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PubMed1992

Enzyme activities in the term human placenta: in vitro effect of cadmium.

The effect of cadmium (Cd) as CdCl2 on some placental enzyme activities were studied after explants had been incubated with the salt for 6 or 24 hr. The results indicated that, for both incubation periods, Cd at low doses had a stimulatory effect on aryl hydrocarbon hydroxylase (AHH) (a phase I enzyme) and on quinone reductase and catecholamine-O-methyltransferase (COMT) (both phase II enzymes). This effect was dose- and time-dependent. Only the activities of AHH and COMT showed a biphasic response, (i.e., increases at the lower dose levels and decreases with the higher ones), whereas that of quinone reductase continually increased with all the dose levels of the metal administered. Glucose-6-phosphate dehydrogenase (G-6-PD) activity was found to be inhibited at all the dose levels of Cd tested, the effect also being time- and dose-dependent. In conclusion, it appears that the use of placental explants can serve as a valuable means for studying the toxic effects of certain xenobiotics, as reflected in the activity of various important enzymes.

Analysis of Variance↗
PubMed1999

Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats.

To elucidate the importance of catechol-O-methyltransferase, we performed striatal microdialysis studies in conscious rats given tolcapone, an inhibitor of catechol-O-methyltransferase, together with four compounds each of which elevates the extracellular dopamine content through a different mechanism. Tolcapone itself did not alter dopamine levels in the striatal microdialysis fluid but increased DOPAC and decreased homovanillic acid levels. However, tolcapone pretreatment (30 mg/kg) multiplied the already high dopamine levels after levodopa, and less so the moderately elevated dopamine levels after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopamine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elevated DOPAC levels. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homovanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-12909 on extracellular dopamine but not on DOPAC. In conclusion, when levodopa and carbidopa are given together, COMT inhibition becomes extremely meaningful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapone is able to further elevate extracellular dopamine levels only when dopamine turnover is normal or low but not when it is high. Overall, the role of COMT in the elimination of synaptic dopamine remains minor compared to the dominance of the reuptake process.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

The guinea-pig trachea O-methylating system is more effective in modulating beta 2- than beta 1-adrenoceptor-mediated responses to isoprenaline.

Assuming that responses of the guinea-pig trachea to isoprenaline in the presence of atenolol (10 mumol L-1) are exclusively, or at least predominantly, beta 2-adrenoceptor mediated and that responses to isoprenaline in the presence of ICI 118,551 (erythro-DL-1(7-methylindan-4-yloxyl)-3-isopropylaminobut an-2-ol) (1 nmol L-1) are exclusively, or at least predominantly beta 1-adrenoceptor mediated, the influence of inhibition of COMT by U-0521 (dehydroxy-2-methyl propiophenone) (50 mumol L-1) has been compared in both conditions. U-0521 enhanced beta 2-adrenoceptor mediated responses to isoprenaline 3.3-fold, while those mediated by beta 1-adrenoceptors were enhanced only 2.2-fold. It is concluded that in guinea-pig trachea COMT activity is functionally more effective in modulating responses which are mediated by beta 2-adrenoceptors than responses mediated by beta 1-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1992

Influence of inhibition of extraneuronal uptake and of O-methylation on the hyperglycaemia caused by sympathomimetic amines in depancreatized rats.

This study aimed at testing whether the O-methylating system (extraneuronal uptake + O-methylation) modulates, in-vivo, beta-adrenoceptor-mediated responses. The influences of U-0521 (3,4-dihydroxymethylpropiophenone, an inhibitor of catechol-O-methyl transferase (COMT)) and hydrocortisone (an inhibitor of extraneuronal uptake) on the hyperglycaemia evoked by isoprenaline and adrenaline were compared. Both inhibitors enhanced the increase of the plasma glucose level induced by either isoprenaline (0.36 nmol kg-1 min-1) or adrenaline (0.55 nmol kg-1 min-1). The enhancement caused by U-0521 developed faster than that caused by hydrocortisone, but was of the same magnitude. This is the first report of supersensitivity to sympathomimetic amines caused by inhibition of either COMT or extraneuronal uptake in-vivo and for a response not involving smooth muscle cells.

Analysis of Variance↗
PubMed2002

Kinetic interactions of dopamine and dobutamine with human catechol-O-methyltransferase and monoamine oxidase in vitro.

Dopamine and dobutamine are often infused together into acutely ill patients requiring temporary support of cardiac and renal function, but whether these catecholamines affect the metabolic clearance of each other is not established. We determined the kinetics of dopamine and dobutamine as substrates and inhibitors of each other, i.e., apparent V(max), K(m), and K(i), with crude preparations of human blood mononuclear cell catechol-O-methyltransferase (COMT) and platelet monoamine oxidase (MAO) at pH 7.4 and 37 degrees C. Values of V(max) for dopamine and dobutamine as substrates for COMT were 0.45 and 0.59 nmol of 3-O-methyl product formed per milligram of protein per minute, whereas those for K(m) were 0.44 and 0.05 mM, respectively. Dopamine and dobutamine were competitive inhibitors of each other in this reaction. The K(i) for dopamine as an inhibitor of dobutamine methylation was 1.5 mM, whereas that for dobutamine as an inhibitor of dopamine methylation was 0.015 mM. Dopamine but not dobutamine was a substrate for MAO. The V(max) for dihydroxyphenylacetaldehyde formation from dopamine was 0.29 nmol/mg protein/min and the K(m) for dopamine was 0.38 mM. Dobutamine was a noncompetitive inhibitor of dopamine oxidation in this reaction (K(i) congruent with 1.19 mM). The high apparent K(m) and K(i) values derived for dopamine and dobutamine when tested with these two human enzymes in vitro suggest that these catecholamines do not interfere with the metabolism of each other when both are infused together at therapeutic concentrations.

Adult↗
PubMed1977

Competitive inhibition of catechol O-methyltransferase by RO-4-4602.

RO-4-4602, a peripheral L-DOPA decarboxylase (EC 4.1.1.28) inhibitor was shown to also inhibit the activity of catechol O-methyltransferase (COMT) (EC 2.1.1.6). Kinetic study indicated that the inhibition is of a competitive nature. The apparent Ki values of 7 X 10(6), 5.3 X 10(-6, and 9 X 10-6) M calculated from Lineweaver-Burke plots when dopamine, norepinephrine, and epinephrine, respectively, were used as substrate, showed that this drug is the most potent inhibitor of COMT yet known.

Animals↗
PubMed1977

Red blood cell catechol O-methyltransferase activity in thyroid dysfunction.

Using a modification of the method of Mannl et al. (Mannl, H.F.K., Hempel, K., and Kubler, W. 1972. Catechol O-methyltransferase in human erythrocytes. Arch. Pharmacol. 272, 265-276), we have measured the activity of catechol O-methyltransferase (COMT) (EC 2.1.1.6) in red blood cells (RBC) of patients with hyperthyroidism and hypothyroidism to establish whether thyroid dysfunction is associated with alterations in catecholamine catabolism. The activity of COMT averaged 4.4+/-0.54 nmol/ml RBC per hour of incubation (mean+/-SEM) in euthyroid subjects compared to 4.76+/-0.64 nmol/ml RBC per hour of incubation in hyperthyroidism and 4.42+/-0.81 nmol/ml RBC per hour of incubation in hypothyroidism; these values are not significantly different. There were no significant differences observed in urinary excretion of vanillylmandelic acid, epinephrine, and norepinephrine among the three groups. These data are compatible with the possibility that thyroid status has little influence on the degradation of circulating catecholamines and suggest that hypothyroidism, with its attendant elevations in serum norepinephrine concentration, may be related to a compensatory noradrenergic response.

Catechol O-Methyltransferase↗
PubMed1979

The time course of brain and blood catecholamines, catechol O-methyltransferase, and amino acids in rats convulsed by oxygen at high pressure.

The time course of changes in blood and brain catecholamines, catechol O-methyltransferase (COMT), ammonia, and amino acids leading to convulsion by high pressure oxygen breathing (OHP) in rats has been investigated. Brain catecholamines were suppressed by OHP. They changed in phase with brain COMT concentration and consequently were not due to the action of this degrading enzyme. Convulsive actions seem not to be influenced by brain catecholamine concentration. Blood adrenaline concentrations are, however, significantly elevated both prior to and during convulsions. In both brain and blood, ammonia concentration increases, glutamate decreases, and glutamine-aspargine increases. It is proposed that the efficacy of the glutamate-glutamine ammonia buffering system in blood and brain is important in the prevention of the onset of convulsions but that when brain gamma-aminobutyric acid is depressed to critical levels, convulsions result.

Amino Acids↗
PubMed1981

Ketamine potentiates catecholamine responses of vascular smooth muscle by inhibition of extraneuronal uptake.

Effects of ketamine on responses to sympathomimetic amines were studied using isolated aortic and pulmonary artery strips from the rabbit. Ketamine (1.1 x 10(-5) to 3.7 x 10(-4) M) potentiated adrenaline-contracted strips. Potentiation was not impaired in tissues from animals pretreated with reserpine, with 6-hydroxydopamine, or its tissues pretreated with cocaine. Pretreatment of the strips with the catechol O-methyltransferase (COMT) inhibitors tropolone or pyrogallol or the inhibitor of extraneuronal uptake 17 beta-estradiol blocked the potentiation by ketamine; in addition, potentiation by the COMT and extraneuronal uptake inhibitors was abolished or greatly reduced by ketamine. In rabbit aorta, ketamine potentiated responses to the catecholamines (adrenaline greater than nordefrine greater than noradrenaline) but not to the noncatecholamines phenylephrine, methoxamine, and synephrine; instead a slight relaxant effect was observed. Ketamine potentiated, whereas cocaine inhibited, responses to tyramine Experiments using the technique of oil immersion demonstrated that ketamine reduced the rate at which aortic strips inactivate adrenaline even when monoamine oxidase (MAO) and neuronal uptake processes were fully inhibited. Uptake studies showed that ketamine and 17 beta-estradiol reduced extraneuronal accumulation of [3H]adrenaline in aortic strips. We conclude that ketamine is an inhibitor of extraneuronal uptake in the vascular smooth muscles studied and the importance of this mechanism in producing its known cardiovascular effect is discussed.

Animals↗
PubMed1987

Norepinephrine metabolism in neuronal cultures is increased by angiotensin II.

In this study we have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, we determined that ANG II (10 nM-1 microM) stimulates increased neuronal [3H]NE uptake by acting at specific receptors. We have confirmed these results here and in addition have shown that ANG II (1 nM-10 microM, 10-120 min) has no significant effects on neuronal [3H]DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem we have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism.

Angiotensin II↗
PubMed1997

Plasma 2-hydroxycatecholestrogen responses to acute submaximal and maximal exercise in untrained women.

Exercise-induced menstrual problems are accompanied by an increase in catecholestrogen (CE) formation. It has been hypothesized that hypoestrogenemia may be secondary to an increased turnover from estrogens to CE, which then may disrupt luteinizing hormone release. In addition, the strong affinity of CE for the catecholamine-deactivating enzyme catechol-O-methyltransferase (COMT) has led to speculations about their possible role in safeguarding norepinephrine from premature decomposition during exercise. We investigated whether acute exercise on a cycle ergometer produces any changes in CE homeostasis. Nine untrained eumenorrheic women (body fat, 24.8 +/- 3.1%) volunteered for this study. Baseline plasma CE averages for total 2-hydroxyestrogens (2-OHE) were 218 +/- 29 (SE) pg/ml during the follicular phase (FPh) and 420 +/- 58 pg/ml during the luteal phase (LPh). 2-Methoxyestrogens (2-MeOE) measured 257 +/- 17 pg/ml in the FPh and 339 +/- 39 pg/ml in the LPh. During incremental exercise, total estrogens (E) increased, but 2-OHE and 2-MeOE levels did not significantly change in either phase. The 2-OHE/E ratio (measure of CE turnover) decreased during exercise in both menstrual phases, whereas the 2-MeOE/2-OHE ratio (correlates with COMT activity) did not significantly change. These findings suggest that there is insufficient evidence to conclude that brief incremental exercise in untrained eumenorrheic females acutely produces increased CE formation.

Adult↗
PubMed1997

Effects of a training program on resting plasma 2-hydroxycatecholestrogen levels in eumenorrheic women.

Catecholestrogens (CE) represent a major metabolic pathway in estrogen metabolism. Previous information on CE and training is limited to two cross-sectional studies that did not involve standardized training. Our purpose, by means of a prospective design, was to evaluate the effects of a brief, exhaustive training program on resting plasma concentrations of 2-hydroxy CE. The experimental design spanned two menstrual cycles; a control cycle and a training cycle. The subjects were nine previously untrained, eumenorrheic women [body fat: 24.8 +/- 1.0 (SE) %]. Data were collected during the follicular (FPh) and the luteal phases (LPh). Posttraining FPh and LPh tests were held the day after the last day of a 5-day period of training on a cycle ergometer. Total 2-hydroxyestrogens (2-OHE) averaged 200 +/- 29 pg/ml during the FPh and 420 +/- 54 pg/ml during the LPh (P < 0.05). Levels of total 2-methoxyestrogens (2-MeOE) were 237 +/- 32 pg/ml during the FPh and 339 +/- 26 pg/ml during the LPh (P < 0.05). After training, although the plasma levels of 2-OHE significantly decreased (21%; P < 0.05) during the LPh, the actual CE formation (as estimated from the 2-OHE-to-total estrogens ratio) increased (+ 29%; P < 0.05). CE activity, as expressed by the 2-MeOE-to-2-OHE ratio, showed significantly higher values in both phases (FPh, + 14%; LPh, + 13%; P < 0.05). At the same time, resting levels of norepinephrine (NE) were increased by 42% (P < 0.05). CE strongly inhibit biological decomposition of NE by catechol-O-methyltransferase (COMT). Results of the present study suggest that, in response to training, CE are increasingly competing with the enzyme COMT, thus preventing premature NE deactivation.

Adult↗
PubMed2005

Catechol-O-methyl-transferase functional polymorphism and nicotine dependence: an evaluation of nonreplicated results.

Review articles have focused attention on and cited possible reasons for the nonreplication of genetic association studies. Herein, we illustrate how one might work through these possible reasons to make a judgment about the most plausible reason(s) when faced with two or more studies which yield seemingly inconsistent results. In the first study, 342 treatment-seeking smokers were genotyped for the Val108Met polymorphism in the functional catechol-O-methyl-transferase (COMT) locus. Alleles coding Val at codon 108 are denoted as H and those coding Met are denoted as L. An association between presence of the "H" (high activity) allele and pretreatment level of nicotine dependence level using the Fagerstrom Test for Nicotine Dependence was detected (P = 0.0072), after controlling for baseline body mass index (BMI, kg/m2), depression symptoms, and age. To validate this initial finding, 443 treatment-seeking smokers from an independent smoking cessation clinical trial were genotyped for the COMT polymorphism. Within the second study, no association between presence of the "H" allele and nicotine dependence was detected (P = 0.6418) after controlling for baseline BMI, depression symptoms, and age. We critically reviewed both studies with regard to often cited reasons for nonreplication, including type I error, population stratification, low statistical power, and imprecise measures of phenotype. Although in our opinion the failure to replicate the initial association in the second study is likely either the result of low statistical power to detect a small effect or effect heterogeneity, thorough analyses failed to definitively identify the reason for nonreplication.

Adult↗
PubMed2005

Estrogen metabolism-related genes and breast cancer risk: the multiethnic cohort study.

Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk. We investigated the associations between breast cancer and sequence variants in several genes in the estradiol/estrone metabolism pathway (CYP1A1*2A, CYP1A2*1F, CYP1B1 Leu432Val, CYP3A4*1B, COMT Val158Met, SULT1A1Arg213His) as well as the Arg554Lys variant in AHR (a transcription factor for CYP1A1, CYP1A2, and CYP1B1) in a case-control study of 1,339 breast cancer cases and 1,370 controls nested in the Multiethnic Cohort Study. The Multiethnic Cohort Study is a large prospective study of men and predominantly postmenopausal women of Japanese, White, African American, Latino, and Native Hawaiian ancestry, residing in Hawaii and Los Angeles. We found no association between breast cancer and these polymorphisms, except for CYP1A2*1F which was inversely associated with risk. The odds ratio (95% confidence interval) for the AA, AC, and CC genotype was 1.0, 0.9 (0.7-1.0), and 0.7 (0.5-1.0), respectively (P for gene dosage effect=0.03). This association seemed somewhat stronger for estrogen receptor (ER)/progesterone receptor (PR)-negative tumors than for ER/PR-positive tumors, and no statistically significant interaction with estrogen-related risk factors was detected. The findings provide no evidence for a role of COMT Val58Met, CYP1A1*2A, CYP3A4*1B, CYP1B1 Leu432Val, SULT1A1 Arg213His, and AHR Arg554Lys in breast cancer etiology. They also provide support for an inverse association between CYP1A2*1F and breast cancer, which is consistent with the observation of lower circulating estrogen levels in premenopausal women with the CC genotype in a previous study.

Aged↗
PubMed2006

Estrogens, enzyme variants, and breast cancer: a risk model.

Oxidative metabolites of estrogens have been implicated in the development of breast cancer, yet relatively little is known about the metabolism of estrogens in the normal breast. We developed a mathematical model of mammary estrogen metabolism based on the conversion of 17beta-estradiol (E(2)) by the enzymes cytochrome P450 (CYP) 1A1 and CYP1B1, catechol-O-methyltransferase (COMT), and glutathione S-transferase P1 into eight metabolites [i.e., two catechol estrogens, 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)); three methoxyestrogens, 2-methoxyestradiol, 2-hydroxy-3-methoxyestradiol, and 4-methoxyestradiol; and three glutathione (SG)-estrogen conjugates, 2-OHE(2)-1-SG, 2-OHE(2)-4-SG, and 4-OHE(2)-2-SG]. When used with experimentally determined rate constants with purified enzymes, the model provides for a kinetic analysis of the entire metabolic pathway. The predicted concentration of each metabolite during a 30-minute reaction agreed well with the experimentally derived results. The model also enables simulation for the transient quinones, E(2)-2,3-quinone (E(2)-2,3-Q) and E(2)-3,4-quinone (E(2)-3,4-Q), which are not amenable to direct quantitation. Using experimentally derived rate constants for genetic variants of CYP1A1, CYP1B1, and COMT, we used the model to simulate the kinetic effect of enzyme polymorphisms on the pathway and identified those haplotypes generating the largest amounts of catechols and quinones. Application of the model to a breast cancer case-control population identified a subset of women with an increased risk of breast cancer based on their enzyme haplotypes and consequent E(2)-3,4-Q production. This in silico model integrates both kinetic and genomic data to yield a comprehensive view of estrogen metabolomics in the breast. The model offers the opportunity to combine metabolic, genetic, and lifetime exposure data in assessing estrogens as a breast cancer risk factor.

Area Under Curve↗
PubMedDate not supplied

Regulation of dopamine-induced natriuresisby the dopamine-metabolizing enzyme catechol-O-methyltransferase.

Dopamine (DA) is an intrarenal natriuretic hormone involved in sodium homeostasis. A study was performed to elucidate two possible regulatory pathways of DA-induced natriuresis, i.e., metabolism and precursor delivery. This was done by use of an intraperitoneal injection of a catechol-O-methyltransferase (COMT) inhibitor, entacapone, or intravenous infusion of the DA precursor, L-dopa. Entacapone (30 mg/kg i.p.) induced a more than fivefold increase in renal sodium excretion which occurred without changes in renal haemodynamics. The natriuretic response was highly dependent on DA D(1)-like receptor activation, since the selective D(1)-like receptor antagonist SCH23390 attenuated the natriuretic response by 61%, while the selective D(2)-like receptor antagonist sulpiride was ineffective. The urinary excretion of DA did not increase. Infusion of L-dopa (60 microg/h/kg) only induced a twofold increase in sodium excretion, but the urinary excretion of DA increased more than 17-fold. The L-dopa-induced natriuretic response occurred without increments in glomerular filtration rate and could be blocked with the D(1)-like receptor antagonist SCH23390. It is concluded that the DA-metabolizing enzyme COMT is involved in the regulation of the natriuretic effect of intrarenal DA. It may be speculated that intrarenal DA activity is not primarily determined on the basis of delivered precursor, but on that of the level of DA metabolism.

Animals↗
PubMed2001

Association analysis of a functional catechol-o-methyltransferase gene polymorphism in schizophrenic patients in Taiwan.

The catechol-O-methyltransferase (COMT) gene was thought to be a candidate gene for schizophrenia because of its role in inactivating dopamine. This study examined the relationship between a functional polymorphism (val158met) of the COMT gene, schizophrenia and its associated behaviors. One hundred and ninety-eight Chinese schizophrenic patients and 188 controls were genotyped by polymerase chain reaction restriction fragment length polymorphism. Of the schizophrenic patients, 72 had a history of violence and 62 had a history of suicide attempts. The results failed to show significant association between val158met polymorphism and schizophrenia, violence or suicide. However, our results showed a significant difference in age at disease onset among different genotypes (F = 5.501, p = 0.005).

Adult↗
PubMed2003

Association between catechol-O-methyltransferase gene polymorphisms and wearing-off and dyskinesia in Parkinson's disease.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates catecholamines, including levodopa. An amino acid change (Val-108-Met) in the COMT protein has been found to result in a change from high to low enzyme activity. In the present study, we genotyped 121 Japanese patients with Parkinson's disease (PD) and 100 controls. Comparison of the allele frequencies revealed that homozygosity for the low-activity allele was significantly more common among PD patients than the controls (p = 0.047, odds ratio = 3.23). In addition, homozygosity for the low-activity allele was overrepresented in PD patients that exhibited the 'wearing-off' phenomenon (p = 0.045, odds ratio = 3.82) or dyskinesia (p = 0.030, odds ratio = 4.80) compared with controls, although these differences were not significant after Bonferroni's correction. Our results may help understand the mechanism that cause complications of levodopa therapy in PD patients.

Aged↗