Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “COMT”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 595 records · Page 33Linked to original sources
PubMed2006

Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics.

Catechol-O-methyltransferase (COMT) is a gene involved in the degradation of dopamine and may both increase susceptibility to develop schizophrenia and affect neuronal functions involved in working memory. A common variant of the COMT gene (val(108/158)met) has been widely reported to affect pre-frontally mediated working memory function, with the high-activity val allele associated with poorest performance across a number of tests sensitive to updating and target detection. Pharmacological manipulations of COMT val(108/158)met also have reliably produced alterations in cognitive function, in line with an inverted U function of prefrontal dopamine signaling. Furthermore, there is accumulating evidence that COMT val(108/158)met genotype may influence the cognitive response to antipsychotic treatment in schizophrenia patients, with met allele load predicting the greatest improvement with medication. Recently, other single-nucleotide polymorphisms (SNPs) across the COMT gene have emerged as possible risk alleles for schizophrenia, although little is known about whether they affect prefrontal cognition in a manner similar to COMT val(108/158)met. Preliminary evidence suggests a modest role for a SNP in the 5' region of the gene on select tests of attention and target detection. Haplotype effects also may account for a modest percentage of the variance in test performance, and are an important area for future study.

Catechol O-Methyltransferase↗
PubMed2006

Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.

Variations in the gene encoding catechol-O-methyltransferase (COMT) are linked to individual differences in pain sensitivity. A single nucleotide polymorphism (SNP) in codon 158 (val(158)met), which affects COMT protein stability, has been associated with the human experience of pain. We recently demonstrated that three common COMT haplotypes, which affect the efficiency of COMT translation, are strongly associated with a global measure of pain sensitivity derived from individuals' responses to noxious thermal, ischemic, and pressure stimuli. Specific haplotypes were associated with low (LPS), average (APS), or high (HPS) pain sensitivity. Although these haplotypes included the val(158)met SNP, a significant association with val(158)met variants was not observed. In the present study, we examined the association between COMT genotype and specific pain-evoking stimuli. Threshold and tolerance to thermal, ischemic, and mechanical stimuli, as well as temporal summation to heat pain, were determined. LPS/LPS homozygotes had the least, APS/APS homozygotes had average, and APS/HPS heterozygotes had the greatest pain responsiveness. Associations were strongest for measures of thermal pain. However, the rate of temporal summation of heat pain did not differ between haplotype combinations. In contrast, the val(158)met genotype was associated with the rate of temporal summation of heat pain, but not with the other pain measures. This suggests that the val(158)met SNP plays a primary role in variation in temporal summation of pain, but that other SNPs of the COMT haplotype exert a greater influence on resting nociceptive sensitivity. Here, we propose a mechanism whereby these two genetic polymorphisms differentially affect pain perception.

Adolescent↗
PubMed2004

Catechol-O-methyltransferase Val 108/158 Met polymorphism in premenopausal breast cancer patients.

There is compelling evidence to suggest that catecholestrogens may play a role in the development of breast cancer. Particularly, inactivation of catecholestrogens may prevent the genesis and arrest the development of breast cancer. Catechol-O-methyltransferase (COMT) is polymorphic and responsible for the detoxification of catecholestrogens. In the present study, we examined what role COMT gene polymorphisms may play in the development of breast cancer in a case-control study of 130 sporadic unrelated premenopausal Turkish breast cancer patients with 233 unrelated healthy controls. The frequency of COMT-L allele was more significantly represented in the breast cancer cases (48.08%) than in the controls (38.20%). The genotype frequencies of COMT-HH, HL and LL were 25.4, 53.1 and 21.5% in the breast cancer subjects and 26.6, 62.7 and 10.7% in the controls respectively. In conclusion, the COMT-L allele and COMT-LL genotype are genetic risk factors for sporadic breast cancer in premenopausal Turkish women.

Adult↗
PubMed1996

Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers.

OBJECTIVE: To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise. BACKGROUND: Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide. DESIGN AND METHODS: This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise. RESULTS: Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone. CONCLUSION: The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG.

Administration, Oral↗
PubMed2003

Catechol-O-methyltransferase inhibition protects against 3,4-dihydroxyphenylalanine (DOPA) toxicity in primary mesencephalic cultures: new insights into levodopa toxicity.

Inhibition of catechol-O-methyltransferase (COMT) has protective effects on levodopa (L-DOPA), but not D-DOPA toxicity towards dopamine (DA) neurons in rat primary mesencephalic cultures [Mol. Pharmacol. 57 (2000) 589]. Here, we extend our recent studies to elucidate the mechanisms of these protective effects. Thus, we investigated the effects of all main L-DOPA/DA metabolites on survival of tyrosine hydroxylase immunoreactive (THir) neurons in primary rat mesencephalic cultures. 3-O-Methyldopa, homovanillic acid, dihydroxyphenyl acetate and 3-methoxytyramine had no effects at concentrations up to 300 micro M after 24h, whereas DA was more toxic than L-DOPA with toxicity at concentrations of >or=1 micro M. The coenzyme of COMT, S-adenosyl-L-methionine (SAM), and its demethylated product S-adenosylhomocystein caused no relevant alteration of THir neuron survival or L-DOPA toxicity. In contrast, inhibition of SAM synthesis by selenomethionine showed time- and dose-dependent increase of THir neuron survival, but did not affect L-DOPA toxicity. L-DOPA-induced lipid peroxidation in mesencephalic cultures was not modified by the COMT inhibitor Ro 41-0960 (1 micro M). Increased contamination of the cultures with glial cells attenuated L- and D-DOPA toxicity, but caused significant enhancement of protection by COMT inhibitors against L-DOPA toxicity only. Investigations of L-DOPA uptake in rat striatal cultures using HPLC revealed a significant reduction of extracellular L-DOPA concentrations by Ro 41-0960. Our data confirm that L-DOPA toxicity towards DA neurons is mediated by an autooxidative process, which is attenuated by glial cells. In addition, we demonstrate a second mechanism of L-DOPA toxicity in vitro mediated by a COMT- and glia-dependent pathway, which is blocked by COMT inhibitors, most likely due to enhanced glial uptake of L-DOPA.

Animals↗
PubMed2001

Genetic interaction between shibire and comatose mutations in Drosophila suggest a role for snap-receptor complex assembly and disassembly for maintenance of synaptic vesicle cycling.

NSF is an ATPase required for the fusion of secretory vesicles with plasma membrane. Conditional comatose (Drosophila homolog of N-ethylmaleimide sensitive fusion factor (NSF)) mutations in Drosophila block synaptic transmission at restrictive temperature. Current models hold that NSF-mediated dissociation of SNARE (SNAp REceptor) complexes on mature synaptic vesicles primes them for exocytic release. Paralysis in comt mutants thus reflects defective exocytosis due to buildup of unresolved SNARE complexes. Here, we analyze effects of blocking synaptic vesicle recycling on behavioral, physiological and biochemical phenotypes of comt. Behavioral recovery of comt animals and recovery of comt synapses, as assayed by electroretinograms, after exposure to high temperature is faster if synaptic vesicle recycling is simultaneously blocked using shi(ts) mutants. Concurrently, 7S complex buildup in comt shi double mutants is substantially lower than in comt mutants alone. In addition, we find that 7S complexes can form on presynaptic plasma membrane if NSF is inhibited after synaptic-vesicle depletion. Thus, our experiments demonstrate a need for continuous NSF activity required not only for dissociating cis-SNARE complexes on plasma membrane after exocytosis, but also for maintaining these cis-SNARE complexes in a dissociated state.

Animals↗
PubMed2003

Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females.

Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia.

Adult↗
PubMed1992

Dihydroxynitrobenzaldehydes and hydroxymethoxynitrobenzaldehydes: synthesis and biological activity as catechol-O-methyltransferase inhibitors.

A series of nitro derivatives of dihydroxy- and hydroxymethoxybenzaldehyde was synthesized and tested as potential inhibitors of partially purified pig liver catechol-O-methyltransferase (COMT). All the dihydroxynitrobenzaldehydes prepared were potent inhibitors of COMT, but only one hydroxymethoxynitrobenzaldehyde (3-hydroxy-4-methoxy-5-nitrobenzaldehyde) showed activity as a COMT inhibitor. Although previously reported data showed that the presence of electron-withdrawing substituents at position 5 seemed to be very important for activity as COMT inhibitor, our results suggest that the requirement necessary to enhance the activity of the dihydroxyni-trobenzaldehyde derivatives toward COMT is the presence of the nitro group in a position ortho with respect to one hydroxyl group. The assayed compounds showed a reversible inhibition of COMT, which was mixed for all the dihydroxynitro derivatives but noncompetitive for 3-hydroxy-4-methoxy-5-nitrobenzaldehyde when pyrocatechol was the variable substrate and uncompetitive in all the inhibitors with respect to S-adenosyl-L-methionine.

Animals↗
PubMed2002

Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.

A homologous series of novel nitro-catechol structures (7a-7e) were synthesized and tested as inhibitors of the enzyme catechol-O-methyltransferase (COMT). Increasing chain length was found to have significant impact on both brain penetration and duration of COMT inhibition in the rat. Of this series, compound 7b (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone) was found to exhibit the most potent and selective inhibition of peripheral COMT, with an inhibition profile more similar to entacapone 2 than tolcapone 1 (an equipotent peripheral and central inhibitor) but with much improved duration of action (7b, 70% inhibition and 2, 25% inhibition at 9 h after administration). The effects of structural modifications to 7b on COMT inhibitory profile were investigated, and it is concluded that the carbonyl group and preferably unsubstituted aromatic ring are essential features to maintain prolonged peripheral COMT inhibition. The introduction of the alpha-methylene group, the major structural difference between 7b and 1, would appear responsible for the observed enhancement in selectivity of peripheral COMT inhibition of 7b, which has more limited access to the brain than 1.

Acetophenones↗
PubMed1998

A semiempirical study on inhibition of catechol O-methyltransferase by substituted catechols.

Catechol and endogenous catechol derivatives are readily methylated by catechol O-methyltransferase (COMT). In contrast, many catechol derivatives possessing electronegative substituents are potent COMT inhibitors. The X-ray structure of the active site of COMT suggests that the methylation involves a lysine as a general base. The lysine can activate one of the catecholic hydroxyl groups for a nucleophilic attack on the active methyl group of the coenzyme S-adenosyl-L-methionine (AdoMet). We studied the effect of dinitrosubstitution of the catecholic ring at the semiempirical PM3 level on the methylation reaction catalysed by COMT. The electronegative nitro groups make the ionized catechol hydroxyls less nucleophilic than the corresponding hydroxyl groups of the non-substituted catechol. As a consequence, dinitrocatechol is not methylated but is instead a potent COMT inhibitor. The implications of this mechanism to the design of COMT inhibitors are discussed.

Binding Sites↗
PubMed1984

Difference in erythrocyte catechol-O-methyltransferase activity between Orientals and Caucasians: difference in levodopa tolerance.

The same bimodal distribution of erythrocyte catechol-O-methyltransferase (RBC-COMT) was found in normal Caucasians and Orientals, but the frequency distribution of high RBC-COMT activity of the Orientals was significantly greater than that of the Caucasians. There was no difference in RBC-COMT frequency distribution between Oriental ethnic groups studied (i.e., Chinese and Filipinos). Since Caucasians with Parkinson's disease who had high RBC-COMT activity appeared to have more adverse effects from levodopa (L-dopa) than had those with low RBC-COMT activity, L-dopa doses and adverse responses in Filipinos with parkinsonism were compared to those of Caucasians with parkinsonism. The Filipinos were prescribed substantially lower doses than were the Caucasian patients, and more Filipinos than Caucasians developed dyskinesia at comparable doses of L-dopa. The possible association of the clinical differences in L-dopa tolerance and response between Filipinos and Caucasians with Parkinson's disease, with the racial differences in RBC-COMT activity is discussed.

Adult↗
PubMed2007

Gene-gene effects on central processing of aversive stimuli.

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val(158)Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

Adult↗
PubMed2002

Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil.

The gene for catechol-O-methyltransferase (COMT) plays a key modulatory role in dopaminergic and noradrenergic neurotransmission. Recent evidence suggests that modafinil, like other stimulants, might act through the dopaminergic system. We have reported a sexual dimorphism and a strong effect of the COMT genotype on narcolepsy symptoms and hypothesized that response to modafinil treatment may be associated with the COMT genotype. Here we confirm that COMT genotype distribution between men and women narcoleptics is associated with response to modafinil. In addition, the optimal daily dose of modafinil is approximately 100 mg lower in women narcoleptics and lower in all narcoleptics with low activity COMT genotype. Our results suggest that a sexual dimorphism in COMT activity affects the response to modafinil and probably to other dopaminergic stimulants.

Adolescent↗
PubMed1998

Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior.

Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced. The basal concentrations of brain catecholamines were measured in the striatum, frontal cortex, and hypothalamus of adult male and female mutants. Locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior also were analyzed. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice.

Amino Acid Sequence↗
PubMed2005

Effect of exercise training on peak aerobic power, left ventricular morphology, and muscle strength in healthy older women.

The effect that aerobic (AT) and/or strength training (ST) has on altering peak aerobic power (VO2peak), muscle strength, left ventricular (LV) morphology, and diastolic filling in healthy older women is not known. We assessed the effects of 12 weeks of AT, ST, combined aerobic and strength training (COMT), or no training (NT) on VO2peak, muscle strength, LV morphology, and diastolic filling in 31 healthy women (68 +/- 4 years). Relative VO2peak was significantly greater after 12 weeks of AT, ST, or COMT. Upper and lower extremity strength were significantly higher after 12 weeks of ST or COMT with no change after AT or NT. LV morphology and diastolic filling were not altered after 12 weeks of AT, ST, COMT, or NT. Twelve weeks of ST or COMT are as effective as 12 weeks of AT for increasing relative VO2peak, however, ST and COMT are more effective than AT for improving overall muscle strength.

Age Factors↗
PubMed1990

Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers.

A new catechol-O-methyltransferase (COMT) inhibitor, nitecapone, was given in increasing doses of 0-100 mg concomitantly with L-Dopa/carbidopa (100/25 mg or 100/100 mg) to healthy male volunteers. Plasma concentrations of L-Dopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), as well as the excretion of catecholamine metabolites in urine were followed to evaluate the changes in the metabolism of L-Dopa after nitecapone. Plasma concentrations of nitecapone and the soluble COMT activity in erythrocytes were also measured. The area under the plasma concentration-time curves (AUC) values for plasma nitecapone, L-Dopa and its metabolites were calculated. Nitecapone dose-dependently inhibited the soluble COMT activity in erythrocytes at 30 min after drug intake. Nitecapone slightly but significantly increased the relative bioavailability of L-Dopa. The AUC values of plasma 3-OMD decreased dose-dependently after nitecapone, and those of HVA decreased less, whereas the AUC values of DOPAC increased significantly. The elevation of the dose of carbidopa from 25 to 100 mg increased the AUC value of L-Dopa, but the effect of nitecapone was not clearly modified. Nitecapone decreased the excretion of the methylated dopamine metabolites 3-methoxytyramine (3-MT) and HVA at an L-Dopa/carbidopa dose of 100/25 mg. At a dose of 100/100 mg, the excretion of metanephrine, in addition to 3-MT and HVA, was also significantly decreased by nitecapone. The biochemical changes in L-Dopa metabolism and erythrocyte COMT activity indicate that nitecapone is an active COMT inhibitor in humans, when given orally in single doses. The changes in L-Dopa metabolism by COMT inhibitor warrant further clinical studies in Parkinson's disease.

Adult↗
PubMed1997

Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families.

Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamines, noradrenaline and adrenaline. It exists as common high and low activity alleles in the population (determined by a valine 158 methionine polymorphisms), and high red blood cell activity of COMT has previously been associated with schizophrenia. To examine the relationship between COMT and schizophrenia genetically, the transmission disequilibrium test was performed on 22 multiply affected Caucasian and Japanese families genotyped for val158met and a second, silent, polymorphism (C256G), using PCR based assays. The high activity val158 allele was transmitted from parents to the affected individuals more frequently than the low activity met158 allele, although this was not statistically significant. Combining this data with a previous study using Chinese family trios with schizophrenia (Li et al., 1996) gave a highly significant result (p = 0.0015). The G256 allele was also transmitted preferentially to the affected offspring, and this was statistically significant when schizophrenia, schizoaffective disorder and unspecified functional psychosis were included in the definition of the affected phenotype (p = 0.03). Overall, these findings may indicate an effect of COMT alleles on susceptibility to schizophrenia, or reflect linkage disequilibrium with a different causative polymorphism in the vicinity. Other reported associations of COMT with obsessive compulsive and rapid cycling bipolar disorder indicate that the COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Amino Acid Substitution↗
PubMed2004

Neuronal expression of catechol O-methyltransferase mRNA in neonatal rat suprachiasmatic nucleus.

We examined the expression profile of catechol O-methyltransferase (COMT) mRNA and its protein in the neonatal rat hypothalamus by in situ hybridization and immunohistochemistry to clarify the sites of dopamine degradation. Strong COMT mRNA expression was observed in the suprachiasmatic nucleus (SCN) throughout its rostrocaudal extent at postnatal day 1 (P1) and P2, and the mRNA levels decreased gradually until P16. COMT mRNA was predominantly localized to the ventral and medial parts of the SCN. Intense COMT immunoreactivity was demonstrated in the ventral SCN and was detected in neuronal perikarya and processes at P1. Ependymal and microglial cells also exhibited strong COMT immunoreactivity. These results indicate that COMT may directly be involved in dopaminergic signaling in the neonatal SCN.

Animals↗