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PubMed1983

Effect of hypothermia on beta 1-adrenoceptor-mediated relaxation of pig bronchus.

The relaxant potencies of (+/-)-isoprenaline and of (-)-noradrenaline (NA) in the pig isolated bronchus were increased 5.4 and 3.1 fold respectively by lowering the organ bath temperature from 37 degrees C to 27 degrees C, whereas the potencies of the non-catecholamine beta-adrenoceptor agonists fenoterol and orciprenaline were not significantly changed. At 37 degrees C, the catechol-O-methyl transferase (COMT) inhibitor U-0521 (30 microM), caused a 7.2 fold increase in the potency of isoprenaline but had no effect on the potency of fenoterol. At 27 degrees C the potency of isoprenaline was similar in the absence or presence of U-0521 (30 microM). Furthermore, in bronchi where extraneuronal uptake was inhibited by phenoxybenzamine, the potency of NA was not significantly altered by reducing bathing temperature from 37 degrees C to 27 degrees C. These results suggest that the hypothermic potentiation of isoprenaline in pig bronchus resulted from inhibition of COMT or of access to COMT, rather than from sensitization of beta 1-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1977

Monoamine oxidase and catechol-O-methyl transferase activity in Tetrahymena.

Tetrahymena pyriformis strain HSM was found to have monomine oxidase (MAO) and a catechol-3-methyl transferase-like (COMT) activity. As in mammalian tissues, the MAO activity is predominantly localized in the mitochondrial pellet and COMT in the cytosol. The COMT-like activity was present in amounts comparable to several mouse tissues and was inhibited by tropolone. MAO activity was much lower than in any of the mouse tissues tested, and its activity varied greatly from preparation to preparation. The substrate preference of Tetrahymena MAO was tryptamine greater than serotonin greater than dopamine, and activity increased with increasing pH from pH 6.5 to pH 7.8, as does that of mouse liver MAO. Teh Km of Tetrahymena MAO for tryptamine was approximately 4 micrometer, an order of magnitude lower than that of mouse liver MAO. Sensitivity of inhibition by MAO inhibitors was variable. In some preparations, no inhibition was observed. In others clear inhibition was obtained, harmine and clorgyline being among the most potent inhibitors.

Animals↗
PubMed1991

In vitro effect of mercury on aryl hydrocarbon hydroxylase, quinone reductase, catecholamine-O-methyltransferase and glucose-6-phosphate dehydrogenase activities in term human placenta.

The effect of HgCl2 on human term placental aryl hydrocarbon hydroxylase (AHH), quinone reductase (QR), catecholamine-O-methyltransferase (COMT), and glucose-6-phosphate dehydrogenase (G-6-PD) enzyme activities was studied after incubation of placental explants with the salt for either a 6 or 24 hr period. Mercury (Hg) increased the activities of AHH, QR and COMT, but decreased that of G-6-PD. The increases in enzyme activities, as well as the decrease in G-6-PD activity observed were in all cases time- and dose-dependent. The data suggest that Hg exerts an enhancing effect on the activity of placental phase I enzyme (AHH) and phase II enzymes (QR and COMT). This enhancement may be due to increased de novo synthesis, elimination of some suppressing agent(s), or the decreased breakdown of enzyme protein. Also, the inhibitory effect of Hg on G-6-PD activity appears to indicate that this enzyme is appreciably more sensitive to Hg than the other three enzymes. These findings may imply increased cellular resistance to Hg toxicity. The altered state of activity may also be used as a tool for monitoring exposure to this metal.

Aryl Hydrocarbon Hydroxylases↗
PubMed2003

Conjugation of catechols by recombinant human sulfotransferases, UDP-glucuronosyltransferases, and soluble catechol O-methyltransferase: structure-conjugation relationships and predictive models.

Conjugation of a structurally diverse set of 53 catechol compounds was studied in vitro using six recombinant human sulfotransferases (SULTs), five UDP-glucuronosyltransferases (UGT) and the soluble form of catechol O-methyltransferase (S-COMT) as catalyst. The catechol set comprised endogenous compounds, such as catecholamines and catecholestrogens, drugs, natural plant constituents, and other catechols with diverse substituent properties and substitution patterns. Most of the catechols studied were substrates of S-COMT and four SULT isoforms (1A1, 1A2, 1A3, and 1B1), but the rates of conjugation varied considerably, depending on the substrate structure and the enzyme form. SULT1E1 sulfated fewer catechols. Only low activities were observed for SULT1C2. UGT1A9 glucuronidated catechols representing various structural classes, and almost half of the studied compounds were glucuronidated at a high rate. The other UGT enzymes (1A1, 1A6, 2B7, and 2B15) showed narrower substrate specificity for catechols, but each glucuronidated some catechols at a high rate. Dependence of specificity and rate of conjugation on the molecular structure of the substrate was characterized by structure-activity relationship analysis and quantitative structure-activity relationship modeling. Twelve structural descriptors were used to characterize lipophilicity/polar interaction properties, steric properties, and electronic effects of the substituents modifying the catechol structure. PLS models explaining more than 80% and predicting more than 70% of the variance in conjugation activity were derived for the representative enzyme forms SULT1A3, UGT1A9, and S-COMT. Several structural factors governing the conjugation of catechol hormones, metabolites, and drugs were identified. The results have significant implications for predicting the metabolic fate of catechols.

Catechol O-Methyltransferase↗
PubMed2001

Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase.

Molecular mechanisms determining the turn-over rate and specificity of catechol O-methylation were studied by combining enzyme kinetic measurements, computational modeling of substrate properties and fitting ligands in a 3D model of the active site of the enzyme. Enzyme kinetic measurements were carried out for 46 compounds, including most clinically used catechol drugs, by using recombinant human soluble catechol O-methyltransferase (COMT). The most important mechanism decreasing the turnover rate and increasing affinity was the electron withdrawing effect of substituents. Several other mechanisms by which substituents affected reactivity and affinity were identified. Highest turnover rates were determined for unsubstituted catechol and pyrogallol. Pyrogallol derivatives generally seemed to be more specific substrates than catechols. Catecholestrogens were the most specific endogenous substrates, whereas catecholamines were rather poor substrates. Among the catechol drugs used in the L-DOPA treatment of Parkinson's disease, the COMT inhibitors entacapone and tolcapone were not methylated, whereas the DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than L-DOPA, the target of COMT inhibition. The structure-activity relationships found allow the prediction of reactivity, affinity, and specificity with useful accuracy for catechols with a wide range of structures and properties. The knowledge can be used in the evaluation of metabolic interactions of endogenous catechols, drugs and dietary catechols, and in the designing of drugs with the catechol pharmacophore.

Binding Sites↗
PubMed2006

Genetic predictors for acute experimental cold and heat pain sensitivity in humans.

BACKGROUND: The genetic contribution to pain sensitivity underlies a complex composite of parallel pain pathways, multiple mechanisms, and diverse inter-individual pain experiences and expectations. METHODS: Variations for genes encoding receptors related to cold and heat sensation, such as transient receptor potential A subtype 1 (TRPA1), M subtype 8 (TRPM8), V subtype 1 (TRPV1), delta opioid receptor subtype 1 (OPRD1), catechol O-methyltransferase (COMT), and fatty acid amide hydrolyase (FAAH), were investigated in four major ethnic populations. RESULTS: We defined 13 haplotype blocks in European Americans, seven blocks in African Americans, seven blocks in Hispanic subjects, and 11 blocks in Asian Americans. Further study in European American subjects found significant associations between short duration cold pain sensitivity and variations in TRPA1, COMT, and FAAH in a gender dependent manner. Our observations demonstrate that genetic variations in TRPA1, COMT, and FAAH contribute gender specifically to individual variations in short duration cold pain sensitivity in a European American cohort. CONCLUSIONS: The effects of TRPA1 variations on experimental short duration heat pain sensitivity may contribute to inter-individual variation in pain sensitivity in humans.

Amidohydrolases↗
PubMed1994

Effect of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson's disease.

Catechol-O-methyltransferase (COMT) inhibitors may be useful in the treatment of Parkinson's disease by improving the bioavailability of levodopa and by prolonging its effects. Entacapone (OR-611), a novel COMT inhibitor, which does not cross the blood brain barrier, was assessed in 12 patients with Parkinson's disease and motor fluctuations in a randomised, double-blind, cross-over, single dose study. The magnitude and duration of the therapeutic response to a single dose of 200 mg levodopa/50 mg carbidopa was evaluated after concomitant placebo, or 200 or 800 mg entacapone. A significant increase in the duration of the motor response to levodopa was seen when 200 mg entacapone was given with levodopa/carbidopa. Plasma levodopa concentrations were increased with both doses of the COMT inhibitor. The latency to onset of motor response did not differ significantly between active drug and placebo. Entacapone may prove useful in prolonging the duration of the benefit obtained from individual doses of levodopa.

Aged↗
PubMed2004

Association study of catechol-O-methyltransferase gene and dopamine D4 receptor gene polymorphisms and personality traits in healthy young chinese females.

Human personality traits, which are substantially heritable, may be modulated by monoamine neurotransmitters. It has been demonstrated that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect monoamine metabolism, is possibly associated with specific personality traits. In addition, a polymorphism in the dopamine D4 receptor (DRD4) gene exon 3 has been associated in some, but not all, studies with the novelty seeking personality trait, as evaluated by the Tridimensional Personality Questionnaire (TPQ). In this study, associations between these two polymorphisms and TPQ personality traits were investigated in a sample population of 120 healthy young Chinese females. The results of this analysis reveal that the COMT Val158Met polymorphism was significantly associated with novelty seeking (p = 0.017) and reward dependence scores (p = 0.015) in our sample. However, no significant differences were demonstrated comparing TPQ-specific scores for subjects bearing different DRD4 genotypes. The present study suggests that the functional COMT Val158Met genetic polymorphism contributes to individual differences in the personality traits novelty seeking and reward dependence. Similar to the results of a recent meta-analytic review, however, no association was demonstrated between this DRD4 polymorphism and novelty seeking in our young Chinese female sample population.

Adult↗
PubMed2005

Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment.

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.

Adolescent↗
PubMed2006

Association of eating disorders with catechol-o-methyltransferase gene functional polymorphism.

AIM: The aim of this study was to evaluate functional catechol-O-methyltransferase (COMT) genetic variation as a risk factor for eating disorders (ED). METHOD: Eighty women receiving treatment for serious ED (52 for anorexia nervosa, 28 for bulimia nervosa) and 116 age-matched females in the control group underwent COMT genotyping for polymorphism in exon 4 (codon 158). Both the low-activity allele and the high-activity allele (H) were determined. RESULTS: The H/H genotype was twice as frequent in the ED group as in the control group (52.5% in the ED group and 25% in controls, chi(2) = 15.5, d.f. = 2, p < 0.001, odds ratio = 3.343). The H/H genotype was found in 57.7% of anorexia nervosa patients (chi(2) = 16.860, p < 0.001, Hardy-Weinberg equilibrium = 0.003, odds ratio = 4.202). The H allele (val) was discovered in 66.9% of ED patients in comparison to 47.8% of patients from the control group (chi(2) = 13.89, p < 0.001, odds ratio = 6.088). In the anorexia group, H allele frequency was enhanced even higher (70.2 vs. 47.8%, chi(2) = 14.48, p < 0.001, odds ratio = 8.175). The genotype associations in the subgroup of bulimia patients were not significant, but a trend for a higher frequency of the H allele was found (p = 0.084, odds ratio = 5.309). CONCLUSIONS: These findings seem to suggest that a turnover of catecholamines, connected with polymorphism determining high activity of COMT enzyme, is connected with the risk of ED occurrence, particularly anorexia nervosa. The risk is significantly higher for women with an allele of higher activity.

Adolescent↗
PubMed1976

A comparative study of the role played by some inactivation pathways in the disposition of the transmitter in the rabbit aorta and the saphenous vein of the dog.

The aim of this study was to determine the relative importance of neuronal uptake, catechol-O-methyltransferase (COMT) and diffusion in the disposition of endogenous nor-adrenaline (NA) in the rabbit aorta and dog saphenous vein. Helical strips of dog saphenous vein and rabbit aorta were stimulated transmurally, relaxation occurring either in oil or in Krebs-Henseleit solution. The rate of inactivation of NA by various mechanisms was assessed from the decrease in the rate of relaxation after blockade of one or more of these processes. Cocaine was used to inhibit neuronal uptake and COMT was blocked with 3,4-dihydroxy-2-methyl propiophenone. Diffusion out of the tissue was prevented by replacing the Krebs-Henseleit solution in the muscle bath with mineral oil. Neuronal uptake was the primary mechanism of inactivation in the saphenous vein whereas diffusion and COMT appear to be more important in the aorta. The differences in the relative importance of the inactivation mechanisms (neuronal uptake, O-methyltransferase and diffusion) existing between these two vessels are attributed primarily to differing density and distribution of the adrenergic innervation.

Animals↗
PubMed1979

Influence of progressive starvation upon brain and adrenal monoaminergic activity in developing rats of two different ages.

Experiments show the influence of progressive starvation upon the synthetic and metabolic activity of monoaminergic function in the brain and the adrenal gland of young rats of two different ages. Brain and adrenal monoamine oxidase (MAO) showed a tendency to decline with the prolongation of the starvation interval. After 60 h of starvation, MAO activity was irreversibly decreased, even with 24 h of feeding, in the two age groups. Cerebral catechol-O-methyltransferase (COMT) activity was very slightly affected in response to the starvation in the older group, but the younger group showed an increased level of enzyme activity, and refeeding after 60 h of starvation of the young rats produced further increases. 60 h of starvation produced an increase in COMT activity of the adrenal gland of the older rats whereas the younger group did not show any marked change. Adrenal phenylethanolamine-N-methyltransferase (PNMT) declined after 24 and 48 h of starvation in the older rats, but the younger rats showed progressive increases after similar intervals of starvation. After 60 h of starvation, PNMT in the adrenal gland of the old rats increased significantly when compared to the control value, but the younger rats did not show any important change. Adrenal stores of adrenaline rose progressively up to 60 h of starvation in the old rats whereas the younger group responded in a contrary manner. Adrenal noradrenaline followed a similar pattern of evolution in both groups up to 60 h of starvation (when the results are expressed per milligram of adrenal protein), and refeeding had very little influence on the effects of starvation. The effects of starvation upon adrenal and cerebral MAO activity were verified with two different substrates. The results provide evidence that the metabolism of monoamines by oxidative deamination can be markedly affected by starvation, and this can be irreversible even after 24 h of feeding of starved rats. COMT activity augments when MAO activity declines.

Adrenal Glands↗
PubMed2002

Catechol-o-methyltransferase and blood pressure in humans.

BACKGROUND: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. METHODS AND RESULTS: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone. CONCLUSIONS: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.

Baroreflex↗
PubMed1976

Red blood cell catechol O-methyl transferase and response to imipramine in unipolar depressive women.

When baseline red blood cell catechol O-methyltransferase (COMT) was measured in 15 unipolar depressive women, the authors found a linear correlation between COMT and response to imipramine (best outcome occurring at low COMT). The results of this study were not related to such variables as intensity of depression, family history, or psychiatric history. The authors suggest that this assay may be useful either as a predictor of response to the drug or as a guide in choosing the optimum dose.

Adult↗
PubMed2007

Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children.

OBJECTIVE: The study aimed to determine the cognitive effect of the Val108/158Met polymorphism in the catechol-O-methyltransferase (COMT) gene in children before and during puberty. This polymorphism affects cognitive function in healthy adults and may contribute to risk for schizophrenia. METHOD: COMT genotype was determined for 8,707 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically defined general population cohort of children born between April 1, 1991, and Dec. 31, 1992, in the southwest of England. Fourteen measures of cognitive function--including working memory, verbal and motor inhibition, attentional control, and IQ--were assessed at ages 8 and 10 years. Any pubertal development at age 9 years was reported by parents. Effects of COMT genotype on cognition and interactions with gender and puberty were assessed using general linear models. RESULTS: In boys, genotype significantly affected executive function and explained up to 10 points normal variation in verbal IQ. The effects on IQ were significantly greater in pubertal than in prepubertal boys. In girls, there were no significant effects of genotype on cognition. CONCLUSIONS: This common polymorphism may be one of the genes of small effect that contribute to normal variation in IQ. The gender-specific nature of the effect and its possible interaction with puberty may be relevant to both normal cognitive and brain development and to abnormal development in disorders such as schizophrenia.

Adolescent↗
PubMed2003

Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism.

OBJECTIVE: Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)). METHOD: The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms. RESULTS: Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms. CONCLUSIONS: This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.

Adult↗
PubMed2004

Catechol O-methyltransferase polymorphism and eye tracking in schizophrenia: a preliminary report.

OBJECTIVE: This study examined associations between functional polymorphism (Val(108/158) Met) in the catechol O-methyltransferase (COMT) gene and eye tracking measures in schizophrenia. METHOD: Predictive pursuit and closed-loop gains of 62 patients with schizophrenia and 53 healthy comparison subjects with Val-Val, Val-Met, and Met-Met genotypes were compared. RESULTS: There was a significant diagnosis-by-genotype interaction: patients with the Met-Met genotype showed poor predictive pursuit. The Met-Met genotype in healthy subjects was associated with significantly higher predictive pursuit gain values than the Val-Val genotype in healthy subjects. The COMT genotype explained about 10% of the variance in each group's predictive pursuit performance. DISCUSSION: These preliminary data suggest that the COMT gene is associated with predictive eye tracking performance in healthy subjects. Predictive pursuit abnormality in schizophrenia is not attributable to the Val allele. These findings suggest a complex interaction with other etiological factors (e.g., another gene), and/or with prefrontal cortical dopaminergic activity.

Adult↗
PubMed2004

Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility.

OBJECTIVE: The catechol O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and behavioral phenotypes in schizophrenia. Whether COMT genotype is beneficial may depend on phenotype definition. The authors examined the effects of COMT genotype on a task that distinguishes imitation from reversal learning. They hypothesized that the Val and Met alleles would be associated with deficits in imitation learning and reversal learning, respectively. METHOD: Twenty-six patients with schizophrenia and schizoaffective disorder completed a task requiring alternation between imitation and reversal rules. RESULTS: Met homozygotes showed better acquisition of the imitation rule but greater deficit shifting from imitation to reversal. Val homozygotes had poorer imitation performance and slower reaction times. CONCLUSIONS: The Met allele, by increasing tonic dopamine, may promote cognitive stability but limit cognitive flexibility.

Adult↗