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PubMed2002

Catechol-O-methyltransferase and Parkinson's disease.

Parkinson's disease (PD) is one of the main causes of neurological disability in the elderly. Levodopa is the gold standard for treating this disease, but chronic levodopa therapy is complicated by motor fluctuation and dyskinesia. The catechol-O-methyltransferase (COMT) inhibitors represent a new class of antiparkinsonian drugs. When coadministered with levodopa/decarboxylase inhibitor, 2 COMT inhibitors, tolcapone and entacapone have been shown to improve the clinical benefit of levodopa. COMT activity is genetically polymorphic, and individuals with the low activity (COMT(L/L)) genotype have a thermolabile COMT protein; studies suggest that this genotype is less common in Asians than in Caucasians. Differences in COMT activity may determine the individual response to levodopa and result in ethnic differences in PD susceptibility. Our recent study suggests that the COMTL allele can interact with the MAOB gene to increase the occurrence of PD in Taiwanese. In order to understand this new class of antiparkinsonian drugs, we review their basic properties, pharmacology, and clinical efficacy. The frequency distribution of COMT genetic polymorphisms among different populations and its implications in the etiology and drug response is also discussed.

Catechol O-Methyltransferase↗
PubMed1996

Catechol-O-methyltransferase inhibition increases the uptake of 11C-3-(3,4-dihydroxyphenyl)-L-alanine in the rat pancreas.

BACKGROUND: The objective of the present investigation was to evaluate the uptake and metabolism of 3-(3,4-dihydroxyphenyl-L-alanine) (L-DOPA) in the rat pancreas. METHODS: The procedure included intravenous injection of the positron-emitting radiotracer L-[beta-11C] DOPA (DOP) into unanaesthetized male Sprague-Dawley rats and evaluation of uptake of radioactivity in organs in animals only given the tracer and in animals given therapeutic doses of three different catechol-O-methyltransferase (COMT) inhibitors, OR-486, OR-611, or Ro 41-0960. Selected pancreati were homogenized, and the chemical form bearing the radioactivity was analysed with high-performance liquid chromatography (HPLC). RESULTS: The main finding was that the tracer uptake in the pancreas increased fourfold when the rats were pretreated with COMT inhibitors. Half maximum effect of OR-486 was found at a dose of 0.2 mg/kg. HPLC analysis showed that with COMT inhibitor, the radioactivity in the pancreas consisted of 90% DOPAC. When administering MAO-A and COMT inhibitor together, the pancreas radioactivity corresponded to dopamine. Also in the pig pancreas a significant increase of DOP was observed after COMT inhibition. CONCLUSIONS: This study has shown a high turnover of L-DOPA in the rat pancreas, which can be modulated to give enhanced levels of DOPAC or dopamine by COMT and MAO inhibition.

Analysis of Variance↗
PubMed1994

Kinetics of the reversible tight-binding inhibition of pig liver catechol-O-methyltransferase by [2-(3,4-dihydroxy-2- nitrophenyl)vinyl]phenyl ketone.

The inactivation of partially purified pig liver catechol-O-methyltransferase (COMT) by [2-(3,4-dihydroxy-2-nitrophenyl)vinyl]phenylketone has been studied. The results demonstrated that COMT is inhibited in a reversible tight-binding fashion with an apparent Ki of 0.2 microM. IC50 values were determined at different concentrations of both substrates of the enzymatic reaction, pyrocatechol and S-adenosyl-L-methionine (AdoMet). The plot of IC50 versus pyrocatechol concentration gave a straight line, suggesting competitive inhibition. However the nitrocatechol derivative showed an uncompetitive inhibition pattern when measured as a function of AdoMet concentration.

Animals↗
PubMed2003

Catechol-O-methyl transferase (COMT) inhibitors in patients with Parkinson's disease: is COMT genotype a useful indicator of clinical efficacy?

In clinical practice, two potent and selective catechol-O-methyl transferase (COMT) inhibitors are available for the control of motor fluctuation in patients with Parkinson's disease. However, because of the complexity of fluctuating motor symptoms, it is difficult to evaluate the clinical efficacy of COMT inhibitors in each individual. Therefore, an objective factor predicting the clinical efficacy of COMT inhibitors is needed. Individual variation in COMT activity is regulated by a single nucleotide of the COMT gene on the long arm of chromosome 22. Therefore, there could be a correlation between COMT genotype and the clinical efficacy of COMT inhibitors. Three double-blind studies evaluating the efficacy of a single or repeated doses of a COMT inhibitor failed to find significant difference in the improvement in the duration of daily 'on' time and degree of motor abilities between patients with different COMT genotypes. Furthermore, there were no significant differences in the severity and frequency of dopaminergic adverse effects between patients with different COMT genotypes. These data suggest that the COMT genotype is not a major factor in deciding the clinical efficacy of COMT inhibitors.

Animals↗
PubMed2004

[A comparative study of efficacy of dopamine receptors agonists and catechol-O-methyltransferase in the treatment of late stages of Parkinson's disease].

Dopamine receptors agonists and catechol-O-methyltransferase (COMT) inhibitors are the novel classes of the drugs for Parkinson's disease (PD) treatment in both early and late stages. In the latter one, there is an increase of substantia nigra neurons degeneration, striatum denervation, changes of dopamine receptors state, dysregulation of Levadopa uptake, dopamine synthesis and storage, decrease of dopamine receptors density in striatum that results in clinical picture alteration and development of pharmaco-therapeutic side-effects, as well as motor fluctuations and drug diskinesias. The use of dopamine receptors agonists and COMT inhibitors at the late PD stages in combination with other antiparkinsonian medications allows improving pharmaco-therapeutic efficacy, along with patient's daily activity and quality of life.

Activities of Daily Living↗
PubMed1988

Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease.

A selective catechol-O-methyltransferase inhibitor, OR-462, was studied for its ability to affect pharmacokinetic properties of L-dopa after the p.o. administration of the inhibitor to rats and mice. When OR-462 was given to rats at the dose range of 0.3 to 30 mg/kg in conjunction with L-dopa and carbidopa, a dose-related and long-lasting (greater than 5 hr) increase in striatal L-dopa and dopamine levels as well as a reduction in 3-O-methyldopa levels were shown. For a 50% reduction of the 3-O-methyldopa levels a dose of 6 mg/kg of OR-462 was needed. The increase in striatal homovanillic acid, an O-methylated metabolite of dopamine which poorly penetrates the blood brain barrier, indicates that O-methylation was not inhibited in the brain. In order to get the same dopamine levels in striatum the L-dopa dose could be lowered to one-fourth when OR-462 was added. The L-dopa-sparing effect of OR-462 given p.o. was also demonstrated in two behavioral parkinsonian models. OR-462 given at doses of 3 to 30 mg/kg in conjunction with L-dopa and carbidopa, dose-dependently potentiated the L-dopa-induced reversal of hypoactivity in reserpinized mice. Likewise, the same doses of OR-462 caused a marked potentiation of L-dopa-induced contralateral turning behavior in rats with unilateral nigrostriatal lesions produced by 6-hydroxydopamine. The data suggest a possible beneficial effect of OR-462 in the therapy of Parkinson's disease.

Animals↗
PubMed1982

In vitro effect of haloperidol, chlorpromazine, imipramine and lithium on the erythrocyte catechol-O-methyltransferase.

Haloperidol, chlorpromazine, imipramine and lithium in concentrations similar to the average therapeutic plasma levels did not exert any in vitro inhibition on the erythrocyte catechol-O-methyltransferase (COMT). The inhibitory effects of haloperidol, chlorpromazine and imipramine were noted first at concentrations 1000-10 000 times their respective average therapeutic plasma levels. Unlike the former three psychotropic drugs, lithium exerted an in vitro inhibition already at a concentration 40 times the average therapeutic plasma level and that in a competitive way. The inhibitory effect of lithium could be neutralized by increasing the magnesium concentration, likewise in a competitive way.

Catechol O-Methyltransferase↗
PubMedDate not supplied

Identification of major metabolites of the catechol-O-methyltransferase inhibitor nitecapone in the rat and dog.

Metabolites of nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], a potent catechol-O-methyltransferase inhibitor with gastroprotective and antiulcerogenic effects, were isolated by extraction and HPLC from dog and rat urine after enzymatic hydrolysis and as glucuronic acid and sulfate conjugates. Eight and 10 nonconjugated metabolites and unchanged nitecapone were found in hydrolyzed dog and rat urine, respectively, and identified by HPLC with diode-array UV detection, electron ionization mass spectrometry, and IR spectroscopy. In both species the main phase I metabolic pathways were: 1) reduction of the side chain carbon-carbon double bond and carbonyl groups and 2) cleavage of the side-chain double bond, giving an aromatic aldehyde that was partly oxidized to the corresponding carboxylic acid. These phase I metabolites and unchanged nitecapone were excreted in urine mainly as their glucuronides and sulfates in both species. Additionally, the 3-O-methylated metabolite, not found in urine, was identified in rat plasma.

Animals↗
PubMed1994

Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats.

Normetanephrine (NMN) and metanephrine (MN), are the O-methylated metabolites of norepinephrine (NE) and epinephrine (E), whereas dihydroxyphenylglycol (DHPG) is the deaminated metabolite of both NE and E. This study compared production of NMN, MN and DHPG during tracer and high-dose infusions of Ne and E in rats, with and without inhibition of catechol-O-methyltransferase (COMT) or the A and B forms of monoamine oxidase (MAO). Animals also received infusions of NMN and MN to compare plasma clearances and spillovers of NMN and MN with and without MAO inhibition. Inhibition of COMT increased plasma DHPG and decreased plasma NMN and MN, whereas inhibition of MAO decreased plasma DHPG and increased plasma NMN and MN. The increase in NMN and MN after MAO inhibition reflected blocked deamination of NMN and MN by MAO-A, but not MAO-B. The A form of MAO was also largely responsible for deamination of NE. Infused E was deaminated to DHPG less efficiently than NE. High doses of infused E were O-methylated more efficiently than NE, whereas tracer doses were O-methylated similarly. After MAO inhibition NE was O-methylated more efficiently than E. Increased plasma NMN after MAO inhibition reflected the combined effects of a decrease in the plasma clearance of NMN and an increase in the spillover of NMN into plasma, whereas the smaller increase in plasma MN was due solely to a decrease in the plasma clearance of MN. Thus, E and MN are not deaminated at extraneuronal sites of O-methylation, whereas NE is both O-methylated and deaminated with proportionally more deaminated than O-methylated as the concentration of NE increases. The above results support the preference of NE over E for neuronal pathways of metabolism, but indicate considerably more complex differences in the metabolism of NE and E by extraneuronal O-methylation and deamination.

Animals↗
PubMed1995

The role of monoamine oxidase and catechol O-methyltransferase in dopaminergic neurotransmission.

The action of dopamine (DA) released in the synaptic cleft is mainly terminated by its reuptake and catabolism by the enzymes monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Preclinical data show that the reduction of the catabolism of DA elicited by MAO and COMT inhibitors leads to an enhancement of DA neurotransmission. Moreover, there is evidence suggesting that MAO-B inhibition might protect DA neurons from oxidative stress. Nevertheless, due to differences in enzyme localization and activity between man and rodents, results obtained in experimental animals might not reflect the actual situation in humans. Today the availability of potent and selective MAO and COMT inhibitors makes it feasible for the clinician to test whether the blockade of catabolic enzymes would result in a symptomatic improvement in Parkinsonian patients, and whether MAO-B inhibition might additionally exert a neuroprotective effect.

Catechol O-Methyltransferase↗
PubMed1997

Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase.

Catechol-O-methyltransferase (COMT) is an enzyme that plays an important role in the inactivation of catecholamine neurotransmitters. Experimental and clinical data suggest that COMT inhibitors may be useful in Parkinsonian patients. Among COMT inhibitors, nitrocatechol derivatives are the most potent and selective. In this study, we evaluated the kinetics of rat brain COMT, as well as its mechanisms of inhibition by tolcapone. Rat whole-brain homogenates and the corresponding soluble and membrane-bound fractions were evaluated for their epinephrine 3-O-methylating activity. Tolcapone exhibited a very low IC50 in all the three enzyme preparations. In whole-brain homogenates, saturation curves made in the presence of 1 nM tolcapone displayed, when compared with controls, a reduction in Vmax without changes in Km, which suggested a noncompetitive type of inhibition. This was confirmed by experiments in which the IC50 value for tolcapone was not affected by substrate concentration. Nevertheless, this classic kinetic analysis is not suitable for a tight-binding inhibitor. A very low IC50, an inhibition potency that is dependent on the previous contact time of the inhibitor with the enzyme and an enzyme titrating capacity were the three criteria that tolcapone met as a tight-binding inhibitor in the rat brain. In conclusion, our results show that tolcapone is a highly potent tight-binding inhibitor of brain soluble and membrane-bound COMT, but because of difficulties in determining the type of inhibition for this type of compound, we cannot confirm previous claims about the competitive type of COMT inhibition produced by tolcapone.

Animals↗
PubMed1976

Electrophoretic pattern of red blood cell catechol-o-methyltransferase in schizophrenia and manic-depressive illness.

Human red blood cell (RBC) catechol-O-methyltransferase (COMT) was analyzed by polyacrylamide gel electrophoresis (PAGE). One major enzyme band (B) is observed after electrophoresis. In addition, a minor band (A) of COMT activity comprising no more than 25% of the total activity, is also detectable. The rate of migration during electrophoresis of both bands of RBC COMT was the same in manic depressive, schizophrenic, and normal individuals. These results did not reveal genetic variations in the COMT molecule among these three groups. Furthermore, when total RBC COMT was measured there were no statistically significant differences between schizophrenic, manic-depressive, and control individuals.

Bipolar Disorder↗
PubMed1975

Lithium carbonate response in depression. Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history.

The antidepressant efficacy of lithium carbonate was assessed in a double-blind trial in 23 hospitalized depressed patients. Unequivocal response was significantly more frequent in bipolar than in unipolar depressed patients. Lithium carbonate responders had a greater visual average-evoked response amplitude increase in response to increased stimulus intensity, termed "augmenting". No correlation could be demonstrated between lithium carbonate efficacy and either erythrocyte catechol-O-methyl transferase activity, age of symptom onset, number of hospitalizations, or family history of affective disorders.

Adult↗
PubMed1975

Erythrocyte soluble catechol-O-methyl transferase activity in primary affective disorder. A clinical and genetic study.

Erythrocyte catechol-O-methyl transferase (COMT) activity was studied in 53 patients with primary affective disorders and 38 controls and in selected relatives. Patients with affective disorders tended to have higher activity levels than normals, after correcting for sex differences. The COMT activity was positively correlated between relatives and is heritable. Within families, elevation of COMT activity distingushed healthy relatives from probands and ill relatives. This suggests that COMT activity elevation and affective illness do not show independent assortment and implies that COMT activity identifies genetic vulnerability to affective order.

Affective Symptoms↗
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↗
PubMed2003

Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia.

BACKGROUND: Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. METHODS: Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. RESULTS: A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. CONCLUSIONS: A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.

Adult↗
PubMed2005

Catechol O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder.

CONTEXT: Early-onset antisocial behavior accompanied by attention-deficit/hyperactivity disorder is a clinically severe variant of antisocial behavior that is associated with a particularly poor outcome. Identifying early predictors is thus important. Genetic and prenatal environmental risk factors and prefrontal cortical function are thought to contribute. Recent evidence suggests that prefrontal cortical function is influenced by a valine/methionine variant in the catechol O-methyltransferase (COMT) gene. OBJECTIVE: To test the a priori hypothesis that this genetic variant predicts early-onset antisocial behavior in a high-risk sample and further examine the effects of birth weight, an environmentally influenced index of prenatal adversity previously linked to childhood disruptive behaviors and genotype x birth weight interaction. DESIGN, SETTING, AND PARTICIPANTS: A family-based genetic study was undertaken between 1997 and 2003. Participants were prospectively recruited from child and adolescent psychiatry and child health clinics in the United Kingdom and included 240 clinic children who met diagnostic criteria for attention-deficit/hyperactivity disorder or hyperkinetic disorder. Participants underwent comprehensive standardized assessments including measures of antisocial behavior and IQ. Main Outcome Measure DSM-IV symptoms of childhood-onset conduct disorder rated by trained interviewers using a standard diagnostic interview. RESULTS: The results show main effects of the COMT gene variant (P = .002), birth weight (P = .002), and a significant gene x environment (COMT x birth weight) interaction (P = .006). CONCLUSIONS: Early-onset antisocial behavior in a high-risk clinical group is predicted by a specific COMT gene variant previously linked with prefrontal cortical function and birth weight, and those possessing the val/val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight.

Adolescent↗
PubMed2006

Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.

CONTEXT: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking. DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes. RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility. CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

Adult↗