Showing papers on "Catechol-O-methyl transferase published in 1997"
TL;DR: It is shown that a common functional allele of this gene, which results in a 3- to 4-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males.
Abstract: In the present study, we address the role of the gene for catechol-O-methyltransferase (COMT), a key modulator of dopaminergic and noradrenergic neurotransmission, in the genetic predisposition to obsessive-compulsive disorder (OCD). We show that a common functional allele of this gene, which results in a 3- to 4-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males. This association is further supported by psychiatric evaluation of patients who carry microdeletions encompassing the comt gene. The mechanism underlying this sex-selective association remains to be defined and may include a sexual dimorphism in COMT activity, although close linkage with a nearby disease susceptibility locus cannot be excluded at this point.
316 citations
Journal Article•
TL;DR: The findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.
Abstract: Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMTLL). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMTHL and COMTLL genotypes were 1.30 [confidence interval (CI), 0.66–2.58] and 1.45 (CI, 0.69–3.07), respectively. Postmenopausal COMTLL women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93–5.11]. The association of COMTLL with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07–11.98). When COMTLL was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.
282 citations
TL;DR: It is found that schizophrenic patients who are homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygously for the high activity allele.
Abstract: We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 1043; P = 0003)
223 citations
TL;DR: Individuals with the high-activity COMT variant may have greater genetic vulnerability to drug abuse, as compared with control research volunteers reporting insignificant lifetime use of addictive substances.
Abstract: Allelic variants at the catechol-O-methyltransferase (COMT) locus are candidates to contribute to genetic components of interindividual differences in vulnerability to substance abuse. COMT plays a prominent role in dopaminergic circuits important for drug reward, and COMT alleles encode enzymes whose activities vary from three- to four-fold. We compared COMT allele frequencies in control research volunteers reporting insignificant lifetime use of addictive substances with those in volunteers reporting substantial polysubstance use. Homozygosity for the high-activity COMT allele was found in 18% of controls, 31% of volunteers with high lifetime substance use, and 39% meeting DSMIII-R substance abuse criteria [odds ratio (relative risks) 2.0 (control vs. use; 95% confidence interval 1.2-3.5; P < 0.013) and 2.8 (control vs. DSM; 1.3-6.1; P < 0.008)]. Individuals with the high-activity COMT variant may have greater genetic vulnerability to drug abuse.
186 citations
TL;DR: The catechol-O-methyltransferase (COMT) gene occurs as two polymorphic alleles, which code for a high activity thermostable and low activity thermolabile form of the enzyme, which are shown to be equally distributed in the Finnish population.
Abstract: The catechol-O-methyltransferase (COMT) gene occurs as two polymorphic alleles, which code for a high activity thermostable and low activity thermolabile form of the enzyme. We devised a fast solid-phase minisequencing assay for genotyping the COMT gene at nucleotide position 544 encoding amino acid residue 158. The method was applied to correlate the genotype of the COMT gene with the biological activity of the COMT enzyme. In red blood cells from individuals homozygous for G at nucleotide position 544 coding for Val-158, the activity of COMT ranged from 0.55-1.03 pmol min-1 mg-1 protein, and in individuals homozygous for A at position 544 coding for Met-158, the activity ranged from 0.21-0.43 pmol min-1 mg-1. Heterozygotes showed intermediate activities of 0.20-0.88 pmol min-1 mg-1. The thermostability (heated/unheated) at 48 degrees C of the high activity form was shown to be about two-fold compared to that of the low activity form of the enzyme. By analysing 76 individual samples and three pooled samples representing altogether 3140 individuals using the solid-phase minisequencing method, the two COMT alleles were shown to be equally distributed in the Finnish population. No statistically significant difference in the frequencies of the COMT alleles was found when comparing the normal population with a sample of 158 Finnish patients with Parkinson's disease.
162 citations
TL;DR: Japanese patients with Parkinson's disease and controls were genotyped by using polymerase chain reaction (PCR) amplification and digestion by the restriction enzyme NlaIII to determine high and low activity alleles of the COMT gene, suggesting that homozygosity for the low activity allele may increase susceptibility to PD.
130 citations
TL;DR: The intracellular localization of both COMT forms implies that COMT acts in the cytoplasm and possibly also in the nuclear compartment, and that the physiological substrates of COMT enzymes may have to be internalized before their methylation by COMT.
Abstract: The intracellular localization of soluble and membrane-bound isoforms of rat and human catechol O-methyltransferase (COMT) was studied by expressing the recombinant COMT proteins either separately or together in mammalian cell lines (HeLa and COS-7 cells) and in rat primary neurons. The distribution of soluble and membrane-bound COMT enzyme was visualized by immunocytochemistry. For comparison, the localization of native COMT was studied in rat C6 glioma cells by immunoelectron microscopy. Staining of cells expressing membrane-bound COMT with a COMT-specific antiserum revealed an immunofluorescence signal in intracellular reticular structures and in the nuclear membrane. Double-staining of the cells with antisera against proteins specific for the rough endoplasmic reticulum indicated that they colocalized with membrane-bound COMT, suggesting that it resided in the endoplasmic reticulum. Notably, no COMT-specific fluorescence of plasma membranes was detected. The signal in the endoplasmic reticulum was also evident in the cells expressing both recombinant COMT forms. Intracellular native COMT reaction was detected by immunoelectron microscopy in rat C6 glioma cells and an intense cytoplasmic signal was seen in the primary neurons infected with the recombinant Semliki Forest virus. The cells expressing recombinant soluble COMT revealed intense nuclear staining together with diffuse cytoplasmic immunoreactivity, suggesting that a part of soluble COMT is transported to nuclei. Western blotting from rat liver and brain revealed soluble COMT in the nuclei. Enzyme activity measurements from liver cytoplasmic and nuclear fractions suggested that about 5% of the soluble COMT resided in nuclei. The intracellular localization of both COMT forms implies that COMT acts in the cytoplasm and possibly also in the nuclear compartment, and that the physiological substrates of COMT enzymes may have to be internalized before their methylation by COMT.
113 citations
TL;DR: Findings may indicate an effect of COMT alleles on susceptibility to schizophrenia, or reflect linkage disequilibrium with a different causative polymorphism in the vicinity.
Abstract: 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.
110 citations
TL;DR: It is concluded that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in the sample of patients with bipolar disorder and unipolar depression.
105 citations
TL;DR: It is hypothesize that either the low activity allele of catechol-O-methyltransferase is a risk factor for bipolar affective disorder in Chinese populations or is in linkage disequilibrium with a nearby susceptibility gene or polymorphism.
Abstract: Catechol-O-methyltransferase catalyses the O-methylation of biologically active or toxic catechols and is a major component of the metabolism of drugs and neurotransmitters such as L-dopa, noradrenaline, adrenaline, and dopamine. Human catechol-O-methyltransferase activity is an autosomal partially dominant trait and is strongly associated with a valine to methionine substitution at codon 158 of the protein. About 25% of Caucasians have low activity, 50% intermediate activity and 25% high activity as determined by either phenotypic or genotypic measurement. In black populations, the low activity allele (Met158; COMTL) is less frequent with about 7% being homozygous. Using a PCR based genotyping assay, we report that the Met158 allele is also less frequent in normal Han Chinese subjects with about 3% of the population being homozygous. Because of its role in catecholamine metabolism and several lines of evidence pointing to a locus for psychosis near the COMT gene on chromosome 22q11, we have analysed the COMT Val158Met polymorphism as a candidate susceptibility factor for bipolar affective disorder. We report an association between bipolar affective disorder and the Met158 allele (p = 0.004) and genotype (p = 0.01) in 93 affected Chinese subjects and 98 controls. We hypothesize that either the low activity allele of catechol-O-methyltransferase is a risk factor for bipolar affective disorder in Chinese populations or is in linkage disequilibrium with a nearby susceptibility gene or polymorphism.
95 citations
TL;DR: The lack of association between two recently described DNA polymorphisms at the COMT gene and bipolar disorder suggests that the COMt gene is not a major risk factor for bipolar disorder.
Abstract: Objective: Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression. Method: The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin. Results: The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed. Conclusions: The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder. (Am J Psychiatry 1997; 154:113‐115)
TL;DR: It is concluded that catechol-O-methyltransferase plays an important role in determining the natriuretic effects of the renal dopamine system.
TL;DR: It is concluded that tolcapone can either slightly improve or impair the memory functions depending on task specific elements and performance factors.
TL;DR: Results show that peripherally acting entacapone, unlike the brain-penetrating tolcapone, is a safe catechol-O-methyltransferase inhibitor for the treatment of Parkinson's disease, since it does not interfere with mitochondrial energy metabolism at pharmacologically effective concentrations.
TL;DR: The results show that this polymorphism and hence the thermostability of COMT enzyme are not related to a risk of developing Parkinson's disease.
Abstract: High and low catechol-O-methyltransferase (COMT) activity is significantly determined by thermostability, which is caused by a valine/methionine108 polymorphism associated with polymorphic G/A1947 bases, in exon 4 of the COMT gene. Our allelic association study on this polymorphism did not find any statistically significant difference between our Chinese Parkinson's disease and that of control subjects. These results show that this polymorphism and hence the thermostability of COMT enzyme are not related to a risk of developing Parkinson's disease.
TL;DR: The allele frequency for −108Val was higher in PD patients compared with controls, although the differences did not reach the statistical significance, and COMT gene polymorphism may constitute a genetic risk factor for PD among Japanese.
Abstract: We report −108Met/Val polymorphism of the COMT gene in Japanese patients with Parkinson's disease (PD). The allele frequency for −108Val was higher in PD patients compared with controls, although the differences did not reach the statistical significance. However, the frequency of -108Val homozygotes was significantly higher in PD patients (56.8%) than in control subjects (44.2%), and heterozygotes of −108Met/Val were less in PD. COMT gene polymorphism may constitute a genetic risk factor for PD among Japanese.
TL;DR: The results suggest that entacapone can be safely administered together with L‐Dopa and selegiline in patients with PD, although further studies with larger number of patients and longer treatment periods are necessary to confirm this finding.
Abstract: The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study. An L-Dopa test was performed on 3 study days. The first study day was with L-Dopa/benserazide only (control), the second after 14 days of treatment with 200 mg entacapone taken concomitantly with L-Dopa/benserazide in combination with either selegiline (10 mg daily) or placebo. After a 2-week washout period, selegiline and placebo treatments were switched, and the third study day was after 14 days of treatment. During the study days, clinical response was evaluated at 30-min intervals for 6 h, by using the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). In addition, repeated blood pressure measurements were made, and plasma samples were taken for analysis of L-Dopa, 3-O-methyldopa (3-OMD), dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), dopamine, noradrenaline, and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Monoamine oxidase B (MAO-B) and COMT enzyme activities were measured from platelets and erythrocytes, respectively. Entacapone improved the clinical response to L-Dopa during both selegiline and placebo (p 35% (p < 0.001), and platelet MAO-B activity was almost completely inhibited by selegiline (p < 0.001). One patient withdrew because of diarrhea, dizziness, and loss of sleep when receiving selegiline treatment. Otherwise no differences in adverse events, mean daily blood pressures, or other safety parameters were observed between selegiline and placebo treatments. Our results suggest that entacapone can be safely administered together with L-Dopa and selegiline in patients with PD, although further studies with larger number of patients and longer treatment periods are necessary to confirm this finding.
TL;DR: No significant association was detected with the codon 158 COMT polymorphism, which suggests that the catechol-O-methyltransferase polymorphism is not a susceptibility gene in BPD.
Abstract: Abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders. Consequently, alterations in genes that are involved in catecholamine metabolism could be potential candidates for bipolar affective disorder (BPD) vulnerability. One such candidate is catechol-O-methyltransferase (COMT). A functional polymorphism has recently been characterized that is responsible for substantial variability in COMT enzymatic activity. A relatively low activity allele is associated with a methionine residue at amino acid 158 of membrane bound COMT whereas a high activity variant has a valine at this site. We have now screened 63 unrelated patients with BPD for this functional polymorphism. However, no significant association was detected. This suggests that the codon 158 COMT polymorphism is not a susceptibility gene in BPD.
TL;DR: The multiple‐dose tolerability, pharmacokinetics, and pharmacodynamics of tolcapone, a novel catechol‐O‐methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving concomitant carbidopa and levodopa.
Abstract: Objectives
The multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving concomitant carbidopa and levodopa.
Methods
Thirty-six volunteers from 55 to 75 years old participated in this double-blind, placebo-controlled, ascending multiple-dose study. Tolcapone was studied at dosages of 100, 200, 400, or 800 mg three times daily (t.i.d.) in four sequential groups. Each group consisted of nine participants who had been randomized to receive either placebo (n = 3) or tolcapone (n = 6). Tolcapone or placebo was coadministered with carbidopa and levodopa (25 and 100 mg, respectively) for 7 days. Assessments included tolerability, pharmacokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes.
Results
By inhibiting COMT, tolcapone reduced levodopa metabolism to 3-O-methyldopa, resulting in a twofold increase in levodopa exposure (area under the curve) and elimination half-life, without changing levodopa peak plasma concentration. These effects were similar on days 1 and 7 of treatment. Development of tolerance to COMT inhibition was not observed. Onset of effect was rapid (day 1 of treatment), and the maximum effect on levodopa pharmacokinetics was already observed with 100 or 200 mg tolcapone t.i.d. At these dosages, tolcapone pharmacokinetics were linear and stable; accumulation occurred with 800 mg t.i.d. The combination of tolcapone and carbidopa-levodopa was generally well tolerated, although more nausea and vomiting were observed at higher dosages (400 to 800 mg t.i.d.), particularly in women.
Conclusion
Tolcapone shows promise as an effective adjunct to levodopa in the treatment of Parkinson's disease. Clinical pharmacology data indicate that the therapeutic regimen should be 100 or 200 mg t.i.d.
Clinical Pharmacology & Therapeutics (1997) 62, 300–310; doi:
TL;DR: It is indicated that COMT inhibitors prolong retention latencies in a single-trial passive avoidance test assessed at several memory phases and only entacapone improved memory storage.
TL;DR: These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates.
Abstract: Objective To determine the role of catechol-O-methyltransferase (COMT) in the biodisposition of pharmacologic concentrations of dopamine. Design The study was an open-label dose escalation trial in which dopamine was employed as the sole exogenous catecholamine. The dosage was adjusted to achieve improvements in cardiac output or to augment renal function. Setting A 16-bed pediatric intensive care unit serving both medical and surgical patients. Patients The study was performed using 14 dopamine-treated and five untreated control patients. Children ranged in age from 16 days to 12 yrs; five of the treated patients and two of the untreated controls were female. All but one of the study patients were enrolled within 24 hrs of palliative or corrective surgery for congenital heart disease. Control patients had noncardiac surgical procedures. Both treated and control groups were similar with respect to severity of illness, as judged by Therapeutic Intervention Scoring System score. Interventions All treated patients received dopamine as a continuous intravenous infusion. Infusion rates were determined by caregivers and ranged from 3.0 to 20 micro g/kg/min. Measurements and Main Results Serial, timed blood samples were obtained from patients and control subjects for the determination of plasma dopamine concentrations and for the determination of mononuclear cell COMT activity. Measured rates of dopamine infusion (3.0 to 18.3 micro g/kg/min) were consistently less than the nominal rates (3.0 to 20.0 micro g/kg/min) of infusion (p 200 ng/mL. Mononuclear cell COMT activity was assessed simultaneously in these patients. Baseline COMT activity varied over a six-fold range and was unrelated to dopamine clearance or patient age. COMT activity increased two- to six-fold in dopamine-treated patients with plasma steady-state dopamine concentrations of >100 ng/mL. Conclusions These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates. While concomitant variability in COMT activity is observed, the lack of correlation between dopamine clearance and COMT activity suggests that COMT is not rate-limiting for the clearance of exogenously administered dopamine. (Crit Care Med 1997; 25:181-189)
TL;DR: It is anticipated that COMT inhibitors will prove beneficial in extending and smoothing the effects of levodopa in patients with Parkinson's disease and end‐of‐dose wearing‐off fluctuations.
Abstract: Substitution therapy with levodopa and a peripheral inhibitor of aromatic L-amino acid decarboxylase (AADC) is the cornerstone in the treatment of Parkinson's disease. Chronic therapy with levodopa, however, is associated with the occurrence of motor complications that are partially related to the pharmacokinetics of levodopa. The formation of 3-O-methyldopa (3-OMD), a long-lived metabolite that confers no clinical benefit, is catalyzed by catechol-O-methyltransferase (COMT), an enzyme that is particularly abundant in the gastrointestinal tract, liver, and kidneys. Potent, reversible, selective, and orally active COMT inhibitors have become available. The nitrocatechols, entacapone and tolcapone, have undergone extensive clinical testing as adjuncts to levodopa in the therapy of Parkinson's disease. Studies in healthy subjects and parkinsonian patients have shown the inhibitory effect of both drugs on the formation of 3-OMD, leading to an increase in levodopa bioavailability and elimination half-life, without a change in peak plasma concentrations (Cmax) or time to reach Cmax (tmax). In patients, COMT inhibitors significantly prolong and smooth, i.e., reduce peak-trough fluctuations, the effects of levodopa, as reflected in improved motor scores and lengthened duration of ON time (periods of good response) without an influence on the time to onset of action or the peak effect. Entacapone 200 mg is given in conjunction with each levodopa dose, whereas tolcapone is administered in a fixed 100 to 200 mg t.i.d. dosing regimen. The tolerability profiles of the two drugs are similar, with urine discoloration and an increase in dopaminergic side effects such as nausea, orthostatic hypotension, and dyskinesias being most prominent. Tolcapone induces a higher incidence of diarrhea and liver enzyme abnormalities. It is anticipated that COMT inhibitors will prove beneficial in extending and smoothing the effects of levodopa in patients with Parkinson's disease and end-of-dose wearing-off fluctuations. Drug Dev. Res. 42:1–25, 1997. © 1997 Wiley-Liss, Inc.
Journal Article•
Bial1
TL;DR: Tolcapone is a highly potent tight-binding inhibitor of brain soluble and membrane-bound COMT, but because of difficulties in determining the type of inhibition for this type of compound, previous claims about the competitive type of COMT inhibition produced by tolcapone cannot be confirmed.
Abstract: Catechol-O-methyltransferase (COMT) is an enzyme that plays an important role in the inactivation of catecholamine neurotransmitters. Experimental and clinical data suggest that COMT inhibitors may be useful in Parkinsonian patients. Among COMT inhibitors, nitrocatechol derivatives are the most potent and selective. In this study, we evaluated the kinetics of rat brain COMT, as well as its mechanisms of inhibition by tolcapone. Rat whole-brain homogenates and the corresponding soluble and membrane-bound fractions were evaluated for their epinephrine 3-O-methylating activity. Tolcapone exhibited a very low IC50 in all the three enzyme preparations. In whole-brain homogenates, saturation curves made in the presence of 1 nM tolcapone displayed, when compared with controls, a reduction in Vmax without changes in Km, which suggested a noncompetitive type of inhibition. This was confirmed by experiments in which the IC50 value for tolcapone was not affected by substrate concentration. Nevertheless, this classic kinetic analysis is not suitable for a tight-binding inhibitor. A very low IC50, an inhibition potency that is dependent on the previous contact time of the inhibitor with the enzyme and an enzyme titrating capacity were the three criteria that tolcapone met as a tight-binding inhibitor in the rat brain. In conclusion, our results show that tolcapone is a highly potent tight-binding inhibitor of brain soluble and membrane-bound COMT, but because of difficulties in determining the type of inhibition for this type of compound, we cannot confirm previous claims about the competitive type of COMT inhibition produced by tolcapone.
TL;DR: It is concluded that the COMT inhibitor tolcapone exhibits clear peripheral and central activity, and this central effect may help preserve and stabilize the synaptic levels of DA and, thus, further improve the effects of L-DOPA therapy in parkinsonian patients.
TL;DR: It is indicated that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA, and the dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.
Abstract: Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liverand brain COMT inhibition as DNC; using 10 mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10–30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5,10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.
TL;DR: The FDOPA accumulation, expressed as striatal‐to‐occipital ratios and modified decarboxylation coefficients (k3R0), increased significantly after entacapone + selegiline administration in all subject populations, and the changes in the studied parameters afterEntacap one + se LEGILine administration probably reflect the effects of entacAPone, since entacabone alone has caused similar changes in previous PET studies.
Abstract: The aim was to investigate the effects of inhibition of monoamine oxidase type B (MAO-B) with selegiline alone and the combined inhibition of peripheral catechol-O-methyltransferase (COMT) with entacapone and MAO-B with selegiline on striatal 6-[18F]fluorodopa (FDOPA) accumulation, and whether the effect of entacapone + selegiline on FDOPA uptake differed depending on the severity of the presynaptic dopaminergic dysfunction. Thus, eight healthy controls, eight de novo patients with Parkinson's disease (PD), and 18 levodopa-treated PD patients were investigated with positron emission tomography (PET). Half of the subjects in each population belonged to the selegiline group and half to the entacapone + selegiline group. Both groups were studied twice with PET using FDOPA. After the first (baseline) FDOPA PET investigation, both groups were on 2 weeks of selegiline treatment, 10 mg daily. Thereafter, the second FDOPA PET was performed for all subjects with a premedication administered 60 min before the PET imaging; one group received 10 mg of selegiline, and the other group received a single 400 mg dose of entacapone coadministered with 10 mg of selegiline. Selegiline treatment alone had no significant influence on striatal FDOPA metabolism. The FDOPA accumulation, expressed as striatal-to-occipital ratios and modified decarboxylation coefficients (k3R0), increased significantly after entacapone + selegiline administration in all subject populations. The FDOPA uptake rate constant (Ki) remained virtually unchanged in controls and in de novo patients but decreased significantly in levodopa-treated PD patients after entacapone + selegiline intake. Entacapone + selegiline administration did not influence significantly the unidirectional blood-to-brain clearance for FDOPA (K1D) or the relative dopadecarboxylase activity (k3D). The changes in the studied parameters after entacapone + selegiline administration probably reflect the effects of entacapone, since entacapone alone has caused similar changes in previous PET studies. Response in FDOPA accumulation to entacapone + selegiline was higher in controls and de novo patients compared with levodopa-treated PD patients. The milder response in levodopa-treated patients might reflect the reduced ability of the degenerated dopaminergic neurons to utilize the prolonged FDOPA availability, produced by entacapone.
TL;DR: This is the first report indicating that microglia contains COMT activity which may be increased in pathological conditions, and the elevation of COMT immunoreactivity co-localized to microglial cells, but not to astrocytes.
TL;DR: The different behaviour of nitecapone compared to the other COMT inhibitors may be due to its hydrophilic 5-substituent, and the longer elimination half-life of tolcapone in vivo compared to entacapone could not be explained by glucuronidation kinetics in vitro.
Abstract: Purpose. Nitrocatechol COMT inhibitors are a new class of bioactive compounds, for which glucuronidation is the most important metabolic pathway. The objective was to characterize the enzyme kinetics of nitrocatechol glucuronidation to improve the understanding and predicting of the pharmacokinetic behavior of this class of compounds.
TL;DR: The results may have implications for the use of central catechol-O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.
TL;DR: The remedy of Noradrenaline and dopamine deficiency in the synaptic cleft depicts depression by the use of tricyclic uptake inhibitors and monoamine oxidase inhibitors has become an established therapy for depression.
Abstract: Publisher Summary Catechol O-methyltransferase (COMT) is an enzyme that catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to one of the phenolic group of the catechol substrate in the presence of Mg2+ and following a sequential ordered mechanism. High COMT activity is found in the liver, kidney, and gut wall. A single COMT gene codes two separate enzymes, the soluble(S-COMT) and membrane-bound (MB-COMT) forms. S-COMT contains 221 amino acids. MB-COMT has an additional amino terminal extension of 43 (rat) or 50 (human) amino acids. Synthesis of recombinant S-COMT in E. coli and MB-COMT in the insect cells using vectors has helped in clarifying the biochemistry, physiology, and pharmacology of COMT. MB-COMT is partially responsible of the termination of dopaminergic and noradrenergic synaptic neurotransmission. S-COMT is a high-capacity enzyme responsible for the elimination of biologically active or toxic, particularly exogenous catechols and some hydroxylated metabolites. Accordingly, MB-COMT is a dominating isoenzyme in the human brain. Second-generation COMT inhibitors are potent, selective, and orally active. The current COMT inhibitors have been divided into three groups—mainly peripherally acting nitrocatechol-type compounds, broad-spectrum nitrocatechols having activity both in the periphery and the brain; and atypical compounds and pyridine, some of which are not COMT inhibitors in vitro but may instead inhibit catechol O-methylation by some other mechanism. COMT inhibitors improve the brain entry of L-dopa and decrease 3-OMD formation in the peripheral tissues. COMT inhibitors should also decrease fluctuations of the dopamine formation. A summary of some preclinical evidence supporting the suggested use is given in this chapter. Noradrenaline and dopamine deficiency in the synaptic cleft depicts depression. The remedy of this deficit by the use of tricyclic uptake inhibitors and monoamine oxidase inhibitors has become an established therapy for depression. The COMT inhibitors reaching the brain would decrease the metabolism of noradrenaline and dopamine.