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PubMed1977

Erythrocyte catechol-o-methyltransferase activity in primary affective disorder.

Previous studies have suggested that the activity of erythrocyte catechol-O-methyltransferase (COMT) may be reduced in women with bipolar and particularly unipolar affective illness. More recently, increased COMT activity in both men and women with affective disorder was reported. The activity of COMT in erythrocytes was determined in 184 outpatients with primary affective disorder at the Lithium Clinic of the New York State Psychiatric Institute. COMT activity was determined by a modification of the Axelrod and Cohn method with dopamine as substrate. This change resulted in an apparent threefold increase in the values for COMT activity; however, when both methods were compared, the results correlated (r = 0.97, p less than 0.001, N = 37). We found that the values for women were not significantly lower than those for men. In addition, there was no difference between patients with affective disorder and controls. Further, no difference was demonstrated between patients diagnosed as bipolar or uni-polar. Parameters such as mood, medication, and inpatient or outpatient status had no effect on COMT activity. The results of previous studies are discussed in an attempt to reconcile the different results.

Adult↗
PubMed1996

17 beta-Estradiol metabolism by hamster hepatic microsomes. Implications for the catechol-O-methyl transferase-mediated detoxication of catechol estrogens.

We have shown that the metabolism of 17 beta-estradiol in hamster liver microsomes is concentration-dependent. At low (< 25 microM) concentrations of 17 beta-estriol, 16 alpha-hydroxylase activity predominated, and estriol was the major metabolite. At higher concentrations (25-75 microM), 16 alpha-hydroxylation and aromatic hydroxylation at C2 contributed equally to 17 beta-estradiol metabolism. Aromatic C4-hydroxylation was maximal at 75 microM of 17 beta-estradiol and was always less than C2-hydroxylation. Dehydrogenation of the 17 beta-hydroxyl group to the ketone (estrone) was also observed, but both estrone and 2-hydroxyestrone were minor (approximately 3%) metabolites of 17 beta-estradiol, only detectable at concentrations of 50 microM and above. Catechol-O-methyl transferase (COMT) effectively converted both 2- and 4-hydroxyl-17 beta-estradiol to their corresponding monomethoxy metabolites. Effective reducing conditions are required for COMT activity, because catechol estrogens are readily oxidized to their corresponding ortho-quinones, and ascorbic acid is routinely added to assays of COMT activity. Interestingly, although ascorbic acid (1 mM) increased the recovery of 2- and 4-hydroxy-17 beta-estradiol from microsomal incubations, it decreased the recovery of the methoxy metabolites (approximately 40%). Since the enediol function of ascorbate resembles that of a catechol group, ascorbate is a substrate for COMT and probably competes with the catechol estrogens for methylation. Because previous studies describing the ability of COMT to inhibit the covalent binding of electrophilic reactive metabolites of [4-(14)C]17 beta-estradiol to microsomal protein were performed in the presence of high (100 mM) Mg2+ concentrations, we also investigated the effects of Mg2+ on 17 beta-estradiol metabolism. Concentrations of Mg2+ > 10 mM inhibited the metabolism of 17 beta-estradiol, as evidenced by i) the increased recovery of substrate; ii) a decrease in the formation of estriol, estrone, and 2-, and 4-hydroxy-17 beta-estradiol; iii) a decrease in the recovery of water-soluble metabolites when incubations were performed in the presence of glutathione (GSH) to trap the reactive electrophilic metabolites; and iv) a decrease in the amount of reactive electrophilic metabolites bound to microsomal protein. GSH also decreased the covalent binding of electrophilic metabolites of [4-(14)C]17 beta-estradiol to microsomal protein, with the concomitant formation of water-soluble metabolites. Thus, both COMT and GSH combine to limit the formation of electrophilic metabolites from 17 beta-estradiol. The relative importance of each of these pathways to the disposition of the catechol estrogens remains to be determined.

Animals↗
PubMed1997

High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers.

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.

Alleles↗
PubMed1997

Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase.

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.

Animals↗
PubMed1998

Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk.

Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of estrogen catechols. In a case-control study, we evaluated the association of the low-activity allele (COMT(Met)) with breast cancer risk. Compared to women with COMT(Val/Val), COMT(Met/Met) was associated with an increased risk among premenopausal women [odds ratio (OR), 2.1; confidence interval (CI), 1.4-4.3] but was inversely associated with postmenopausal risk (OR, 0.4; CI, 0.2-0.7). The association of risk with at least one low-activity COMT(Met) allele was strongest among the heaviest premenopausal women (OR, 5.7; CI, 1.1-30.1) and among the leanest postmenopausal women (OR, 0.3; CI, 0.1-0.7), suggesting that COMT, mediated by body mass index, may be playing differential roles in human breast carcinogenesis, dependent upon menopausal status.

Body Mass Index↗
PubMed1975

Erythrocyte soluble catechol-O-methyl transferase activity in primary affective disorder. A clinical and genetic study.

Erythrocyte catechol-O-methyl transferase (COMT) activity was studied in 53 patients with primary affective disorders and 38 controls and in selected relatives. Patients with affective disorders tended to have higher activity levels than normals, after correcting for sex differences. The COMT activity was positively correlated between relatives and is heritable. Within families, elevation of COMT activity distingushed healthy relatives from probands and ill relatives. This suggests that COMT activity elevation and affective illness do not show independent assortment and implies that COMT activity identifies genetic vulnerability to affective order.

Affective Symptoms↗
PubMed2003

Meta-analysis of the association between the catecholamine-O-methyl-transferase gene and obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic, severely debilitating mental illness that affects approximately 1-2% of the population. Data from twin and family studies have shown that genetic factors contribute to the expression of the disease. The dopaminergic system has been implicated in the pathogenesis of OCD, and catecholamine-O-methyl-transferase (COMT) is a key modulator of dopaminergic and noradrenergic neurotransmission. The gene for COMT has a common polymorphism that has been shown to be correlated with a three- to fourfold change in enzymatic activity. Several groups have searched for an association between the COMT gene polymorphism and the presence or absence of OCD, with contrasting results. We conducted a systematic review and meta-analysis of both the published literature and unpublished data. Available data were stratified according to the original study design as either case-control or family-based, and two separate meta-analyses were conducted, using both fixed-effects and random-effects models. These analyses showed insufficient evidence to support an association between the COMT gene polymorphism and OCD. Subgroup stratification based on gender generated no statistically significant associations. These results should be considered in any future work correlating the COMT gene with OCD.

Catechol O-Methyltransferase↗
PubMed2007

Effects of a catechol-O-methyltransferase inhibitor on catechol estrogen-induced cellular transformation, chromosome aberrations and apoptosis in Syrian hamster embryo cells.

To examine a possible mechanism of endogenous estrogen-induced carcinogenesis, we studied the effect of the catechol-O-methyltransferase (COMT) inhibitor Ro 41-0960 on cell transforming and clastogenic activities of 2 catechol estrogens 2- and 4-hydroxyestrone (2- or 4-OHE1) using Syrian hamster embryo (SHE) cells. COMT activity was assayed by determining the methylation of 2- or 4-OHE1 using gas chromatography. The production of 2-methoxyestrone in cultures treated with 2-OHE1 was approximately 2-fold that of 4-methoxyestrone in cultures treated with 4-OHE1. 4-OHE1 induced morphological transformation at a higher frequency than 2-OHE1 did and the frequencies of cell transformation and chromosome aberrations were not significantly changed in cells treated with 4-OHE1 in the presence of Ro 41-0960. In contrast, the frequencies of cell transformation and chromosome aberrations were markedly increased in cells treated with 2-OHE1 along with Ro 41-0960 when compared to cells treated with 2-OHE1 alone. In addition, both catechol estrogens induced P53 protein expression and apoptosis. The frequencies of apoptotic cells induced by the catechol estrogens were modified by the COMT inhibition in a manner similar to those observed with the chromosome aberrations assay and the cell transformation assay, indicating that each effect by the catechol estrogens at the three measured endpoints might be caused by a mechanism similar to the others. Our findings indicate that COMT activity has an influence on cell transforming activity and its related genetic effects of catechol estrogens in SHE cells, which implies that an individual activity of COMT may be one of the etiological factors in endogenous estrogen-induced carcinogenesis.

Animals↗
PubMed1999

Identification of specific residues involved in substrate discrimination in two plant O-methyltransferases.

Among the large number of plant O-methyltransferases that are involved in secondary metabolism, only a few have been enzymatically characterized, and little information is available on the structure of their substrate binding site and the mechanism which determines their substrate specificity and methylation regiospecificity. We have previously reported the isolation of two O-methyltransferases, S-adenosyl-l-methionine:(iso)eugenol O-methyltransferase (IEMT) and S-adenosyl-l-methionine:caffeic acid O-methyltransferase (COMT) from Clarkia breweri, an annual plant from California. While IEMT and COMT (which methylate eugenol/isoeugenol and caffeic acid/5-hydroxyferulic acid, respectively) share 83% identity at the amino acid level, they have distinct substrate specificity and methylation regiospecificity. We report here that seven amino acids play a critical role in discriminating between eugenol/isoeugenol and caffeic acid/5-hydroxyferulic acid. When these amino acids in IEMT were replaced by the corresponding residues of COMT, the hybrid protein showed activity only with caffeic acid/5-hydroxyferulic acid. Conversely, when these amino acids in COMT were replaced by corresponding IEMT residues, the hybrid protein had activity only with eugenol/isoeugenol. These results provide strong evidence that O-methyltransferase substrate preference could be determined by a few amino acid residues and that new OMTs with different substrate specificity could begin to evolve from an existing OMT by mutation of a few amino acids. Phylogenetic analysis confirms that C. breweri IEMT evolved recently from COMT.

Amino Acid Sequence↗
PubMed1996

No association between Parkinson's disease and low-activity alleles of catechol O-methyltransferase.

Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine. Treatments attempt to correct this deficit by the use of levodopa and inhibitors of dopamine metabolising enzymes such as catechol-O-methytransferase (COMT). A common amino-acid polymorphism in COMT, valine-108-methionine, results in a low activity form of the enzyme which we hypothesised may influence susceptibility to IPD. We examined this polymorphism in 139 Caucasian subjects with IPD and 173 control subjects, using a PCR-RFLP and a novel Amplification Refractory Mutation System (ARMS) assay. Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD. We have also characterised a new polymorphism, 256C/G, which is not associated with IPD. However it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.

Alleles↗
PubMed2000

Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated metabolism of catechol estrogens: a possible mechanism for carcinogenicity.

Phenolphthalein (PT), used in over-the-counter laxatives, has recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently identified and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. We hypothesize that PT-CAT inhibits the enzyme catechol-O-methyltransferase (COMT) and therefore potentiates genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. The present studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated metabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then euthanized. PT-CAT concentration in urine reached plateau levels by 7 days of exposure. An O-methylated metabolite of PT-CAT was detected in feces. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT. In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis.

Animals↗
PubMed1993

Extraneuronal uptake and O-methylation of 3H-adrenaline in the rabbit aorta.

The influence of uptake2 inhibitors on the O-methylation and accumulation of 3H-adrenaline by the isolated rabbit aorta was studied. Strips were incubated with 0.05 mumol/l 3H-(-)-adrenaline during 15 min. Monoamine oxidase and uptake1 were inhibited and the 3H-adrenaline present in the tissue was measured as well as the metabolites found in the tissue and in the incubation fluid. In another series of experiments, monoamine oxidase, uptake1 and catechol-O-methyl transferase (COMT) were inhibited, and tritium accumulation was measured in the tissue. When COMT was inhibited, inhibitors of uptake2 produced a maximal reduction of 3H-adrenaline accumulation that did not exceed 50%. When COMT was intact, inhibitors of uptake2 diminished total 3H-removal and, more markedly, O-methylation and concomitantly increased the tissue content of 3H-adrenaline. Mineralocorticoids (corticosterone and deoxycorticosterone acetate) inhibited 3H-adrenaline uptake (when COMT was inhibited) and 3H-metanephrine formation (when COMT was functional) as effectively as did sexual steroids (17-beta-oestradiol, progesterone and testosterone); hydrocortisone (hemisuccinate or phosphate) had no effect (for concentrations up to 120 mumol/l). At the end of the incubation some strips were washed out with amine-free solution. Compartmental analysis of the efflux showed that the amine had distributed into three extraneuronal compartments (compartment I, II and III, with half times of 0.4, 4 and 15 min, respectively). Corticosterone (120 mumol/l) decreased the amount of 3H-adrenaline in compartment III and simultaneously increased the amount of the amine in compartment I (extracellular space).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The activity of the neuronal and extraneuronal catecholamine-metabolizing enzymes of the perfused rat heart.

In a comparative study the neuronal and extraneuronal metabolism of several 3H-catecholamines (all of which were tritiated in the C-7 position of the side chain only) was determined in isolated rat hearts perfused at a concentration of the 3H-amines of 50 nmol/l. While the neuronal MAO activity was determined after inhibition of extraneuronal uptake (100 mumol/l OMI) and COMT (10 mumol/l U-0521), the extraneuronal MAO activity was estimated after inhibition of neuronal uptake (30 mumol/l cocaine) and COMT. The extraneuronal COMT activity was determined under conditions of inhibition of both neuronal uptake and MAO (pretreatment with pargyline). Hearts were perfused with the 3H-catecholamines until the rate of appearance of the various 3H-metabolites in the venous effluent has reached a steady state. From these rates (vst-st) and the steady-state content of the unchanged 3H-catecholamines in the tissue (Si), the rate constants (Vmax/Km) for the unsaturated intracellular enzymes COMT (kCOMT) and MAO (kMAO) were calculated. The kCOMT values for all four catecholamines, (-)-noradrenaline, dopamine, (-)-adrenaline and (+/-)-isoprenaline exhibit a range from 0.24 to 0.78 min-1; the metabolism of the catecholamines by the COMT differs: (-)-noradrenaline = dopamine less than (-)-adrenaline less than (+/-)-isoprenaline. The extraneuronal MAO activity was low for all three catecholamines, (-)-adrenaline, (-)-noradrenaline and dopamine (range of kMAO from 0.05 to 0.28 min-1) and declined in the order.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Dopamine and adrenaline, but not isoprenaline, are substrates for uptake and metabolism in isolated perfused lungs of rats.

The uptake and subsequent metabolism by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) of dopamine, adrenaline, isoprenaline and noradrenaline in isolated perfused lungs of rats has been examined. In lung preparations in which COMT and MAO were inhibited, the uptake of 3H-labelled dopamine, (-)-adrenaline and (-)-noradrenaline, but not (+/-)-isoprenaline, was reduced by cocaine (10 or 100 mumol/l). The rank order of the Km values of the amines that were substrates for uptake in the lungs were: dopamine (0.246 mumol/l) less than noradrenaline (0.967 mumol/l) less than adrenaline (3.32 mumol/l). These results are consistent with transport of catecholamines in rat lungs by Uptake1. In lung preparations with COMT and MAO intact, dopamine and noradrenaline were removed from the circulation (50% and 32%, respectively) and mainly metabolized. There was very little (3.0%) removal of isoprenaline by the lungs and adrenaline was not included in this part of the study. In lung preparations in which only MAO was inhibited, the rank order of COMT activity for O-methylation of the amines was dopamine much much greater than noradrenaline greater than or equal to adrenaline (kCOMT values: 4.98 min-1, 0.357 min-1 and 0.234 min-1, respectively). If dopamine or adrenaline are perfused through the pulmonary circulation in isolated lungs of the rat, they are taken up and then metabolized by COMT and MAO, as also occurs for noradrenaline. Isoprenaline is not a substrate for uptake in the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Monoamine oxidase and catechol-O-methyltransferase activity in hamster and rat insulinomas.

Hamster and rat insulinomas were assayed for norepinephrine, dopamine and serotonin concentration and for monoamine oxidase and catechol-o-ethyltransferase (COMT) activity. The concentration of norepinephrine (mean 0.55 mumol/kg, range less than 0.20 to 2.64 mumol/kg) and serotonin (mean 5.22 mucol/kg, rang less than 0.6 to 26.5 mumol/kg) in hamster insulinomas were comparable to previously reported concentrations. Dopamine conentration (mean 0.34 mumol/kg, range less than 0.20 to 0.95 mumol/kg) was only 2 to 2.5% of that reported previously. Monoamine oxidase activity of the hamster and rat insulinomas were comparable to those of normal hamster islets. In contrast, the COMT activity of both insulinomas was much greater than the COMT activity of normal pancreatic islets of both species and was greater than in several other tissues and tumours. The tumour COMT, which was predominantly in the cytosol, was Mg2+ dependent and had a comparable sensitivity to inhibition by tropolone as purified beef-liver COMT. Hamster insulinoma monoamine oxidase was more sensitive than rat insulinoma monoamine oxidase to inhibition by tranylcypromine and deprenyl, while rat insulinoma monoamine oxidase was more sensitive to inhibition by clorgyline and was more heat labile.

Adenoma, Islet Cell↗
PubMed1978

Activity of catechol-o-methyltransferase in brain regions and adrenal gland during the oestrus cycle.

The activity of the enzyme catechol-O-methyltransferase (COMT) during four different phases of the oestrus cycle were determined. Brain and hypothalamus had highest level of COMT activity during oestrus phase, while at pro-oestrus it was at its lowest level. COMT activity in the adrenal gland was also modified during the four phases with the maximum level at met-oestrus and minimum at pro-oestrus phase. The results provide evidence to show that COMT in the brain, hypothalamus and the adrenals is markedly affected by changes in physiological status of the female rats and its evolution in brain is different from adrenal gland during the oestrus cycle. The variations in the activity of COMT may be the consequence of modified endocrine activity which takes place naturally during oestrus cycle.

Adrenal Glands↗
PubMed2004

An assay for determination of rat adrenal catechol-O-methyltransferase activity: comparison of spontaneously hypertensive rats and Wistar-Kyoto rats.

A method has been developed for measurement of catechol-O-methyltransferase (COMT) activity in the rat adrenal gland. Epinephrine, synthesized in the adrenal gland, was used as substrate, and its enzymatic product, metanephrine, was quantified by high-performance liquid chromatography (HPLC) with fluorescence detection. The method has sufficient precision and accuracy. Soluble (S) and membrane-bound (MB) COMT activity in Wistar-Kyoto (WKY) rats was 20.7 +/- 3.5 and 18.6 +/- 3.4 pmol min(-1) mg(-1) protein (n = 5), respectively. To clarify the role of adrenal COMT in blood-pressure regulation, S and MB COMT activity in spontaneously hypertensive rats were determined. Respective activity was 18.6 +/- 3.4 and 17.0 +/- 1.1 pmol min(-1) mg(-1) (n = 5), which is similar to that in WKY rats. This finding suggests that COMT in the adrenal gland might not be related to blood pressure regulation.

Adrenal Glands↗
PubMed1998

PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960.

We previously reported the results of PET (positron emission tomography) studies of [18F]Ro41-0960, a potent COMT inhibitor, in baboon brain. Here we report an evaluation of the pharmacokinetics and specificity of binding of [18F]Ro41-0960 in the peripheral organs of baboon. We observed a rapid clearance of the tracer from the heart and no significant uptake in the lung. In contrast, there was a high uptake and slow clearance in both kidney and liver, consistent with a high level of COMT in these peripheral organs. We also observed a dose-dependent inhibition of [18F]Ro41-0960 uptake by unlabeled Ro41-0960 (ED50 was 0.5 mg/kg in liver, and <0.01 mg/kg in kidney), with a halftime for recovery of COMT of about 25 h at the dose of 2 mg/kg of unlabeled Ro41-0960. This indicates a reversible tight binding interaction between COMT and Ro41-0960 in both liver and kidney and suggests that [18F]Ro41-0960 may be a useful radiotracer for future examination of the functional activity of COMT in the human body.

Animals↗