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PubMed1993

6-[18F]fluoro-L-dihydroxyphenylalanine metabolism and positron emission tomography after catechol-O-methyltransferase inhibition in normal and hemiparkinsonian monkeys.

Increased and sustained central delivery of L-dihydroxyphenylalanine (L-DOPA) is a desirable therapeutic strategy in Parkinson's disease. We investigated the effects of peripheral catechol-O-methyltransferase (COMT) inhibition, by the non-toxic drug nitecapone on the metabolism of 6-[18F]fluoro-L-dihydroxyphenylalanine (6FD) and on its positron emission tomography (PET) imaging in non-human primates. Nitecapone produced a dose-dependent inhibition in the formation of 3-O-methyl-6-[18F]fluorodihydroxyphenylalanine (OMFD). This inhibition of OMFD formation was attended by increased production of other metabolites, in particular 6-[18F]fluorodopamine (6FDA), 6-[18F]fluorodihydroxyphenylacetic acid (FDOPAC), 6-[18F]fluorohomovanillic acid (FHVA) and [18F]-sulfated conjugates (FSC). Although nitecapone had no effect on plasma 6FD pharmacokinetics, high-dose nitecapone increased contrast of cerebral 18F uptake and retention between regions with high (striatum) versus sparse (parieto-occipital lobes) dopaminergic innervation. 18F uptake contrast was also improved between structures known to possess an intermediate dopaminergic innervation, including the upper brainstem, frontal and temporal lobes, versus sparsely innervated regions. This increased contrast was secondary to decreased activity in sparsely innervated structures and not to increased activity in highly innervated structures. Contrast was correlated inversely with the plasma OMFD/6FD concentration ratio, OMFD being the main 6FD metabolite which can cross the blood brain barrier. We conclude that nitecapone is an effective inhibitor of COMT in non-human primates. This inhibition results in increased 6FD flux through other catabolic pathways. Because of decreased OMFD formation, however, COMT inhibition improves the specificity of 6FD-PET and facilitates in-vivo detection of a wide range of dopaminergic innervation densities in cerebral structures.

Animals↗
PubMed1978

Influence of endogenous S-adenosylmethionine on the determination of catechol O-methyltransferase activity in red blood cells.

A double isotope method for the simultaneous determination of S-adenosylmethionine (SAM) and catechol O-methyltransferase (COMT) activity in red blood cells was developed. Healthy persons contained 7.9 +/- 1.9 nmol SAM per ml red blood cells and 1.9 to 3.8 nmol per ml plasma. Epinephrine increases the SAM biosynthesis rate in red blood cells. The possible influence of endogenous SAM on previous methods to determine COMT activity in red blood cells is discussed. The statement of Briggs and Briggs (Briggs, M.H. and Briggs, M. (1973) Experientia 29, 278--281) that COMT activity in red blood cells is lower during the last 3 months of pregnancy could not be verified by us.

Catechol O-Methyltransferase↗
PubMed1993

Endogenous dopamine and duodenal bicarbonate secretion in humans.

BACKGROUND: Catechol-O-methyltransferase (COMT) inhibition prevents tissue degradation of catecholamines including dopamine. This study was undertaken to investigate the effect of intraluminal nitecapone, a peripherally acting COMT inhibitor, on duodenal mucosal bicarbonate secretion in humans and to compare the effect with that of the prostaglandin E1 analogue misoprostol. METHODS: The duodenal bulb was isolated by means of a three-balloon six-channel tube as previously described. Basal bicarbonate secretion and secretion after intraluminal administration of 30 and 150 mg nitecapone were determined in 11 healthy subjects. In 7 of these subjects, effects of intraluminal administration of 30 and 150 micrograms of misoprostol were studied in a second experiment. RESULTS: Even the lower dose of misoprostol increased duodenal bicarbonate secretion from 121 +/- 12 to 221 +/- 36 and the lower dose of nitecapone from 149 +/- 18 to 277 +/- 48 microEq.cm-1 x h-1, respectively (P < 0.05). With 150 micrograms of misoprostol or 150 mg of nitecapone there was a further increase in secretion to 296 +/- 33 (P < 0.01) and 421 +/- 36 (P < 0.001) microEq.cm-1 x h-1, respectively. The rise in bicarbonate secretion in response to nitecapone was associated with some increase in the release of prostaglandin E2 to the luminal perfusate. CONCLUSIONS: It seems likely that peripheral COMT inhibition increases duodenal mucosal bicarbonate secretion and protection by inhibition of mucosal degradation of dopamine, an increase similar in magnitude to that obtained by a prostaglandin E1 analogue.

Adult↗
PubMed1986

Substrate dependency of specific and non-specific estrogen-2/4-hydroxylase activities measured by the radio-enzymatic method in rat brain microsomes.

Putative specific and non-specific estrogen-2/4-hydroxylase activities which might affect the radio-enzymatic assay were characterized in terms of their requirements for NADPH and their substrate dependency. Using rat brain microsomes and partially purified rat liver COMT three main sources of estrogen-2/4-hydroxylase activity could be distinguished; a COMT-related component and NADPH-dependent and NADPH-independent microsomal components. The COMT-related activity required NADPH and showed about equal preferences for estrone and estradiol. The NADPH-dependent component was highly specific for estradiol, the relative activities observed with estrone and estriol being 7 and 1% of that observed with estradiol. The NADPH-independent component exhibited substrate saturation, was heat-labile and could not be inhibited by alpha-naphthoflavone or metyrapone. It showed a preference for estrone over estradiol, with estriol being a very poor substrate. These findings indicate that non-enzymatic factors contribute very little to product formation in the radio-enzymatic assay. The specificity of the major NADPH-dependent microsomal component towards estradiol suggests a stereo-specific requirement for the D-ring configuration of this estrogen. The use of no-cofactor blanks in the radio-enzymatic assay may be very important when different estrogens are compared as substrates for estrogen-2/4-hydroxylases.

Animals↗
PubMed1990

Catecholoestrogen synthesis and metabolism in the rabbit uterus during the periimplantation period.

Microsomal oestradiol-2/4-hydroxylase (OE-2/4-H) and cytosolic catechol-O-methyltransferase (COMT) (EC 2.1.1.6) activity in the uteri of pregnant and pseudopregnant rabbits during the periimplantation period were studied. The apparent Km for the 4-hydroxylation of oestradiol (3.18 microM) was considerably less than for the 2-hydroxylation reaction (13.36 microM), whereas the Vmax were almost equal. This suggests that 4-hydroxyoestradiol (4-OH-OE2) is the predominant product of OE-2/4-H in the rabbit uterus. These reactions were inhibited by SKF-525A, indicating the involvement of cytochrome P450 dependent monooxygenases. Uterine cytosolic COMT utilized 2-hydroxyestradiol (2-OH-OE2) as the preferred substrate as compared to 4-hydroxyoestradiol (4-OH-OE2). Since the rabbit uterus has a considerable capacity to synthesize 4-OH-OE2 and a lower capacity to metabolize it, it could be suggested that more 4-OH-OE2 than 2-OH-OE2 could be available to the uterus for its physiological activities. Furthermore, an increase in OE-2/4-H in Day 6 pseudopregnant and pregnant uteri with a concomitant decrease in COMT suggests the involvement of catecholoestrogens in the implantation process in the rabbit.

Animals↗
PubMed1990

Coordinated induction of estrogen hydroxylase and catechol-O-methyl transferase by xenobiotics in first trimester human placental explants.

The estrogen phenol A-ring metabolism was investigated in the first trimester placenta using radioenzymatic techniques. In untested explants cultured for 16 h, estrogen hydroxylase (EH) but not catechol-O-methyl transferase (COMT) activity was increased significantly 1.8-fold (P less than 0.05). Cultures made in the presence of chemoprotectors, 25 microM of 1-phenylazo-2-naphthol (Sudan I) and coumarin but not 2(3)-tert-butyl-4-hydroxyanisole (BHA) caused a significant increase in EH activity, 1.8- and 2.2-fold, respectively (P less than 0.05). This was coupled with a significant, P less than 0.05, increase in the COMT activity by 25 microM of all three chemoprotectors, BHA, Sudan I, and coumarin, 2.7-, 2.3-, and 2-fold respectively. The carcinogens benzo(a)pyrene and 20-methylcholanthrene at 50 microM concentration, however, had no effect upon both enzymes' activity. Finally, the two enzymes's activities were correlated under the experimental conditions tested. Except for zero time where no correlation was found (r2 = 0.3), in all other experimental conditions, a significant (r2 = 0.75) correlation was observed. In conclusion, EH and COMT enzyme activities appear to undergo a coordinated induction in cultured placental explants in the first trimester. The implications of catechol metabolism for embryonal development are discussed.

Butylated Hydroxyanisole↗
PubMed1989

Effects of specific alpha-adrenoceptive agents on extraneuronal uptake (uptake2) of isoproterenol in perfused rat heart.

Effects of specific alpha-adrenoceptive agents (alpha 1-agonist, alpha 1-antagonist, alpha 2-agonist and alpha 2-antagonist) on the extraneuronal accumulation of 3H-isoproterenol in the perfused rat heart were examined. The extraneuronal accumulation of 3H-isoproterenol in the hearts perfused with 3H-isoproterenol (10(-6)M) under COMT inhibition by tropolone (10(-4)M) was about 6 times higher than that of intact COMT. The increase in the accumulation by COMT inhibition was regarded as 100% and the effects of specific alpha-adrenoceptive agents on the accumulation was evaluated. alpha 1-agonists, methoxamine and phenylephrine, did not affect the accumulation. alpha 1-antagonists, prazosin, bunazosin and YM-12617, significantly decreased the accumulation of 3H-isoproterenol and these IC50 values were 2 x 10(-6)M, 3.5 x 10(-6)M and 2.3 x 10(-5)M, respectively. alpha 2-agonists, clonidine and guanabenz, significantly reduced the accumulation and these IC50 values were 3.4 x 10(-5)M and 2.9 x 10(-7)M, respectively. The alpha 2-antagonist, yohimbine, did not affect the accumulation. The present experiments clearly demonstrated that the tested alpha 1-antagonists and alpha 2-agonists inhibited uptake2 in rat heart but the tested alpha 1-agonists and an alpha 2-antagonist did not inhibit it.

Adrenergic alpha-Agonists↗
PubMed1990

A more sensitive and specific radioenzymatic assay for catecholamines.

This modification of the catechol-O-methyltransferase (COMT) based radioenzymatic assay for norepinephrine (NE) and epinephrine (E) improves sensitivity, selectivity and eliminates many inhibitors of COMT. Prior to assay, samples are extracted into heptane with diphenylborate, then into dilute acetic acid. This extraction procedure has an efficiency of 78% for NE but less than 2% for S-adenosylmethionine (SAM). The extraction procedure also excludes calcium and other COMT inhibitors present in urine, plasma and every tissue tested. This eliminates the requirement for individual standardization of tissue and urine samples. Sensitivity of the assay for NE and E is 10 and 6 pg/ml respectively in 1 ml of plasma. The intraassay coefficients of variation for NE and E are 4 and 13% and the interassay coefficients of variation for NE and E are 10 and 16% in a human plasma sample containing low catecholamine levels. The assay permits quantitation of plasma E levels that were undetectable in prior assays.

Animals↗
PubMed1975

Progesterone mediated increase in monoamine stores and the regulation of enzymes of biosynthesis and metabolism in the adrenal gland during late pregnancy in the rat.

The influence of repeated injections of progesterone to pregnant rats upon monoamine storage and regulation of enzymes phenylethanolamine-N-methyltransferase (PNMT), monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) was studied. All the pregnant females received progesterone (4 mg/100 g body weight) on 19, 20 and 21 days post-coitum but one group was killed at 21 days of pregnancy and the other one at 0 h parturition. Adrenal epinephrine demonstrated highly significant increase in progesterone treated rats. At the same time norepinephrine content declined significantly from the control value. The activity of enzyme PNMT also showed marked increase in the adrenals of progesterone treated females. Activity of enzyme MAO showed a slight decline after progesterone treatment to pregnant rats. Enzyme COMT in progesterone treateed animals showed decline at 0 h parturition but at 21 days post-coitum it was significantly higher from non-injected females. All the increases and decreases in monoamines and the three enzymes were significant when the results were expressed per adrenal gland or per gram of adrenal. The results suggest that exogenous progesterone administration during late pregnancy increases epinephrine stores by declining monoamine metabolism by MAO and COMT and increasing their synthesis by PNMT which is responsible for N-methylation of norepinephrine to epinephrine.

Adrenal Glands↗
PubMed1988

The effects of soman on norepinephrine uptake, release, and metabolism.

The effects of 7-day administration of 5 micrograms/kg/day of soman sc on norepinephrine (NE) content, and catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO) activities of three rabbit tissues were examined. Effects on NE uptake by, and electrically stimulated release from, rabbit aorta were also determined, both in the 7-day study and with acutely applied soman. Tissues examined were the thoracic aorta, mesenteric artery, and brain stem. Significant (p less than 0.05) increases following 7 days of soman were observed in NE content: thoracic aorta, 20%; mesenteric artery, 48%; and brain stem, 121%. MAO activity decreased by 29% in the thoracic aorta, 20% in the mesenteric artery, and 48% in the brain stem. COMT activity also significantly decreased in two tissues, the thoracic aorta by 18% and brain stem by 23%. Acutely applied soman reduced electrically released NE from the thoracic aorta, but 7-day soman administration increased it. Seven-day soman administration, but not acutely applied soman increased NE uptake by the thoracic aorta. Thus, 7-day soman administration increased sympathetic capability by increasing NE content, nerve stimulation evoked NE release, and NE uptake, and by decreasing MAO and COMT activity. Therefore, repeated low-dose exposure to soman might exaggerate the response to any given level of sympathetic nerve stimulation and to NE-releasing agents.

Animals↗
PubMed1992

Borate and molybdate inhibition of catechol estrogen and pyrocatechol methylation by catechol-O-methyltransferase.

The possibility that boron and molybdenum anions can influence sex steroid metabolism by forming complexes with catechol estrogens has been studied in vitro. The formation of 2-methoxyestrone (2-OHE1 2-Me) from 2-hydroxyestrone (2-OHE1) by catechol-O-methyltransferase (COMT) was followed by measuring the transfer of the radiolabeled methyl group from S-adenosylmethionine. In the presence of both sodium tetraborate and sodium molybdate using a phosphate buffer medium, the formation of 2-OHE1 2-Me decreased as the anion:2-OHE1 molar ratio was increased. However, the reverse effect was observed when using a tris buffer medium and further investigation showed that phosphate and sulphate also enhanced COMT activity in a tris buffer medium. Boric acid affinity medium, used as a substitute for borate salt, also showed a negative relationship with enzyme activity in a phosphate buffer medium, and inhibition of methylation was more marked than with the free anion. Erythrocytes contain appreciable amounts of COMT, which is mostly responsible for the rapid O-methylation of catechol estrogens in blood. The methylation of a simple catechol compound, 1,2-dihydroxybenzene (pyrocatechol) was therefore studied using rat red blood cell lysates. Methylation was inhibited in a concentration-related manner by borate, as found in the studies of 2-OHE1. It is possible that high dietary intakes of boron or molybdenum could regulate the rate of catabolism, or even the metabolic fate of the major estrogens.

Animals↗
PubMed1980

Monoamine oxidase and catechol-O-methyltransferase activities in cultured fibroblasts and blood cells from children with autism and the Gilles de la Tourette syndrome.

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) activities were measured in cells from children with autism (n = 5) and the Gilles de la Tourette syndrome (n = 5). Monoamine oxidase activities in cultured skin fibroblasts (type A) and platelets (type B) from the same individual were not correlated. COMT activities in fibroblasts and red blood cells showed a negative but not significant correlation (r = -0.42). Fibroblast MAO and COMT activities from patients were similar to values from controls matched for age, race, and sex. Increasing clinical severity of illness in both disorders, however, correlated significantly with higher fibroblast MAE activity. Cultured fibroblasts provide a means of measuring enzyme activities independently of the individual's current physiological and psychological state.

Adolescent↗
PubMed1981

Catechol-O-methyltransferase of erythrocytes in patients with endogenous psychoses.

A significant decrease in catechol-O-methyltransferase (COMT) activity of erythrocytes was found in both male and female schizophrenic patients, as well as in male patients with schizophreniform psychosis. Among control subjects, a sex difference in COMT activity of erythrocytes was found, with males showing significantly higher activity than females. It is suggested that a genetically determined deficiency of catecholamine degradative enzymes in the central nervous system or, alternatively, influences of nongenetic hormonal factors could be implicated in the findings of altered erythrocyte COMT activity reported.

Adult↗
PubMed1994

3-O-methyl-DOPA is not involved in the development of behavioral supersensitivity after repeated L-dopa administration in 6-OHDA lesioned rats.

The underlying cause of long-term complications of L-DOPA therapy in Parkinson's disease is largely unknown. Recently, centrally and peripherally acting catechol-O-methyltransferase (COMT) inhibitors became available. These drugs are capable of inhibiting the generation of 3-O-methyl-DOPA (3-OMD), a major metabolite of L-dopa developing considerable plasma levels during L-dopa therapy. The use of these drugs offers the opportunity to study the involvement of 3-OMD in the development of behavioral supersensitivity following repeated doses of L-dopa over 11 days in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic system. Repeated daily administration of L-dopa/Carbidopa produced continuous increase of contralateral rotations to both L-dopa/Carbidopa and to challenge doses of apomorphine. This increase was not influenced by peripherally and peripherally plus centrally acting COMT inhibitors, OR-462 and OR-486, respectively, administered simultaneously with L-dopa/Carbidopa. Both COMT inhibitors suppressed the L-dopa induced increase of 3-OMD plasma levels, OR-486 being more effective than OR-462. This indicates that 3-OMD is not involved in the development of behavioral supersensitivity following repeated L-dopa treatment in rats with unilateral 6-OHDA lesion of the nigrostriatal system.

Animals↗
PubMed1983

Metabolic fate of 3,4-dihydroxyphenylethyleneglycol (DHPG) in mouse brain.

Mouse brain DHPG and MHPG turnover rates were estimated by determining their initial rates of disappearance or accumulation following MAO and/or COMT inhibition. Similar turnover estimates of brain DHPG were obtained following MAO or COMT inhibition, which were comparable to the estimated NE turnover obtained from its initial accumulation following MAO plus COMT inhibition. It was estimated that negligible amounts of DHPG were eliminated directly from brain, the majority being cleared through O-methylation. These findings indicate that mouse brain NE is primarily cleared through DHPG formation followed by O-methylation, and also suggest that brain DHPG turnover is more indicative of NE turnover.

Animals↗
PubMed1995

Structure-based sequence alignment of three AdoMet-dependent DNA methyltransferases.

M.HhaI, M.TaqI and COMT are DNA methyltransferases (MTases) which catalyze the transfer of a methyl group from the cofactor AdoMet to C5 of cytosine, to N6 of adenine and to a hydroxyl group of catechol, respectively. The larger catalytic domains of the bilobal proteins, M.HhaI and M.TaqI, and the entire single domain of COMT have an alpha/beta structure containing a mixed central beta-sheet. These domains have very similar folding. By allowing appropriate 'insertions' or 'deletions' in the backbones of the three structures, it was possible to find more conserved motifs in M.TaqI and COMT. The similarity in protein folding and the equivalence of amino-acid sequences revealed by the structural alignment indicate that many AdoMet-dependent MTases may share a common catalytic domain structure.

Amino Acid Sequence↗
PubMed1995

Improved assay of reaction products to quantitate catechol-O-methyltransferase activity by high-performance liquid chromatography with electrochemical detection.

We applied coulometric detection (three electrochemical electrodes in series) to quantitate vanillic acid and isovanillic acid using reversed-phase HPLC. The formation of these reaction products from dihydroxybenzoic acid was used as a precise and reproducible measure of catechol-O-methyltransferase (COMT) activity in striatal homogenates and recombinant membrane-bound COMT protein. This detection system has a higher sensitivity (0.5 pmol per injection) than a single-cell amperometric detection. As in a previous method, the deproteinized supernatants of the COMT assay could be injected directly onto the HPLC system allowing the handling of a large number of samples in one day.

Animals↗
PubMed2006

Prefrontal electrophysiologic "noise" and catechol-O-methyltransferase genotype in schizophrenia.

BACKGROUND: Increased variability of stimulus-induced prefrontal electromagnetic activity ("noise") has been associated with genetic risk for schizophrenia. On the basis of animal experiments and computational models, we have predicted that this prefrontal "noise" phenotype would be related to variation in prefrontal dopamine (DA) signaling, which itself might be abnormal in schizophrenia. In the present study, the effect of a functional single nucleotide polymorphism (val(108/158)met) within the catechol-O-methyltransferase (COMT) gene on prefrontal "noise" was examined, because the COMT enzyme is involved in cortical synaptic dopamine metabolism and weakly predictive of risk for schizophrenia. METHODS: A Caucasian sample comprising 112 unrelated normal subjects, 83 schizophrenic probands, and 87 of their unaffected siblings was investigated, all of whom had measures of prefrontal "noise" estimated from event-related electroencephalogram during an auditory oddball task. RESULTS: The val(108/158)met genotype was significantly associated with prefrontal "noise"; homozygous Val-carriers had greatest prefrontal "noise" values; odds ratio (OR) = 2.37 (95% confidence interval [CI] 1.37-4.10), p = 003. The genotype-phenotype association was stronger when only considering male subjects with an OR = 3.37 (95% CI: 1.63-6.98), p = 002. CONCLUSIONS: The results suggest that COMT genotype impacts the level of prefrontal physiologic "noise."

Acoustic Stimulation↗