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PubMed2006

Catechol-O-methyltransferase and the clinical features of psychosis.

A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density Schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P < 0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication.

Catechol O-Methyltransferase↗
PubMed1989

Determination of catechol-O-methyltransferase activity in erythrocytes by high performance liquid chromatography with electrochemical detection.

A rapid assay employing HPLC with electrochemical detection for catechol-O-methyltransferase (COMT) activity in red blood cells is described. Enzyme activity is determined from erythrocyte lysates using S-adenosyl-L-methionine as methyl donor and 3,4-dihydroxybenzoic acid as substrate. The 3-O- and 4-O-methylated reaction products are measured by high-performance liquid chromatography with electrochemical detection. Human erythrocyte soluble form of COMT had Km values of 6.1 microM and 26.0 microM for S-adenosyl-L-methionine and dihydroxybenzoic acid, respectively. The mean O-methylation ratio for the soluble form of COMT was 5.3. An O-methylation ratio of 15.5 was estimated in the membrane fraction of an erythrocyte pool from three samples. The activities of soluble COMT in erythrocytes of some animal species are also reported. The procedure is easily automated, and a large number of samples can be processed during one working day.

Animals↗
PubMed1989

Purification of rat liver soluble catechol-O-methyltransferase by high performance liquid chromatography.

The soluble form of catechol-O-methyltransferase (EC 2.1.1.6) from rat liver was purified to homogeneity by high-performance anion-exchange chromatography and high-performance gel-filtration chromatography. The specific activity of the final pool was 270 U/mg protein. The purification was 1180-fold and recovery of the enzyme activity was 15%. During this rapid and gentle purification there were no problems with loss of activity, and the estimated half of the final purified enzyme pool was 5.5 days at +4 degrees C. The only additive used was phenylmethylsulfonylfluoride in the homogenizing buffer.

Animals↗
PubMed1990

L-dopa as substrate for human duodenal catechol-O-methyltransferase and aromatic L-amino acid decarboxylase.

Catechol-O-methyltransferase (COMT) and aromatic L-amino acid decarboxylase (AADC) activities were determined in human gastrointestinal samples. L-dopa was used as the substrate and the reaction products 3-O-methyldopa (3OMD) and dopamine were separated by reversed phase HPLC and detected by electrochemical or UV detection. COMT activities varied between 40-350 pmol/mg/min and AADC activities between 100-3300 pmol/mg/min in different parts of the gastrointestinal tract. COMT inhibitors nitecapone (OR-462) and OR-611 effectively inhibited human gastrointestinal COMT activity in vitro, the IC50 values ranging from 10-20 nM and 5-75 nM, respectively. In vitro carbidopa inhibited AADC slightly more effectively than benserazide.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed2002

A rapid assay method for catechol-O-methyltransferase activity by flow injection analysis.

A rapid assay employing flow injection analysis (FIA) to determine the activity of purified catechol-O-methyltransferase (COMT) from porcine liver is described. The method was based on the determination of normetanephrine, the 3-O-methyl metabolite of the substrate norepinephrine. Excess norepinephrine was removed from the incubation mixture by alumina extraction twice to allow normetanephrine to be subjected to flow injection analysis, coulometrical oxidation, fluorogenic reaction with ethylenediamine and fluorescence detection. K(m) and V(max) values for COMT obtained with the system were 503 microM and 4.51 nmol/min/mg protein, respectively. The method is suitable for screening of COMT inhibitors or activators, as a large number of samples, up to 200, can be processed in one working day.

Animals↗
PubMed2002

Rat liver and kidney catechol-O-methyltransferase activity measured by high-performance liquid chromatography with fluorescence detection.

We have previously reported a highly sensitive method for the measurement of catechol-O-methyltransferase (COMT) activities in rat erythrocytes with norepinephrine (NE), an endogenous native substrate, using high-performance liquid chromatography (HPLC)-fluorescence or peroxyoxalate chemiluminescence reaction detection. Applying this method to COMT activities in rat liver and kidney, known to have the highest activities of all organs, the optimum reaction conditions were investigated. Under the optimum conditions, soluble (S)-COMT and membrane-bound (MB)-COMT activities in rat liver, with NE as a substrate, were 2.17 +/- 0.33 and 0.16 +/- 0.02 nmol/min/mg protein (n = 5), respectively. In rat kidney, S-COMT and MB-COMT activities were 1.81 +/- 0.20 and 0.079 +/- 0.009 nmol/min/mg protein (n = 5), respectively. Since liver and kidney play important roles in inactivating catecholamines, using the proposed method would yield critical information to delineate the role of metabolism of catecholamines in rat tissues.

Animals↗
PubMed2005

Supramolecular assembly of 2,7-dimethyldiazapyrenium and cucurbit[8]uril: a new fluorescent host for detection of catechol and dopamine.

The formation of a highly stable inclusion complex between 2,7-dimethyldiazapyrenium (Me(2)DAP(2+)) and the cucurbit[8]uril host (CB8) was demonstrated by X-ray crystallography; MALDI-TOF mass spectrometry; and (1)H NMR, electronic absorption, and emission spectroscopy. The equilibrium association constant was determined to be 8.9(+/-0.2)x10(5) L mol(-1) from UV-visible data and 8.4(+/-1.5) x 10(5) L mol(-1) from fluorescence data. The Me(2)DAP(2+).CB8 inclusion complex acted as a host to bind compounds containing aromatic pi-donor moieties (D), such as catechol and dopamine. This point was demonstrated by (1)H NMR spectroscopy, and electrochemical and emission measurements. Fluorescence detection of the Me(2)DAP(2+).D.CB8 ternary complexes was evident in aqueous solution and on the surface of silica particles, to which fluorescent diazapyrenium units had been covalently immobilized.

Bridged-Ring Compounds↗
PubMed2006

Triphenylantimony(v) catecholates and o-amidophenolates: reversible binding of molecular oxygen.

Novel neutral antimony(V) complexes were isolated as crystalline materials and characterized by IR and NMR spectroscopy: o-amidophenolate complexes [4,6-di-tert-butyl-N-(2,6-dimethylphenyl)-o-amidophenolato]triphenylantimony(V) (Ph3Sb[AP-Me], 1) and [4,6-di-tert-butyl-N-(2,6-diisopropylphenyl)-o-amidophenolato]triphenylantimony(v) (Ph3Sb[AP-iPr], 2); catecholate complexes (3,6-di-tert-butyl-4-methoxycatecholato)triphenylantimony(V) (Ph3Sb[(MeO)Cat], 3), its methanol solvate 3CH3OH (4); (3,6-di-tert-butyl-4,5-di-methoxycatecholato)triphenylantimony(V) (Ph3Sb[(MeO)2Cat], 5) and its acetonitrile solvate 5CH3CN (6). Complexes 1-7 were synthesized by oxidative addition of the corresponding o-iminobenzoquinones or o-benzoquinones to Ph3Sb. In the case of the phenanthrene-9,10-diolate (PhenCat) ligand, two different complexes were isolated: Ph3Sb[PhenCat] (7) and [Ph4Sb]+[Ph2Sb(PhenCat)2]- (8). Complexes 7 and 8 were found to be in equilibrium in solution. Molecular structures of 2, 4, 6, and 8 were determined by X-ray crystallography. Complexes 1-7 reversibly bind molecular oxygen to yield Ph3Sb[L-Me]O2 (9), Ph3Sb[L-iPr]O2 (10), Ph3Sb[(MeO)L']O2 (11), Ph3Sb[(MeO)2L']O2 (12) and Ph3Sb[PhenL']O2 (13), which contain five-membered trioxastibolane species (where L is the O,O',N-coordinated derivative of a 1-hydroperoxy-6-(N-aryl)-iminocyclohexa-2,4-dienol, and L' the O,O',O''-coordinated derivative of 6-hydroperoxy-6-hydroxycyclohexa-2,4-dienone). Complexes 9-13 were characterized by IR and 1H NMR spectroscopy and X-ray crystallography.

Catechols↗
PubMed2003

Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population.

BACKGROUND: Estrogen is one of the crucial hormones participating in the proliferation and carcinogenesis of the prostate glands. Genetic polymorphisms in the estrogen metabolism pathway might be involved in the risk of prostate carcinoma development. The authors evaluated the association between genetic polymorphisms in estrogen-related enzymes and receptors and the risk of developing familial prostate carcinoma. METHODS: In the current study, 101 cases with prostate carcinoma whose first-degree relatives had prostate carcinoma and 114 healthy age and residence-matched male controls were enrolled. The genotypes of estrogen receptor (ER) alpha, aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed. RESULTS: For single polymorphisms, a significant association of the T/T genotype of the PvuII site in the ER alpha gene (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.97-5.99; P = 0.0028), and the C/T and T/T genotypes of the CYP19 gene (OR, 1.77; 95% CI, 1.02-3.09; P = 0.037) with prostate carcinoma risk, was observed. The G/A genotype of the COMT gene showed a weak tendency toward increased risk (OR, 1.48; 95% CI, 0.85-2.57; P = 0.18). Stratification of cases according to clinical stage and pathologic grade showed that the C/T and T/T genotypes of the CYP19 gene were associated significantly with high-grade carcinoma (OR, 2.59; 95% CI, 1.47-4.46; P = 0.048). The number of high-risk genotypes (the T/T in ER alpha, the C/T and T/T in CYP19, and the G/A in COMT) significantly increased the risk of developing prostate carcinoma (2 genotypes: OR, 3.00; 95% CI, 1.72-5.23; P = 0.008; 3 genotypes: OR, 6.30; 95% CI, 3.61-10.99; P = 0.002). CONCLUSIONS: Genetic polymorphisms of genes in the estrogen metabolism pathway were associated significantly with familial prostate carcinoma risk. Single nucleotide polymorphisms of low-penetrance genes are targets for understanding the genetic susceptibility of familial prostate carcinoma.

Adult↗
PubMed1985

Segregation analysis of dopamine-beta-hydroxylase (DBH) and catechol-O-methyltransferase (COMT): identification of major locus and polygenic components.

Enzymes of catecholamine metabolism, plasma dopamine-beta-hydroxylase (DBH), and erythrocyte catechol-O-methyltransferase (COMT) were each previously shown to be transmitted as single codominant loci in a sample of approximately 30 multigenerational families that were analyzed with the single major locus model. Here, both major locus and polygenic hypotheses are tested by applying the mixed model of analysis to the identical samples, after breaking the families into two-generation units. For plasma DBH, the most parsimonious model is a dominant major locus (ie, high values dominant to low values) accounting for 41% of the variance and a polygenic component accounting for 25% of the variance. For erythrocyte COMT, the most parsimonious model is a dominant major locus accounting for 56% of the variance and a polygenic component accounting for 27% of the variance. The major locus for COMT has been supported by previous biochemical studies. The major locus for DBH is supported by the finding from our previous study of possible linkage to the ABO locus. Further biochemical and molecular genetic investigations are needed to better define the genetic loci determining the activity of these enzymes.

Catechol O-Methyltransferase↗
PubMed2005

Activation of catechol-O-methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons.

Elevation of the total homocysteine (tHcy) concentration in plasma has been implicated in neurodegeneration in patients with stroke, dementia, Alzheimer disease, and Parkinson disease. Because the mechanisms controlling brain tHcy are unknown, the present study investigated its synthesis and transport in primary rat brain cell cultures. We found that the catechol-O-methyltransferase (COMT) substrate 3,4-dihydroxybenzoic acid (DHB) increased export of tHcy in astrocytes, but not in neurons. The export mechanism was selective for tHcy over cyst(e)ine, total glutathione (tGSH) or cysteinylglycine (Cys-Gly). tHcy export from astrocytes was also induced by the COMT substrates levodopa (L-DOPA), dopamine and quercetin, and it was blocked by the COMT inhibitors tropolone and entacapone. This export was associated with increased synthesis of tHcy because both intracellular and extracellular tHcy concentrations rose during COMT activation. Incubation in cyst(e)ine-deficient medium inhibited the tHcy export response to COMT activation. Exogenous tHcy (100 muM) was accumulated into neurons, but not into astrocytes. We conclude that activation of COMT causes sustained synthesis of Hcy in astrocytes and transport of this amino acid to neurons.

Amino Acids↗
PubMed1990

The effects of soman in vitro on catechol-O-methyltransferase and monoamine oxidase activities in rabbit tissues.

Soman (pinacolyl methylphosphonofluoridate) not only increases acetylcholine levels by inhibiting cholinesterases, it also alters the levels of some other neurotransmitters including norepinephrine, dopamine, and serotonin. Soman also causes an alteration in the activities of the enzymes metabolizing norepinephrine when it is administered to animals. Because these alterations may result from indirect effects on the enzymes, the effects of in vitro application of soman on catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) activities in rabbit tissues were investigated. Enzyme activities were determined in rabbit lung, liver, cerebellum, cerebrum, brain stem, mesenteric artery, pulmonary artery, renal artery, central ear artery, thoracic aorta, and diaphragm. MAO and COMT activities were not affected by soman in any tissues tested, except the lung and liver, where the activity of COMT was increased (p less than 0.05). Thus, reported effects of soman in vivo on norepinephrine, dopamine, or serotonin concentrations, and MAO and COMT activities do not seem to result from direct effects on the activities of these amine-metabolizing enzymes.

Animals↗
PubMed1981

Catechol-O-methyltransferase activity in cultured human skin fibroblasts from controls and patients with dystonia musculorum deformans.

Fibroblasts provide a source of living cells that can be obtained easily from humans and used to evaluate inherited differences in the activities of enzymes important in neurotransmitter and drug metabolism. Here, we describe biochemical characteristics of catechol-O-methyltransferase (COMT, EC 2.1.1.6) activity in homogenates of cultured human skin fibroblasts. Many properties of the enzyme, including apparent affinity for dihydroxybenzoic acid and S-adenosyl methionine, optimal pH and (Mg++), and inhibition by Ca++, are similar to those reported in lysates of human erythrocytes. Culture and assay conditions have been established for optimal and reproducible measurement of COMT activity in individual fibroblast lines. In 16 control lines, COMT activity ranged from 115 to 263 pmol/min/mg protein with a mean of 181 pmol/min/mg protein. Enzyme activity did not vary with the age or sex of the donor. The COMT activities in fibroblasts from eight patients with dystonia musculorum deformans, an inherited movement disorder of unknown etiology, were not significantly different from controls. Monoamine oxidase (MAO, EC 1.4.3.4) type A activity was measured in 12 lines from patients with dystonia, and values did not differ significantly from age- and sex-matched controls. We conclude that inherited variation in activity of these two catabolic enzymes is not sufficient to explain alterations in monoamine metabolism described in this disorder.

Adolescent↗
PubMed1977

Inhibition of catechol O-methyltransferase and transfer RNA methyltransferases by coralyne, nitidine, and related compounds.

Inhibitory activity against both catechol O-methyltransferase and transfer RNA methyltransferases was observed among the antileukemic alkaloids coralyne, nitidine, and related synthetic alkoxy analogs. Inhibition of both classes of enzymes seems to have a similar profile. The role of water solubility of these compounds with regard to their enzyme inhibitory activity was noted.

Animals↗
PubMed1979

Identification and synthesis of a methylated catechol metabolite of glutethimide isolated from biological fluids of overdose victims.

Urine samples from victims severely intoxicated by glutethimide were hydrolyzed enzymatically. TLC, GLC, and mass spectral analyses revealed a methylated catechol metabolite of the parent drug. Two synthetic pathways are described for the preparation of 2-ethyl-2-(3-methoxy-4-hydroxyphenyl)glutarimide and 2-ethyl-2-(3-hydroxy-4-methoxyphenyl)glutarimde. Comparisons of GLC and mass spectral data to a compound isolated from the body fluids of glutethimide overdose victims conclusively identified a new 3-methoxy-4-hydroxyphenyl metabolite of glutethimide in humans.

Catechols↗
PubMed2002

Case-control study of dopamine transporter-1, monoamine oxidase-B, and catechol-O-methyl transferase polymorphisms in Parkinson's disease.

We investigated the association of Parkinson's disease (PD) with dopamine transporter-1 (DAT1), monoamine oxidase-B (MAO-B), and catechol-O-methyltransferase (COMT) gene polymorphisms. Overall, we observed no significant association of PD with the DAT1-3'-variable numbers of tandem repeats, the MAO-B-(GT)(n), and the COMT-Val108Met gene polymorphisms in a sample of 319 unrelated PD cases and 196 control subjects. Analyses stratified by sex, age at examination, family history of PD, and ethnic origin also yielded negative findings, with three exceptions. We found statistically significant associations of PD with MAO-B polymorphisms in older patients and with a COMT polymorphism in younger subjects and in women. These significant differences at the two-tailed alpha level of 0.05 and restricted to subgroup analyses may have a biological basis or may be chance findings.

Adult↗
PubMed2005

Genetic polymorphism of catechol-O-methyltransferase and levodopa pharmacokinetic-pharmacodynamic pattern in patients with Parkinson's disease.

We explored the potential effect of catechol-O-methyltransferase (COMT) genetic polymorphism on the pharmacokinetics and pharmacodynamics of a standard oral dose of levodopa in patients with Parkinson's disease (PD). We prospectively collected blood samples for COMT genotyping from a population of 104 PD patients. Each patient was examined by a standard oral levodopa/benserazide test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects and dyskinesia ratings, up to 4 hours after dosing. The main levodopa pharmacokinetic outcome variables were time to peak and peak plasma concentration, plasma elimination half-life, and the area under the plasma concentration-time curve. The main outcome levodopa pharmacodynamic variables were latency, duration, and magnitude of the motor effect elicited by the levodopa test dose, the area under the tapping effect-time curve, and the presence of dyskinesias. Nineteen patients (18%) harbored the low-activity homozygous COMT genotype (A/A), 63 patients (61%) carried the intermediate-activity heterozygous COMT genotype (A/G) and 22 patients (21%) had the high-activity homozygous COMT genotype (G/G). The three groups were comparable for vital and clinical characteristics. No significant difference was found in levodopa main pharmacokinetic-pharmacodynamic variables and dyskinesia incidence among the three subgroups of patients. We failed to identify clinically relevant levodopa pharmacokinetic-pharmacodynamic response patterns associated with the COMT polymorphism in PD patients.

Aged↗
PubMed2005

Apolipoprotein E epsilon4 and catechol-O-methyltransferase alleles in autopsy-proven Parkinson's disease: relationship to dementia and hallucinations.

We determined whether apolipoprotein E epsilon4 (ApoE4) or catechol-O-methyltransferase (COMT) genotypes were associated with dementia, hallucinations, Alzheimer's disease pathological findings (AP), or cortical Lewy bodies (CLBs) in autopsy-confirmed cases of Parkinson's disease (PD). Outcomes were obtained from medical records. Pathology reports identified AP and CLBs. Brain tissue was genotyped. A total of 47 subjects (33 men, 14 women) had PD onset at 62.4 +/- 8.7 years of age and died at 77.8 +/- 5.6 years of age. Demented and hallucinating patients did not differ in age at onset (AO) of PD or age at death, or the proportion ApoE4+, AP+, or CLB+ compared to nondemented patients or non-hallucinating patients. ApoE4 and COMT (low metabolizer [LH], intermediate metabolizer [HL], or high metabolizer [HH]) did not influence AO, death, or dementia- or hallucination-free survival, based on age or duration of treatment. All seven subjects with AP were demented and had hallucinations. CLBs were associated with dementia but not hallucinations. In Cox regression models adjusting for AO and duration of treatment, increased risk of dementia was associated with male sex but not significantly with ApoE4; inclusion of AP in the model did not affect the results; COMT was not a risk factor for dementia. Psychosis risk was not associated with ApoE4, COMT, or sex. The observation that males have increased dementia risk and the trend for ApoE4 requires confirmation in larger prospective autopsy studies.

Age of Onset↗