristic of schizophrenics as to question their clinical applicability and to indicate a need for further critical evaluation, with special attention to diagnosis, matching of subjects, and effects of possible spurious environmental variables.

Adolescent↗
PubMed1978

Catechol-O-methyltransferase activity in erythrocytes of pregnant women.

Catechol-O-methyltransferase (COMT) is the enzyme that converts catechols, e.g., catecholamines and catechol estrogens, to their methyl ethers. COMT activity measured in erythrocytes (RBC's) of healthy men (No. = 47) and healthy nonpregnant women (No. = 53) was 8.2 +4- 0.17 nmoles X ml.-1 (mean and standard error). The COMT activity in RBC's of healthy pregnant women (No. = 100) was 10.7 +/- 0.29 nmoles X ml.-1 RBC X hr.-1, a value which is significantly higher than that found in RBC's of men and nonpregnant women (p less than 0.001).

Adolescent↗
PubMed1979

Immunohistochemical demonstration of catechol-o-methyltransferase in mammalian brain.

Catechol-O-methyltransferase (COMT)(EC 2.1.1.6) was localized using fluorescence immunohistochemistry in rat liver and kidney and in rat, chinchilla, and bovine brains. In the brain, specific fluorescence was visable only in non-neuronal cellular elements in all three species. Ventricular ependymal cells and cells of the choroid plexuses exhibited the greatest intensity of immunofluorescence. Glial immunofluorescence appeared prominently in large myelinated fiber tracts. Interfascicular and perineuronal satellite oligodendrocytes as well as fibrous astrocytes were immunoreactive, though myelin itself did not exhibit a positive reaction. Bergmann glial cells in the cerebellum also stained brightly for COMT. Although this study indicates that the predominant localization of COMT is non-neuronal, it is important to note that the presence of small quantities of this enzyme in neurons cannot be excluded. The patterns of localization observed in the non-neuronal elements suggest that this enzyme may function as a barrier to free diffusion of catechol compounds within the central nervous system.

Animals↗
PubMed1978

Influence of endogenous S-adenosylmethionine on the determination of catechol O-methyltransferase activity in red blood cells.

A double isotope method for the simultaneous determination of S-adenosylmethionine (SAM) and catechol O-methyltransferase (COMT) activity in red blood cells was developed. Healthy persons contained 7.9 +/- 1.9 nmol SAM per ml red blood cells and 1.9 to 3.8 nmol per ml plasma. Epinephrine increases the SAM biosynthesis rate in red blood cells. The possible influence of endogenous SAM on previous methods to determine COMT activity in red blood cells is discussed. The statement of Briggs and Briggs (Briggs, M.H. and Briggs, M. (1973) Experientia 29, 278--281) that COMT activity in red blood cells is lower during the last 3 months of pregnancy could not be verified by us.

Catechol O-Methyltransferase↗
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↗
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↗
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↗
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↗