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Showing papers on "Catechol-O-methyl transferase published in 2002"


Journal ArticleDOI
TL;DR: An efficient approach to gene discovery is reported that found a highly significant association between schizophrenia and a COMT haplotype and can be widely implemented for the genetic dissection of other common diseases.
Abstract: Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of ( i ) a large sample size—to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; ( ii ) the use of Ashkenazi Jews, a well defined homogeneous population; and ( iii ) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype ( P =9.5×10 −8 ). The approach presented can be widely implemented for the genetic dissection of other common diseases.

711 citations


Journal ArticleDOI
TL;DR: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.
Abstract: OBJECTIVE: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. METHOD: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. RESULTS: Subjects with only the low-activity met allele made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. CONCLUSIONS: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.

601 citations


Journal ArticleDOI
TL;DR: No single best treatment exists for an individual patient with PD, and particularly in the advanced stage of the disease, treatment should be individually tailored.
Abstract: Current research in Parkinson’s disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.

293 citations


Journal ArticleDOI
TL;DR: A brief overview of the COMT metabolic system is provided with particular attentions being paid to the regulation of this catechol-metabolizing system by endogenous regulatory factors as well as by exogenous factors such as dietary phytochemicals.
Abstract: The metabolic O-methylation of endogenous catecholamines and other catechols catalyzed by catechol-O-methyltransferase (COMT; EC 2.1.1.6) was first described by Dr. Julix Axelrod and his colleagues almost half a century ago. In the past several years, research interest in this catechol-metabolizing system has been renewed because of its potential pathophysiological and pathogenic significance in estrogen-induced hormonal cancers, in the development of degenerative brain disorders, as well as in the development of cardiovascular diseases. In this review paper, I provide a brief overview of the COMT metabolic system, with particular attentions being paid to the following three areas: (i) the regulation of this catechol-metabolizing system by endogenous regulatory factors (mainly S-adenosyl-L-homocysteine and homocysteine) as well as by exogenous factors such as dietary phytochemicals; (ii) decreased metabolic O-methylation of endogenous catecholamines as an important risk factor for the development of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases in the elderly and also as a risk factor for the development of a variety of cardiovascular diseases; and (iii) the relative importance of the COMT-catalyzed O-methylation metabolism of endogenous catechol estrogens in the causation and prevention of estrogen-induced hormonal cancers. Some unifying hypotheses are also discussed in this paper with the hope that they may provide useful mechanistic insights into our understanding of the biological functions that are associated with this important metabolic system.

247 citations


Journal ArticleDOI
TL;DR: Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites, and this finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase‐dependent metabolism in terminating the actions of catecholamines at nerve terminals.
Abstract: Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.

192 citations


Journal ArticleDOI
TL;DR: It is concluded that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males, adding to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease.
Abstract: The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease.

118 citations


Journal ArticleDOI
TL;DR: Findings provide strong evidence for a susceptibility locus for panic disorder either within the catechol-O-methyltransferase gene or in a nearby region of chromosome 22.

117 citations


Journal ArticleDOI
01 Mar 2002-Synapse
TL;DR: Findings in this study are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.
Abstract: Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

105 citations


Journal ArticleDOI
TL;DR: The hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia is not supported.
Abstract: Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both 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 genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia.

102 citations


Journal ArticleDOI
TL;DR: The results suggest that the L/L genotype of the COMT gene may be related to the development and treatment outcome of panic disorder in some patients.
Abstract: OBJECTIVE: The authors examined the distribution of catechol O-methyltransferase (COMT) genotypes in patients with panic disorder as well as the relationship between a COMT polymorphism and the clinical characteristics of these patients. METHOD: Fifty-one patients with panic disorder and 45 healthy comparison subjects were tested for a genetic polymorphism of COMT. Clinical variables were assessed for the patients with panic disorder. RESULTS: The frequency of the L/L genotype was significantly higher in the patients with panic disorder than in the healthy subjects (19.6% versus 2.2%). Panic disorder was significantly associated with the L allele and L/L genotype. Patients with panic disorder who had the L/L genotype showed poorer treatment response than those with other genotypes. CONCLUSIONS: These results suggest that the L/L genotype of the COMT gene may be related to the development and treatment outcome of panic disorder in some patients.

95 citations


Journal ArticleDOI
TL;DR: This is the first report of a three-dimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.
Abstract: Catechol- O -methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics. In particular, inactivation of drugs such asl-3,4-dihydroxyphenylalanine (l-DOPA) via O -methylation is of relevant pharmacological importance, because l-DOPA is currently the most effective drug used in the treatment of Parkinson's disease. This justified the interest in developing COMT inhibitors as potential adjuncts to l-DOPA therapy. The kinetics of inhibition by BIA 3-335 (1-[3,4-dihydroxy-5-nitrophenyl]-3-( N -3′-trifluormethylphenyl)-piperazine-1-propanone dihydrochloride) were characterized using recombinant rat soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K i of 6.0 ± 1.6 nM and displaying a competitive inhibition toward the substrate binding site and uncompetitive inhibition toward the S -adenosyl-l-methionine (SAM) binding site. The 2.0-A resolution crystal structure of COMT in complex with its cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic interactions between the important residues at the active site and the inhibitor. This is the first report of a three-dimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.

Journal ArticleDOI
TL;DR: The role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited, and attenuation of hyperlocomotion was observed after cocaine treatment in genetic background COMT-deficient male mice.
Abstract: Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake(1), followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake(2), followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO). For dopaminergic neurons, uptake by the high-affinity dopamine transporter (DAT) is the most effective mechanism, and the contribution of glial COMT remains secondary under normal conditions. In the present study we have characterized the role of COMT using COMT-deficient mice in conditions where DAT is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12909) or cocaine. In mice lacking COMT, GBR 12909 results in total brain tissue dopamine levels generally higher than in wild-type mice but no such potentiation was ever seen in striatal extracellular fluid. Dopamine accumulation in nerve endings is more evident in striatum and hypothalamus than in cortex. Both GBR 12909 and cocaine induced hyperlocomotion in mice lacking COMT. Unexpectedly, hyperactivity induced by 20 mg/kg GBR 12909 was attenuated only in male COMT knockout mice, i.e., they had an inability to sustain the hyperactivity induced by DAT inhibition. Furthermore, attenuation of hyperlocomotion was observed also after cocaine treatment in both C57BL/6 (at 5 and 15 mg/kg) and 129/Sv (at 30 mg/kg) genetic background COMT-deficient male mice. Despite the possible interaction between DAT and extraneuronal uptake (and subsequently COMT), the role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited.

Journal ArticleDOI
TL;DR: It is concluded that the CYP1B1*3 allele appears to be a factor for susceptibility to breast cancer in Turkish women especially those with a BMI greater than 24 kg/m2.
Abstract: Epidemiological studies indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. Estrogen has been proposed to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). Because of the important role of cytochrome P450 1B1 (CYP1B1) and catechol O-methyltransferase (COMT) in mammary estrogen and carcinogen metabolism, we examined the CYP1B1 and COMT genes to determine whether genetic variations could account for inter-individual differences in breast cancer. In this case-control study, we determined CYP1B1 and COMT genotypes in 84 breast cancer patients and 103 healthy unrelated women controls from a Turkish population. In the case of CYP1B1, we genotyped CYP1B1*3 (L432 V) allele. We found that carriers of the CYP1B1*3 allele were more frequent among breast cancer patients with adjusted odds ratio (OR) for age, age at menarche, age at first full-term pregnancy, body mass index (BMI) and smoking status of 2.32 (95% confidence interval 1.26–4.25) associated with the allele. However, this allele appeared to be a significant factor for susceptibility only in patients with a BMI greater than 24 kg/m2. Menopausal status did not appear to affect susceptibility. In the case of COMT, there was no significant difference in susceptibility for breast cancer development between patients with low activity COMT-L (V158 M) allele and high activity COMT-H allele, and susceptibility was not affected by menopausal status, BMI or CYP1B1 genotype. We conclude that the CYP1B1*3 allele appears to be a factor for susceptibility to breast cancer in Turkish women especially those with a BMI greater than 24 kg/m2.

Journal ArticleDOI
TL;DR: Both in vitro and in vivo results indicate that entacapone does not impair energy metabolism related to uncoupling of oxidative phosphorylation, and tolcapone shows this effect in vitro at clinically relevant concentrations.

Journal ArticleDOI
TL;DR: The results suggest that MAO-A, COMT, catechol-O-methyltransferase, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.
Abstract: The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.

Journal ArticleDOI
TL;DR: The data suggest that the decreased COMT enzymatic activity that has been detected in human tissue in association with the comT(L) allele is not reflected by differences in the affinity or capacity of COMT(H) and COMT (L) for catechol estrogen methylation.
Abstract: The major detoxification pathway of the carcinogenic catechol estrogens is methylation by catechol-O-methyltransferase (COMT). It has been hypothesized that the enzyme encoded by the low-activity allele (COMT L ) has a lower catalytic activity for catechol estrogen methylation than that encoded by the high activity allele (COMT H ). We expressed and purified human soluble (S)-COMT H and S-COMT L in Escherichia cola and characterized the methylation of 2- and 4-hydroxyestradiol (2- and 4-OH-E2). There were no differences between the kinetic parameters for COMT H and COMT L . The kinetic parameters for S-adenosylmethionine (SAM), the methyl donor in these reactions, also did not differ for COMT H and COMT L . S-adenosylhomocysteine, the demethylated SAM metabolite, inhibited methylation of the catechol estrogens in a non-competitive manner similarly for COMT H and COMT L . Each COMT substrate tested inhibited the methylation of other substrates in a mixed competitive and non-competitive fashion similarly for COMT H and COMT L . Furthermore, in cytosolic fractions of COMT HH (MCF-10A and ZR-75-1) and COMT LL (MCF-7 and T47D) human breast epithelial cell lines, no differences were detected between the kinetic parameters of COMT with respect to 2-and 4-OH-E2 methylation; nor were COMT protein levels associated with the COMT genotype. These data suggest that the decreased COMT enzymatic activity that has been detected in human tissue in association with the COMT L allele is not reflected by differences in the affinity or capacity of COMT H and COMT L for catechol estrogen methylation. These results raise the question of what accounts for the difference in COMT activity associated with the COMT and COMT LL genotypes in human tissue.

Journal ArticleDOI
TL;DR: The results obtained suggest that, in male schizophrenic patients the Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye movement disturbances, and point to possible gender differences as to the role of COMT in brain function in schizophrenia.
Abstract: Previous studies suggested an association between the catechol-O-methyltransferase (COMT) Val/Met polymorphism and the performance on neuropsychological tests, measuring prefrontal function in schizophrenia. The aim of this study was to examine the relationship between this polymorphism and performance on oculomotoric tests in schizophrenic patients. The intensity of eye movement disturbances on fixation and smooth pursuit tests and the Val/Met polymorphism of COMT gene were studied in 117 schizophrenic patients (74 male and 43 female). In male schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was lower in subjects who had the Met/Met genotype, with significant difference compared to other genotypes. Also, a significantly higher frequency of the Met allele and the Met/Met genotype was found in male schizophrenic patients exhibiting a lower intensity of smooth pursuit disturbances, and a trend in this direction was observed for the intensity of fixation disturbances. No such relationship was found in female schizophrenic patients. The results obtained suggest that, in male schizophrenic patients the Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye movement disturbances. They also point to possible gender differences as to the role of COMT in brain function in schizophrenia.

Journal ArticleDOI
TL;DR: It is confirmed that COMT genotype distribution between men and women narcoleptics is associated with response to modafinil and probably to other dopaminergic stimulants.
Abstract: 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.

Journal ArticleDOI
TL;DR: It is concluded that the carbonyl group and preferably unsubstituted aromatic ring are essential features to maintain prolonged peripheral COMT inhibition.
Abstract: 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 α-methylene group, the major structural difference between ...

Journal ArticleDOI
TL;DR: Entacapone decreased the peripheral formation of 3-O-methyldopa (3-OMD) to about 55-60% of the placebo treatment level and increased the mean AUC of 3,4-dihydroxy-phenylacetic acid (DOPAC) 2-2.6-fold compared with placebo (P < 0.001, 95% CI 0.26, 0.90).
Abstract: Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral l-dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of l-dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of l-dopa given as standard release l-dopa/carbidopa. Methods Six different doses of l-dopa/carbidopa were investigated in this placebo-controlled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups (n = 14–16). Two different l-dopa/carbidopa doses were administered to each subject (50/12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of l-dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of l-dopa to a similar extent at all doses of l-dopa/carbidopa, that is by about 30–40% compared with placebo (P 0.05, 95% CI –0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC l-dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD (P < 0.001, 95% CI −0.85, −0.68) and HVA (P < 0.001, 95% CI −1.01, −0.18) in plasma at each l-dopa/carbidopa dose, whereas the AUC DOPAC/AUC l-dopa ratio was increased again at all doses (P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did l-dopa/carbidopa affect the pharmacokinetics of entacapone. Conclusions The 200 mg dose of entacapone similarly and significantly increases the AUC of l-dopa by changing the metabolic balance of l-dopa independent of the l-dopa/carbidopa dose and therefore entacapone is likely to have a similar l-dopa potentiating effect independent of l-dopa dose.

Journal ArticleDOI
TL;DR: The data suggest that endogenous COMT activity in mammalian cells may alter neurotransmitter deposition and thus the apparent kinetic characteristics of transport.
Abstract: To determine if catechol-O-methyltransferase (COMT) metabolizes catecholamines within cell lines used for heterologous expression of plasmalemmal transporters and alters the measured characteristics of 3H-substrate transport, the uptake of monoamine transporter substrates was assessed in three cell lines (C6 glioma, L-M fibroblast, and HEK293 cells) that had been transfected with the recombinant human transporters. Uptake and cellular retention of 3H-catecholamines was increased by up to fourfold by two COMT inhibitors, tropolone and Ro 41-0960, with potencies similar to those for inhibition of COMT activity, whereas the uptake of two transporter substrates that are not substrates for COMT, [3H]serotonin and [3H]MPP+, was unaffected. Direct measurement of monoamine substrates by HPLC confirmed that tropolone (1 mM) increased the retention of the catecholamines dopamine and norepinephrine, but not the retention of serotonin in HEK293 cells. Saturation analysis of the uptake of [3H]dopamine by C6 cells expressing the dopamine transporter demonstrated that tropolone (1 mM) decreased the apparent Km of transport from 0.61 microM to 0.34 microM without significantly altering the maximal velocity of transport. These data suggest that endogenous COMT activity in mammalian cells may alter neurotransmitter deposition and thus the apparent kinetic characteristics of transport.

Journal ArticleDOI
TL;DR: The results show that in the normal monkeys L-DOPA does not provoke marked oxidative damage even at high doses, and that there is little or no potentiation of its effects by entacapone.
Abstract: Parkinson's disease (PD) is characterised by a loss of pigmented dopaminergic neurones in the zona compacta of substantia nigra. The mechanisms underlying nigral cell death remain unknown but may involve oxidative damage. There has been concern that L-DOPA treatment may accelerate nigral pathology in PD through chemical and enzymatic oxidation to reactive oxygen species. In the present study, we examined tissues from normal macaque monkeys treated for 13 weeks with high doses of L-DOPA (in combination with the peripheral decarboxylase inhibitor, carbidopa) and/or the COMT inhibitor, entacapone. Plasma was analysed for changes in protein carbonyls as a marker of oxidative damage to protein. Cortical tissue was examined for changes in levels of protein carbonyls, lipid peroxidation and oxidative damage to DNA. The integrity of the nigro-striatal pathway was assessed by nigral tyrosine hydroxylase mRNA levels and specific [(3)H]mazindol binding to dopaminergic terminals in caudate-putamen. No alterations in plasma protein carbonyls were observed in any treatment group. An increase was found in the levels of protein carbonyls, lipid peroxidation and 5-OH uracil, but not other products of oxidative DNA damage, in cerebral cortex of monkeys treated with L-DOPA plus carbidopa or with L-DOPA plus carbidopa and entacapone but this was only statistically significant in the latter group. There was no change in nigral tyrosine hydroxylase mRNA levels or specific striatal [(3)H]mazindol binding in brain tissue from monkeys treated with either L-DOPA plus carbidopa or L-DOPA plus carbidopa and entacapone. The results show that in the normal monkeys L-DOPA does not provoke marked oxidative damage even at high doses, and that there is little or no potentiation of its effects by entacapone. Neither L-DOPA plus carbidopa nor L-DOPA plus carbidopa and entacapone led to obvious damage to the nigro-striatal pathway.

Journal ArticleDOI
TL;DR: Overall, there is 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.
Abstract: 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.

Journal ArticleDOI
TL;DR: The results do not support a major role of APOE, PARKIN and COMT polymorphisms in PD susceptibility in the Finnish population, compared to reports in oriental populations.

Journal ArticleDOI
Myung Sik Lee1, H. S. Kim, E. K. Cho, J. H. Lim, Juha O. Rinne 
TL;DR: The COMT genotype seems to be a minor factor in judging the beneficial effects of entacapone administration, and there was no significant difference in the frequency or severity of dyskinesias between the patients with differentCOMT genotypes.
Abstract: Objective: To investigate the relationship between the catechol- O -methyltransferase (COMT) genotype and the therapeutic efficacy of entacapone. Methods: The efficacy of 2 months of entacapone treatment in 65 patients with PD with end-of-dose deterioration was studied. The efficacy of entacapone was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) score, the daily levodopa dosage, and the patients’ diary card. Results: Thirty-six patients (55.4%) had a high-activity COMT gene ( COMT HH ), 22 (33.8%) had an intermediate-activity COMT gene ( COMT HL ), and 7 patients (10.8%) had a low-activity COMT gene ( COMT LL ). Two months of entacapone treatment resulted in a significant increase in “on” time, a reduction in “off” time, and a reduction in the total UPDRS score, but these results were independent of the COMT genotype of the patient. There was no significant difference in the frequency or severity of dyskinesias between the patients with different COMT genotypes. Conclusion: The COMT genotype seems to be a minor factor in judging the beneficial effects of entacapone administration.

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TL;DR: ComT, MAO-A, and Gbeta3 variants were not associated with lithium outcome, even when possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment, and previous episodes were included in the model.
Abstract: We studied the possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol-O-methyltransferase (COMT) G158A, monoamine oxydase A (MAO-A) 30-bp repeat, G-protein β 3-subunit (Gβ3) C825T. A total of 201 subjects affected by bipolar (n = 160) and major depressive (n = 41) disorder were followed prospectively for an average of 59.8 months and were typed for their gene variants using PCR techniques. COMT, MAO-A, and Gβ3 variants were not associated with lithium outcome, even when possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment, and previous episodes were included in the model. The pathways influenced by those variants are not therefore involved with long-term lithium outcome in our sample. © 2002 Wiley-Liss, Inc.

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TL;DR: Signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.
Abstract: The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.

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TL;DR: The catechol-O-methyltransferase (COMT) inhibitors represent a new class of antiparkinsonian drugs and when coadministered with levodopa/decarboxylase inhibitor, 2 COMT inhibitors, tolcapone and entacapone have been shown to improve the clinical benefit of levodOPA.
Abstract: 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.

Journal ArticleDOI
TL;DR: The established assay method used to assess S- and MB-COMT activities in human erythrocytes could be useful to elucidate catecholamine metabolism in the normal physiological state as well as in the pathology of certain diseases.
Abstract: Background Catechol-O-methyltransferase (COMT) catalyses the inactivation of catecholamines. It is widely distnbuted in most tissues in soluble (S-COMT) and membrane-bound (MB-COMT) forms. Recently, we used a new assay for COMT activity and demonstrated that COMT plays an important role in blood pressure regulation in spontaneously hypertensive rats. In order to investigate whether this is true for human hypertension, we have evaluated the erythrocyte COMT assay in humans. Method The assay procedure included the use of norepinephrine (NE) as a natural substrate and the quantification of the reaction product, normetanephrine, followed by high-performance liquid chromatography separation and fluorescence or chemiluminescence detection. Results After evaluation of the method, the optimum conditions were obtained for the assay of human erythrocyte COMT. The S- and MB-COMT activities obtained were 50.6 (24.5) and 329.8 (179.4) fmol/min/mg protein, respectively [mean (standard deviation); n = 54]. The Km values for NE were 91.3 (14.1) and 11.7 (1.1) micromol/L for S- and MB-COMT, respectively (n = 6). Conclusion The established assay method used to assess S- and MB-COMT activities in human erythrocytes could be useful to elucidate catecholamine metabolism in the normal physiological state as well as in the pathology of certain diseases.

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TL;DR: ComT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering in patients with multiple system atrophy.
Abstract: Background— Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. Methods and Results— We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was ≈3.5 times greater than the maximal response to entacapone. Conclusions— COMT inhibition elicits a...