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PubMed1997

G/A1947 polymorphism in catechol-O-methyltransferase (COMT) gene in Parkinson's disease.

High and low catechol-O-methyltransferase (COMT) activity is significantly determined by thermostability, which is caused by a valine/methionine108 polymorphism associated with polymorphic G/A1947 bases, in exon 4 of the COMT gene. Our allelic association study on this polymorphism did not find any statistically significant difference between our Chinese Parkinson's disease and that of control subjects. These results show that this polymorphism and hence the thermostability of COMT enzyme are not related to a risk of developing Parkinson's disease.

Aged↗
PubMed1975

Catechol-O-methyl transferase and monoamine oxidase activities in brains of mice susceptible and resistant to audiogenic seizures.

The activities of catechol-O-methyl transferase (COMT), monoamine oxidase (MAO), and a methanol forming enzyme were studied in whole brain homogenates and in livers obtained from DBA/2J, C57B1/6J, and F1 hybrid mice. DBA/2J mice are extremely susceptible to audiogenic seizures, whereas C57B1/6J mice are resistant to sound-induced convulsions. C57B1/6J mice were found to have significantly higher brain levels of COMT, while MAO activities were not different in animals of these genotypes. No methanol forming activity was detected in animals of either strain. No differences were found in hepatic activities of either COMT or MAO. Pyrogallol was shown to protect DBA/2J animals against audiogenic seizures.

Acoustic Stimulation↗
PubMed2004

Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.

Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, major depression, and normal controls (n = 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions.

Adult↗
PubMed2000

Kinetics of rat brain and liver solubilized membrane-bound catechol-O-methyltransferase.

Catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of catecholamines, is present in mammals as soluble (S-COMT) and membrane-bound (MB-COMT) forms. The kinetic properties of rat liver and brain solubilized MB-COMT were evaluated and compared with the ones of the respective native enzymes. Treatment with Triton X-100 did not affect the affinity of S-COMT for the substrate (adrenaline) or the activity of the enzyme. Conversely, solubilized MB-COMT presented a lower affinity for the substrate than the native protein, as evidenced by a significant increase in the Km values: 9.3 (6.2, 12) vs 2.5 (0.8, 4.3) microM for the liver enzyme and 12 (11, 13) vs 1.4 (1.0, 1.9) microM for the brain enzyme. A 1.6- and 1.5-fold increase in Vmax was also observed for the liver and brain solubilized enzymes, respectively. The actual enzyme concentrations (molar equivalence, Meq) and their efficiency in the O-methylation reaction (catalytic number, Kcat) were determined from Ackermann-Potter plots. Both liver and brain solubilized MB-COMT were more efficient in methylating adrenaline than the respective native enzymes as revealed by higher Kcat values (P < 0.05): 16.4+/-0.9 vs 10.9+/-0.8 min(-1) (brain) and 5.9+/-0.3 vs 3.3+/-0.2 min(-1) (liver). Subjecting liver solubilized MB-COMT to further purification increased the Km of the enzyme to the levels of liver S-COMT, 252 (127; 377) vs 257 (103; 411) microM. The solubilization process significantly alters MB-COMT kinetic properties but only after partial purification does the enzyme present an affinity for the subtrate identical to S-COMT.

Animals↗
PubMed1996

No association between Parkinson's disease and low-activity alleles of catechol O-methyltransferase.

Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine. Treatments attempt to correct this deficit by the use of levodopa and inhibitors of dopamine metabolising enzymes such as catechol-O-methytransferase (COMT). A common amino-acid polymorphism in COMT, valine-108-methionine, results in a low activity form of the enzyme which we hypothesised may influence susceptibility to IPD. We examined this polymorphism in 139 Caucasian subjects with IPD and 173 control subjects, using a PCR-RFLP and a novel Amplification Refractory Mutation System (ARMS) assay. Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD. We have also characterised a new polymorphism, 256C/G, which is not associated with IPD. However it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.

Alleles↗
PubMed2000

Olive oils rich in natural catecholic phenols decrease isoprostane excretion in humans.

This study was undertaken to evaluate, in humans, the antioxidant activity of olive oil phenolics, namely hydroxytyrosol and oleuropein aglycone that share an orthodiphenolic (catecholic) structure. Human volunteers were administered olive oil samples containing increasing amounts of an olive oil phenolic extract that was characterized by gas-chromatography/mass spectrometry. The administration of phenol-rich oils was dose-dependently associated with a decreased urinary excretion of 8-iso-PGF(2alpha), a biomarker of oxidative stress. Also, a statistically significant negative correlation between homovanillyl alcohol (HValc, hydroxytyrosol's major metabolite, formed through the COMT system) and F(2)-isoprostanes excretion was found. Thus, the administration of oil samples with increasing, albeit low, concentrations of orthodiphenolic compounds, namely hydroxytyrosol and oleuropein aglycone, results in a dose-dependent reduction in the urinary excretion of 8-iso-PGF(2alpha). The statistically significant negative correlation between 8-iso-PGF(2alpha) and HValc urinary concentrations suggests that this metabolite better reflects the in vivo activities of hydroxytyrosol.

Adult↗
PubMed2001

L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase.

High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.

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↗
PubMed1990

Behaviour and properties of catechol-O-methyltransferase from human placenta.

A procedure is reported for the purification of human placental catechol-O-methyltransferase. The preparation is apparently homogeneous and behaves as a monomer with an approximate Mr of 23,000. The sequence of the first 21 amino acid residues from the N-terminal end of the protein is reported. The activity of the enzyme is strongly influenced by the nature of the buffer in which it is assayed.

Amino Acid Sequence↗
PubMed1990

Monoclonal antibodies recognizing both soluble and membrane bound catechol-O-methyltransferase.

Both cytosolic, soluble and membrane-bound catechol-O-methyl-transferase (COMT) from pig and rat liver or kidney were recognized by mouse monoclonal antibodies (MAbs) raised against soluble COMT isolated from pig liver. In ELISA, the MAbs Co 16 and Co 54 reacted better with the pig than with the rat enzyme. The MAb Co 60 showed good reactivity with both pig and rat COMT. In addition, all three MAbs recognize the soluble (23 kDa) as well as the membrane-bound (26 kDa) forms of the COMT enzyme.

Animals↗
PubMed1996

The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines.

To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERp) of the infused amines and the cardiac output of plasma (CO(p)) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results. At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of CO(p)) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P < 0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp = ERp x CO(p)) of noradrenaline and dopamine was 13 and 25 ml kg-1 min-1, respectively, in group I and 12 and 28 ml kg-1 min-1, respectively, in group II. Clp of adrenaline did not differ from zero in either group. Clp of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.

Animals↗
PubMed1995

Evidence for saturation of catechol-O-methyltransferase by low concentrations of noradrenaline in perfused lungs of rats.

Previous studies on the pulmonary removal and metabolism of catecholamines in rat lungs have shown that, when the lungs are perfused with a low concentration (1 nmol/l) of noradrenaline, the amine is metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), but is predominantly O-methylated, and the activities of COMT and MAO are 0.357 min-1 and 0.186 min-1, respectively. The aim of the present study was to examine the changes in the metabolic profile of noradrenaline in rat lungs over a range of concentrations, and to examine the kinetics of the pulmonary O-methylation of noradrenaline and adrenaline. In isolated lungs perfused with 3H-noradrenaline, there was a progressive decrease in the proportion of O-methylated metabolites and a corresponding increase in the proportion of deaminated metabolites, as the noradrenaline concentration in the perfusion solution was increased from 1 to 10 to 100 to 1000 nmol/l. Experiments designed to determine the rate of uptake of noradrenaline in lungs perfused with 1 nmol/l 3H-noradrenaline, under conditions of MAO inhibited, COMT inhibited and COMT and MAO inhibited, showed that the results were compatible with co-existence of COMT and MAO in the pulmonary endothelial cells. Hence, it appeared that the changing metabolic profile with amine concentration in the previous series of experiments was not due to saturation of noradrenaline uptake into cells that contained COMT but not MAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of extraneuronal uptake inhibitors on the positive chronotropic response to isoprenaline and on the accumulation of isoprenaline in perfused rat heart after inhibition of catechol-O-methyl transferase.

Experiments were carried out in isolated perfused rat hearts. The presence of tropolone (100 mumol/l), an inhibitor of catechol-O-methyl transferase (COMT), significantly potentiated the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/l). Two uptake2 inhibitors, 3-O-methylisoprenaline (100 mumol/l) and normetanephrine (100 mumol/l), induced a positive chronotropic response, but corticosterone (100 mumol/l) and hydrocortisone (100 mumol/l) had no such effect. 3-O-methylisoprenaline (100 mumol/l) and normetanephrine (100 mumol/l) enhanced the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/l). Corticosterone (100 mumol/l) potentiated the positive chronotropic response to isoprenaline (0.1 and 1 nmol/l). Hydrocortisone (30 mumol/l) enhanced the response to 0.1 nmol/l isoprenaline but did not affect the positive chronotropic responses to 1, 3 or 10 nmol/l isoprenaline. The addition of uptake2 inhibitors (3-O-methylisoprenaline, 100 mumol/l; normetanephrine, 100 mumol/l; corticosterone, 100 mumol/l) to the perfusion medium significantly reduced the positive chronotropic response to the perfusion with isoprenaline (3 nmol/l) and tropolone (100 mumol/l). The accumulation of 3H-isoprenaline in the heart perfused with 3H-isoprenaline (1, 10 and 100 nmol/l) was significantly increased by the presence of tropolone (100 mumol/l): the accumulation for 1, 10 and 100 nmol/l of 3H-isoprenaline was 5.07, 47.0 and 500 pmol/g, respectively. The high accumulation observed during perfusion with 3H-isoprenaline (3 nmol/l) and tropolone (100 mumol/l) was significantly decreased by the addition of an uptake2 inhibitor, 3-O-methylisoprenaline (100 mumol/l), normetanephrine (100 mumol/l) or corticosterone (100 mumol/l), but not by hydrocortisone (30 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Isolation and characterization of a new spore-forming sulfate-reducing bacterium growing by complete oxidation of catechol.

A new mesophilic sulfate-reducing bacterium, strain Groll, was isolated from a benzoate enrichment culture inoculated with black mud from a freshwater ditch. The isolate was a spore-forming, rod-shaped, motile, gram-positive bacterium. This isolate was able of complete oxidation of several aromatic compounds including phenol, catechol, benzoate, p- and m-cresol, benzyl alcohol and vanillate. With hydrogen and carbon dioxide, formate or O-methylated aromatic compounds, autotrophic growth during sulfate reduction or homoacetogenesis was demonstrated. Lactate was not used as a substrate. SO4(2-), SO3(2-), and S2O3(2-) were utilized as electron acceptors. Although strain Groll originated from a freshwater habitat, salt concentrations of up to 30 g.l-1 were tolerated. The optimum temperature for growth was 35-37 degrees C. The G + C content of DNA was 42.1 mol%. This isolate is described as a new species of the genus Desulfotomaculum.

Bacillaceae↗
PubMed1981

A radioenzymatic assay of catechol-O-methyltransferase in hair root cells: comparison with erythrocyte activity.

A sensitive radioenzymatic assay of catechol-O-methyltransferase (COMT) in hair root cells is presented. Only five hair roots with intact bulb and sheath are needed for one assay. By pulling 15-20 hairs, 3-4 parallel assays can be performed. As in erythrocytes the COMT activity in hair root cells is constant for each individual. Nevertheless, there is no high correlation between the enzyme activities in erythrocyte and in hair root cells (r = 0.26, 0.1 greater than P greater than 0.05, N = 46). The determination of COMT in hair root cells offers a further application of this source in genetic research, as in the study of a correlation between COMT activity and various endogenous psychiatric disorders.

Adult↗
PubMed1986

Assignment of the catechol-O-methyltransferase gene to human chromosome 22 in somatic cell hybrids.

Catechol-O-methyltransferase (COMT) plays an important role in the inactivation of catecholamines. It has been demonstrated that erythrocyte COMT activity is genetically determined and controlled by a major autosomal locus with two alleles. The recent development of a method which allows the detection of COMT isozymes directly in autoradiozymograms has provided the means to investigate the chromosome location of the gene by using somatic cell hybrids. We have found that a single form of the COMT enzyme is expressed in several mouse-human fibroblast cell lines. The data obtained from the segregation analysis of the COMT enzyme in these hybrids and their subclones have provided evidence for the location of a major gene for COMT activity on human chromosome 22.

Animals↗
PubMed1994

Catechol-O-methyltransferase in vitiligo.

Catechol-O-methyltransferase (COMT) is involved in the metabolism of neurotransmitters such as epinephrine, norepinephrine and dopamine. For melanocytes, the enzyme is of particular importance in preventing the formation of toxic o-quinones during melanin synthesis. It has been suggested that COMT plays a regulatory role in melanin synthesis. Indeed, when the melanin precursor molecule DHI(2C) is methylated by COMT it is no longer available for incorporation into melanin. Auto-destruction by intermediates of melanin metabolism has been implicated in the aetiology of vitiligo. Therefore enzyme activities in vitiligo patients and in healthy controls were compared. Systemic COMT activities were measured using red blood cells (RBC) as starting material. However, as local alterations in COMT activity may be specifically involved in vitiligo, the enzyme activity was also measured in epidermal homogenates. Finally, to ascribe epidermal COMT activity to the responsible cell type(s), enzyme activity was measured in cultured vitiligo non-lesional melanocytes and melanocytes from healthy controls as well as in cultured keratinocytes from lesional skin and in purified keratinocytes from control skin. It was found that epidermal homogenates from vitiligo patients expressed higher levels of COMT activity than homogenates from healthy controls. Such differences were not found at the systemic level (i.e. in RBC) nor could they be explained by measurements on separately cultured epidermal cell types, indicating that the COMT activity was induced at the tissue level by extracellular factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Glutathione reductase activity in skin exposed to 4-tertiary butyl catechol.

The effect of 4-tertiary butyl catechol (TBC), a potent depigmenting chemical, on glutathione reductase (GR) in pigmented ear skin of hairless mice was investigated. Three topical applications of TBC, which cause neither skin color changes nor melanocyte degeneration, induced an increase in enzyme activity. Since the same treatment resulted in pheomelanin formation as evidenced by electron microscopy, it is suggested that the GR increase correlates at least in part with changes in melanocyte metabolism. This enzyme generates a reduced form of glutathione which may be involved in the formation of glutathionedopas, substrates for hydrolytic enzymes to produce cysteinyldopas, and pheomelanin. Elevation of GR may be an indication of melanogenesis before clinical skin color changes due to TBC appear. It may be used for the early detection of occupational leukoderma.

Animals↗