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PubMed1993

COMT inhibitors and metabolism of fluorodopa enantiomers in aggregating cell cultures.

Organotypic primary cell cultures of fetal rat brain were used as a model system to study the effect of COMT inhibitors on the cerebral metabolic conversions of fluoro-DOPA enantiomers. The selective COMT inhibitors OR 486 and CGP 28014 were used in conjunction with 5F-L-DOPA, 6F-L-DOPA and 6F-D-DOPA as substrates. Methylation can be clearly reduced by application of OR 486 at nanomolar level, without inhibition of AADC and MAO. The uptake of the substrate is unchanged. CGP 28014, already known to be active only in vivo, has no influence on the metabolic conversion rates of the fluoro-DOPA isomers. These results show that use of this culture system allows statement concerning the in vitro activity of COMT inhibitors. It has not been possible to show an increase of absolute levels of decarboxylation products due to inhibition of COMT, however, but the reduction in levels of methylated product itself may have significance for PET studies of the human brain.

Amidines↗
PubMed1993

Therapy with central active catechol-O-methyltransferase (COMT)-inhibitors: is addition of monoamine oxidase (MAO)-inhibitors necessary to slow progress of neurodegenerative disorders?

Neurotrophic factors, like e.g. nerve growth factor (NGF), neurotrophin 3 (NT-3) or brain-derived neurotrophic factor (BDNF) promote the survival and function of neurones in the peripheral and central nervous system. Dopamine or other biogenic amines induce the biosynthesis of neurotrophic factors in glial and neuronal cells. Therefore inhibition of enzymes, like the extraneuronal and neuronal located MAO or the predominantly glial situated COMT, which both metabolize catecholamines, may induce an increased biosynthesis of neurotrophic factors. Due to clinical studies especially MAO-B-inhibitors appear to slow the progression of neurological deficits in Parkinson's disease and the cognitive decline in Alzheimer's disease. On the one hand inhibition of COMT alone may also slow the metabolisation of biogenic amines in glial cells and may consequently induce synthesis of neurotrophic factors in glial cells. But on the other hand in vivo and in vitro studies show, that COMT-inhibitors may intensify the metabolisation of catecholamines in neurones by MAO, what may cause an enhanced generation of free radicals. This increase of free radicals may induce lipid peroxidation of membranes and therefore cause accelerated neuronal and glial cell death. For that reason we conclude, that centrally active COMT-inhibitors may only be used together with MAO-inhibitors in the neuroprotective treatment of neurodegenerative disorders. Medical treatment with both inhibitors will have to be performed very carefully due to cytotoxic effects of high catecholamine levels on neuronal and glial cells and due to possible prolongation or potentiation of the activity of several noradrenergic drugs in the periphery.

Animals↗
PubMed2003

Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide.

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.

Acetophenones↗
PubMed2004

Negative association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia.

Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD.

Adult↗
PubMed1999

Inhibition of catechol-O-methyltransferase (COMT) in the brain does not affect the action of dopamine and levodopa: an in vitro electrophysiological evidence from rat mesencephalic dopamine neurons.

In order to study whether the membrane hyperpolarization and firing inhibition caused by dopamine and levodopa on rat midbrain dopamine cells are affected by the inhibition of brain catechol-O-methyl-transferase (COMT), intracellular electrophysiological recordings were made from these neurons maintained in vitro. Here we report that a treatment of the cerebral tissue with tolcapone, a central and peripheral inhibitor of COMT, does not change the membrane responses of midbrain dopamine neurons to dopamine and levodopa. The lack of modification of the dopaminergic effects by tolcapone suggests that the pharmacological inhibition of intracerebral COMT does not have detectable action on dopamine neurotransmission. Therefore, the therapeutic action of tolcapone in Parkinson's disease, might be dependent on the reduction of COMT activity in the extracerebral tissue.

Animals↗
PubMed2004

Combined effect of GSTM1, GSTT1, and COMT genotypes in individual breast cancer risk.

Our previous studies suggested that both catechol O-methyl transferase (COMT) and glutathione S-transferase (GST) M1 and T1 genotypes are associated with breast cancer risk. Here we extended the studies to evaluate the potential combined effect of these genotypes in individual breast cancer risk. Incident breast cancer cases (n = 202) and controls (n = 299) with no previous cancer were recruited from three teaching hospitals in Seoul in 1996-1999. Information on putative risk factors was collected by interviewed questionnaire. PCR-based methods were used for the genotyping analyses. Odds ratios (ORs) and 95% confidence (CIs) intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Among pre-menopausal women the low activity associated (COMT *L) allele containing genotypes and the GSTM1 null genotype posed increased risks of breast cancer with ORs of 1.7 (95% CI = 1.0 - 2.8) and 1.7 (95% CI = 1.0-2.8), respectively. A marginally significant effect of GSTT1 null genotype was also observed when the total study population was considered (OR = 1.3, 95% CI = 1.0-2.1). When the combined genotype effects were examined, the concurrent lack of GSTM1 and GSTT1 genes posed a more than 2-fold risk of breast cancer (OR = 2.2, 95% CI = 1.2-3.9); this effect was mainly attributable in pre-menopausal women (OR = 3.2, 95% CI = 1.5-7.2). Moreover, the breast cancer risk increased in parallel with the number of COMT , GSTM1 , and GSTT1 at-risk genotypes (p for trend = 0.003). This association was particularly clear in pre-menopausal women among whom combination of all three high-risk genotypes posed a 4.1-fold breast cancer risk (95% CI = 1.4-12.7) compared with pre-menopausal women without at-risk genotypes (p for trend = 0.001). The trend was more pronounced in women with BMI greater than 22 kg/m2 (p for trend < 0.001) and high-risk status of parity factor (nulliparous or women with the first full term pregnancy at age of over 25-year-old) (p for trend = 0.013). These results suggest the combined effect between reproductive factors and GSTM1, GSTT1 and COMT genotypes in human breast carcinogenesis.

Adult↗
PubMed1992

Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study.

In vivo microdialysis was used to examine the effect of two new catechol-O-methyltransferase (COMT) inhibitors, Ro 40-7592 and OR-611, on extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum. The interactions of the COMT inhibitors with nomifensine, clorgyline and deprenyl were also studied. Ro 40-7592 (3-30 mg/kg, i.p.) decreased dose-dependently the efflux of HVA, increased that of DOPAC, and tended to increase that of dopamine. Higher doses of OR-611 (30-100 mg/kg, i.p.) also decreased the dialysate level of HVA, increased that of DOPAC, and tended to increase that of dopamine. Ro 40-7592 was about ten-fold as potent as OR-611. Neither of the COMT inhibitors changed dialysate levels of 5-HIAA. An OR-611 dose of 10 mg/kg i.p. had no significant effect, in contrast to Ro 40-7592, on any of the parameters studied; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. Both nomifensine (15 mg/kg, i.p.) and clorgyline (4 mg/kg, i.p.) alone elevated extracellular dopamine levels, and lowered those of DOPAC and HVA, though there were quantitative and temporal differences between the drugs. L-Deprenyl (1 mg/kg, i.p.) alone had no significant effect on any of the compounds measured. Ro 40-7592 (10 mg/kg, i.p.) potentiated the effect of nomifensine on dopamine efflux, and it tended to increase clorgyline-induced dopamine efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations.

BACKGROUND: Catechol-O-methyltransferase (COMT) is a strong candidate gene for schizophrenia and cognitive functions disrupted in this disorder. This report examines the relation of COMT genotypes to performance on a battery of working memory tests differing in the cognitive operations to be performed on the material. METHODS: A large sample of 402 healthy adults were tested on four working memory tests: Spatial Delayed Response (SDR), Word Serial Position Test (WSPT), N-back, and Letter-Number Sequencing. A subsample (n = 246) was tested on the Wisconsin Card Sorting Test (WCST). A saliva swab was used to obtain DNA from all participants. RESULTS: Letter-Number Sequencing, which requires both storage and manipulation of information, was the only working memory test that showed expected differences among COMT genotypes, with the met/met group showing the best performance and the val/val group the poorest performance. As in previous studies, the met/met group also performed better than the val/val group on the WCST. CONCLUSIONS: COMT genotypes were not associated with performance on tests measuring simple storage, maintenance of temporal order or updating of information in working memory. Genotype differences in Letter-Number Sequencing and WCST suggest that higher-order components of processing (e.g., mental manipulation) are more closely related to this gene.

Adolescent↗
PubMed2006

Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men.

BACKGROUND: Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men. METHODS: State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val). RESULTS: The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy. CONCLUSIONS: Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance.

Adolescent↗
PubMed2006

Is there an association between the COMT gene and P300 endophenotypes?

P300 wave anomalies correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The COMT gene is thought to influence cognitive performance and to be a susceptibility gene for schizophrenia. Unlike two previous studies, we found no significant influence of the COMT gene on P300 amplitude or latency in 189 individuals examined. The well-supported role of the COMT gene both in dopamine catabolism as well as in prefrontal cognition makes a strong theoretical case for the influence of COMT Val158Met polymorphism on P300 endophenotypes. However, the available neurophysiologic evidence suggests that any such association, if present, must be very subtle.

Adult↗
PubMed2005

Gene-gene interaction between MAOA and COMT in suicidal behavior.

Several lines of evidence suggest that suicidal behavior is associated with altered noradrenergic neurotransmission. Noradrenaline (NA) is catabolized by monoamine oxidase A (MAOA) and cathecol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk for attempted suicide. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the Val 108/158 Met COMT polymorphism in 305 families with at least one member having bipolar disorder (BD). No association with history of suicide attempt was found either in the MAOA polymorphisms (VNTR:LRS = 1.90, d.f. = 1, p = 0.16; 941T > G:LRS = 1.39, d.f. = 1, p = 0.23), or with the Val 158 Met polymorphism (LRS = 1.61, d.f.=1, p = 0.20). When we performed the haplotype analysis for MAOA gene, we found no association between suicide attempt and haplotype distribution (LRS = 3.07, d.f. = 2, p = 0.21). As both genes are involved in degrading noradreanline, we also tested the hypothesis of epistasis between MAOA polymorphisms and Val158Met, however, no additive effect was found in conferring risk for suicide attempt. These findings suggest that MAOA and COMT genes may not influence suicidal behavior in patients with bipolar disorder.

Adult↗
PubMed2005

COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study.

This is the first study of a possible molecular genetic basis for schizophrenia with obsessive-compulsive disorder (OCD). We performed a case-control association study of the catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia-OCD patients, OCD and healthy controls. One hundred and thirteen schizophrenia-OCD patients, 79 OCD patients and 171 control subjects were genotyped for the Val(158)Met polymorphism in the COMT gene. There was no significant difference in allele and genotype distribution of the COMT gene between schizophrenia-OCD patients and healthy controls. The low-activity Met allele and Met/Met genotype were more frequent in OCD men than in schizophrenia-OCD and control individuals. This difference, however, was not statistically significant following correction for multiple comparisons. These results do not support the hypothesis that the COMT Val158Met gene polymorphism is associated with liability to schizophrenia-OCD.

Case-Control Studies↗
PubMed2005

The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.

Catechol-O-methyltransferase (COMT) inactivates dopamine, epinephrine and norepinephrine in the nervous system. A common functional polymorphism (Val158Met) leads to a three- to-four-fold variation in the COMT enzyme activity, the Met form displaying lower enzymatic activity. The Val158Met polymorphism affects pain perception, and subjects with the Met/Met genotype have the most pronounced response to experimental pain. Based on this information we analyzed the influence from the COMT Val158Met polymorphism on the efficacy of morphine in a cohort of patients suffering from cancer pain. We genotyped 207 Caucasian cancer patients on morphine treatment with respect to the Val158Met polymorphism and compared the morphine doses, serum concentrations of morphine and morphine metabolites between the genotype groups. Patients with the Val/Val genotype (n=44) needed more morphine (155+/-160 mg/24 h) when compared to the Val/Met (117+/-100 mg/24 h; n=96) and the Met/Met genotype (95+/-99 mg/24 h; n=67) groups (P=0.025). This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, perceived pain intensity, adverse symptoms, or time until death. These results suggest that genetic variation in the COMT gene may contribute to variability in the efficacy of morphine in cancer pain treatment.

Aged↗
PubMed2004

Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia.

Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission. We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system. In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD. We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia. No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes. Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms. As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed. Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD.

Antipsychotic Agents↗
PubMed2006

DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability.

The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol-O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia. Since DRD2 in mice and the COMT gene in humans modulate working memory, we examined the relationship and possible interaction of both polymorphisms to working memory performance in 188 healthy adults. Subjects having the DRD2 C/C allele showed the poorest performance in a word serial position test. Moreover, the effect of the C957T genotype was strengthened when interaction with the COMT Val158Met polymorphism was included in the analysis. We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia.

Adolescent↗
PubMed2003

A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits.

BACKGROUND: Suicidal behavior is often correlated with other-directed aggression, which is partially mediated by catecholaminergic neurotransmission. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine inactivation. In this study, we examined the influence of a functional COMT (V158M) polymorphism on suicidal behavior and anger-related traits. METHODS: This polymorphism was examined in 149 German suicide attempters and 328 German control subjects. Both groups were administered self-report questionnaires for anger-related traits. RESULTS: There was no overall difference in allele/genotype frequency between patients and control subjects; however, the low-activity L-allele and genotype frequencies were higher among violent suicide attempters. For anger-related traits, a multivariate effect of the COMT genotype was observed after controlling for age and educational level. LL-carriers expressed their anger more outwardly, whereas HH-carriers expressed it more inwardly and reported more state anger, as assessed by the self-report questionnaire. CONCLUSIONS: These findings support the hypothesis that the functional polymorphism in the COMT gene may modify the phenotype of suicide attempts and anger-related traits. This, however, being a novel finding, should warrant further investigation.

Adult↗
PubMed1999

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. METHODS: A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. RESULTS: We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. CONCLUSIONS: Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.

Adolescent↗
PubMed2004

The effect of CYP19 and COMT polymorphisms on exercise-induced fat loss in postmenopausal women.

OBJECTIVE: To examine whether genetic polymorphisms in CYP19 [intron 4 (TTTA)n; n = 7 to 13 and a 3-base pair deletion, which is in strong linkage disequilibrium with the seven repeat] and COMT (Val108/158Met) modified the change in BMI, total and percentage body fat, or subcutaneous and intra-abdominal fat during a year-long exercise intervention trial. These genes metabolize estrogens and androgens, which are important in body fat regulation. RESEARCH METHODS AND PROCEDURES: A randomized intervention trial was used, with an intervention goal of 225 min/wk of moderate-intensity exercise for one year. Participants (n = 173) were postmenopausal, 50 to 75 years old, sedentary, overweight or obese, and not taking hormone therapy at baseline. RESULTS: Exercisers with two vs. no CYP19 11-repeat alleles had a larger decrease in total fat (-3.1 kg vs. -0.5 kg, respectively, p = 0.01) and percentage body fat (-2.4% vs. -0.6%, respectively, p = 0.001). Exercisers with the COMT Met/Met vs. Val/Val genotype had a smaller decrease in percentage fat (-0.7% vs. -1.9%, respectively, p = 0.05). Among exercisers, women with the COMT Val/Val genotype and at least one copy of the CYP19 11-repeat allele vs. those with neither genotype/allele had a significantly larger decrease in BMI (-1.0 vs. +0.1 kg/m2, respectively, p = 0.009), total fat (-2.9 vs. -0.5 kg, respectively, p = 0.004), and percentage body fat (-2.6% vs. -0.4%, respectively, p < 0.001). DISCUSSION: Genetic polymorphisms in CYP19 and COMT may be important for body fat regulation and possibly modify the effect of exercise on fat loss in postmenopausal women.

Adipose Tissue↗