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PubMed1994

Inhibition of MAO and COMT by hypericum extracts and hypericin.

The influence of hypericin, hypericum total extract, and hypericum fractions on the activity of MAO and COMT, prepared in vitro from pork liver, were investigated in several concentration steps. An inhibition of MAO could be shown in the following concentrations (extract correlated to a mean molecular value of 500): hypericin to 10(-3) mol/L, hypericum total extract to 10(-4) mol/L, one extract fraction up to 10(-5). A COMT inhibition could not be shown for hypericin, with hypericum extract to 10(-4) mol/L and with two extract fractions also up to 10(-4) mol/L. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. The concentrations of inhibition shown might not be sufficient to explain the clinically proven antidepressive effect of hypericum particularly with regard to the inhibition of MAO activity.

Animals↗
PubMed2005

Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism.

The authors report two cases of catechol-O-methyltransferase (COMT) inhibitor-induced asymptomatic hepatic dysfunction in women with Parkinson disease. The patients were genotyped for the UDP-glucuronosyltransferase (UGT) 1A9 gene (which encodes the main COMT inhibitor-metabolizing enzyme), and found to carry mutations leading to defective glucuronidation activity. This suggests that UGT1A9 poor metabolizer genotype(s) may be a predisposing factor for COMT inhibitor-induced hepatotoxicity.

Adult↗
PubMed2002

Catechol-O-Methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis.

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.

Animals↗
PubMed1999

Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity.

Although aggressive, violent, and dangerous behavior in man has multifactorial causes, genetic factors are estimated by twin and adoption studies to substantially contribute to the development of such conduct. Recently, homozygosity of a low enzyme activity variant of the catechol O-methyltransferase (COMT) gene was reported to be associated with aggressive behavior in a group of schizophrenic patients. We observe a similar tendency in a group of 30 schizophrenic patients who were confined to a maximum-security psychiatric facility for homicide. Significant excess (46.7% versus 21.0%) homozygosity of the low activity COMTmet/met genotype was observed in 30 mostly male (28 of 30) homicidal schizophrenic patients compared with 415 control subjects (Pearson chi(2) = 10.53, P = 0.005, df = 2). No difference in COMT genotype was found between 62 nonviolent schizophrenic patients and the 415 control subjects (chi(2) = 0.963, P > 0.1, df = 2). A trend for excess (46.7% versus 25.8%) homozygosity of the low activity COMTmet/met genotype was also observed when the homicidal schizophrenic subjects were compared directly with the nonviolent schizophrenic patients (chi(2) = 4.03, P = 0.1, df = 2). Similarly, an excess of the low activity COMTmet allele was observed in homicidal versus nonviolent schizophrenic patients (chi(2) = 2.92, P = 0.087, df = 2). Similar results were obtained if only male subjects were examined. No significant difference was found between control (257 Ashkenazi and 152 non-Ashkenazi Jews) COMT genotypes in the two principal ethnic groups examined (chi(2) = 3.79, P > 0.1, df = 2). Finally, no association was observed between homicidal behavior in schizophrenic patients and the dopamine D4 exon III repeat length polymorphism (D4DR) and the serotonin transporter promoter-region polymorphism (5-HTTLPR). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:628-633, 1999.

Adult↗
PubMed2000

Issues important for rational COMT inhibition.

Levodopa is the most efficacious drug in the symptomatic treatment of Parkinson's disease. However, exogenously administered levodopa is extensively metabolized in the periphery by aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) so that only 1% of an administered dose gains access to the brain. Even when levodopa is co-administered with an inhibitor of AAAD such as benserazide or carbidopa, the bulk (90%) of levodopa is converted by COMT to the therapeutically inactive 3-O-methyldopa. Two COMT inhibitors, tolcapone and entacapone, have recently been introduced as adjuncts to levodopa to further inhibit peripheral levodopa metabolism and thereby enhance brain levodopa availability. This paper reviews the pharmacokinetics, dosing schedule, peripheral and central effects, and safety profile of these agents.

Benzophenones↗
PubMed2000

Effect of COMT inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyl transferase (COMT) is one of the principal levodopa-metabolizing enzymes, particularly when aromatic amino acid decarboxylase (AAAD) is partially inhibited by carbidopa or benserazide. This paper examines the pharmacology of COMT inhibitors such as tolcapone and entacapone, and considers the effects of these drugs on the pharmacolinetics of levodopa. Both agents extend the elimination half-life and plasma area under the curve of levodopa without affecting the maximal plasma concentration of levodopa (Cmax) or the time until an oral dose of levodopa reaches its peak plasma concentration (Tmax). Clinically, these pharmacokinetic effects permit a reduction in the levodopa dose, an increase in "on" time and a decrease in "off" time in fluctuating PD patients. Motor benefits can also be seen in stable PD patients. COMT inhibitors are thus an alternative to increasing levodopa doses or adding dopamine agonists to reduce "off" time and enhance motor function in fluctuating PD patients.

Catechol O-Methyltransferase Inhibitors↗
PubMed2000

Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson's disease: implications for the early use of COMT inhibitors.

Increasing laboratory and clinical evidence indicates that pulsatile stimulation of dopamine receptors contributes to the development of levodopa-related motor complications in PD. In keeping with this concept, clinical trials have demonstrated that initiating therapy with a long-acting dopamine agonist reduces the risk of inducing motor complications in comparison to levodopa. However, the introduction of levodopa is associated with the development of motor complications even in the presence of a long-acting dopamine agonist in both PD patients or MPTP treated monkeys. Administration of levodopa with a catechol-O-methyl transferase (COMT) inhibitor increases its plasma half-life, smoothes out peaks and troughs, and delivers levodopa to the brain in a more continuous fashion. We hypothesize that the risk of developing motor complications in PD patients when levodopa is introduced can be reduced if the levodopa is coupled with a COMT inhibitor so as to provide more continuous dopaminergic stimulation of dopamine receptors. A proposed algorithm for the treatment of the early PD patient is to initiate therapy with a dopamine agonist, and supplement with levodopa coupled with a COMT inhibitor when the dopamine agonist cannot provide satisfactory clinical benefits.

Catechol O-Methyltransferase Inhibitors↗
PubMedDate not supplied

Neurochemical and psychomotor interactions of new selective COMT inhibitors with clorgyline and nomifensine in levodopa-treated rats and mice.

The effects of three new catechol O-methyltransferase (COMT) inhibitors (nitecapone, entacapone and Ro 41-0960) were assessed on brain neurochemistry and psychomotor tests in levodopa/carbidopa-treated rats and mice. In neurochemical studies in rats, neither nitecapone (3 mg/kg) nor Ro 41-0960 (3 mg/kg) enhanced the levodopa/carbidopa (15/30 mg/kg)-induced dopamine levels in the hypothalamus and striatum, whereas 3-O-methyldopa (3-OMD) levels were suppressed. Adding clorgyline (8 mg/kg) elevated dopamine in the hypothalamus and striatum. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were suppressed in the striatum and, to a lesser extent, also in the hypothalamus. Adding nomifensine (10 mg/kg) reversed the action of Ro 41-0960 on the 3-OMD levels and raised the homovanillic acid levels in the striatum. All COMT inhibitors (30 mg/kg) slightly enhanced levodopa/carbidopa (15/30 mg/kg)-induced hypoactivity in rats. Ro 41-0960 also augmented the effects of clorgyline and nomifensine on the locomotor activity. Levodopa/carbidopa (10/10, 25/25, 50/50, 100/100 mg/kg) dose-dependently decreased rectal temperature, rotarod time and spontaneous motility in mice. Additional COMT inhibition (30 mg/kg) had only minor effects on behavior. Ro 41-0960 (30 mg/kg) potentiated several behavioral effects of clorgyline (4 mg/kg) in the levodopa/carbidopa (10/10 mg/kg)-treated mice.

Animals↗
PubMedDate not supplied

[Polymorphisms of CYP1B1 and COMT in breast and endometrial cancer].

CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine a variation of enzymic activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu and COMT polymorphism Val158Met in 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34-4.43, p = 0.000) and endometrial (OR = 2.43, CI 1.72-3.44, p = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58-3.01, p = 0.000 in breast cancer and OR = 2.52, CI 1.78-3.56, p = 0.000 in endometrial cancer. Risk of endometrial, but not breast, cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen reactivity of the endometrium as compared with the mammary gland.

Aryl Hydrocarbon Hydroxylases↗
PubMed1983

Immunoperoxidase localization of catechol-o-methyl transferase (COMT) in human breast cancer.

Immunoperoxidase reaction of appropriately fixed tissue with an antiserum to catechol-o-methyl transferase (COMT), as the primary step in the peroxidase-immunoglobulin bridge technique, has been utilized for the localization of COMT in biopsy specimens of human breast neoplasm and its metastases. Our immunocytochemical identification of a strong activity of COMT in all cases studied might have a diagnostic implication in breast cancer.

Breast↗
PubMed1982

Segregation and linkage studies of plasma dopamine-beta-hydroxylase (DBH), erythrocyte catechol-O-methyltransferase (COMT), and platelet monoamine oxidase (MAO): possible linkage between the ABO locus and a gene controlling DBH activity.

Measurements of dopamine-beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase (MAO) along with 27 polymorphic marker phenotypes were available for 162 patients with major affective disorders and 1,125 of their relatives. Levels of enzymes were previously found not to be associated with illness. Pedigree analysis methods for quantitative traits are used to test single-gene hypotheses for segregation of DBH in 32 families with 411 individuals. COMT in 30 families with 351 individuals, and MAO in 50 families with 309 individuals. The familial distribution of both DBH and COMT are consistent with two codominant alleles at the same locus that account for 56% and 59% of the total variance, respectively. MAO activity cannot be shown to be segregating as a single major gene, but a purely nongenetic hypothesis is also rejected. A possible linkage of a locus for DBH to the ABO locus is indicated by a maximum lod score of 1.82 at 0% and 10% recombination fractions for males and females, respectively. A lod score of 0.61 at 0% recombination for a similar analysis in a single large pedigree was reported by Elston et al., making the combined lod score for the two studies equal to 2.32 at 0% recombination.

Adult↗
PubMed1994

COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise.

We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 variants.

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 beta 3-subunit (Gbeta3) 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 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. The pathways influenced by those variants are not therefore involved with long-term lithium outcome in our sample.

Adult↗
PubMed2002

Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders.

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.

Adult↗
PubMed2004

Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa.

The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (chi(2) = 0, ns). Allele-wise case-control analysis using separate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78-1.24). Analysis by genotype was likewise not significant (overall chi(2) = 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample.

Alleles↗
PubMed2004

Association analysis of the DRD4 and COMT genes in methamphetamine abuse.

We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol-O-methyltransferase gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol-O-methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48-bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148-1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10-1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.

Adolescent↗
PubMed2006

Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity.

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.

Catechol O-Methyltransferase↗
PubMed1993

Administration of the new COMT inhibitor OR-611 increases striatal uptake of fluorodopa.

L-Dopa is metabolized to 3-O-methyldopa (3OMD) by catechol-O-methyltransferase (COMT). This reduces the amount of L-dopa available for entry into brain. We studied the effect of OR-611, a new COMT inhibitor, on plasma and brain 6-[18F]-fluoro-L-dopa (6FD) metabolism in cynomolgus monkeys with positron emission tomography (PET). OR-611 pretreatment substantially reduced plasma 6FD metabolism to 3-O-methylfluorodopa (3OMFD). PET measurements of striatal 6FD concentrations showed an average 2.3-fold increase following OR-611 pretreatment, compared to the same animals in the control state. OR-611 inhibits plasma metabolism of 6FD and increases brain uptake of this L-dopa analog. OR-611 appears to be a promising agent as an adjunct to L-dopa for the treatment of patients with Parkinson's disease.

Animals↗