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PubMed1992

Electrophoretic analysis of low and high activity forms of catechol-O-methyltransferase in human erythrocytes.

Analysis of the catechol-O-methyltransferase (COMT) enzyme in human RBC lysates from 15 samples exhibiting inherited variations in level of activity and thermal stability was performed. Electrophoretic blotting and immune fixation was carried out following sodium dodecyl sulfate polyacrylamide gel electrophoresis or isoelectric focusing of lysate protein. These techniques did not reveal a major structural alteration of the protein that could account for the observed variation in enzyme activity or thermal stability. Future studies utilizing molecular genetic techniques should make it possible to determine the basis for inherited variations in human RBC COMT activity and thermal stability.

Catechol O-Methyltransferase↗
PubMed1981

Hormone mediated changes in monoamine stores and regulation of enzymes of biosynthesis and metabolism in the rat adrenal gland. Influence of progesterone, estradiol, ACTH and testosterone administration.

The influence of daily injections, for 7 days, of 17-hydroxyprogesterone caproate (8 mg/100 g body weight pro die), of estradiol-17 beta 17-undecylate (1.2 mg/100 g body weight pro die) of testosterone enanthate (2 mg/100 g body weight pro die) and of ACTH (4 IU/100 g body weight pro die) to male Wistar rats, weighing 200 g, were investigated. Monamine storage and regulation of enzymes phenylethanolamine N-methyl transferase (PNMT), monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) were studied in the adrenal glands. Results from testosterone treated rats were especially significant : the hormone administration decreased the stores of dopamine and norepinephrine (epinephrine precursors), stimulated PNMT and decreased metabolism of epinephrine by MAO and COMT. However, the adrenal content of epinephrine remained in the normal range. These findings suggest that uptake of epinephrine is accelerated in peripheral tissues by testosterone.

17 alpha-Hydroxyprogesterone Caproate↗
PubMed1992

Effect of cadmium on some enzyme activities in first-trimester human placentae.

Explants from first-trimester placentae obtained from non-smoking women were incubated with doses of 0, 0.75, 1.5, 3, 6 and 12 micrograms of cadmium (Cd) as CdCl2 for 6 or 24 h. At the end of the incubation period, the activities of placental aryl hydrocarbon hydroxylase (AHH) (a phase I enzyme), quinone reductase (QR) and catecholamine-O-methyltransferase (COMT) (both phase II enzymes) and glucose-6-phosphate dehydrogenase (G-6-PD) were determined. Cd at low dose levels increased significantly the activities of placental phases I and II enzymes in a time- and dose-dependent manner. Of the first 3 enzymes, only AHH showed a biphasic response for the two time periods, with the activities of QR and COMT continually increasing at all the dose levels tested for the two incubation periods. However, the G-6-PD activity was inhibited at all the dose levels of Cd, the effect being very drastic after exposure to 0.75 ppm Cd for both incubation periods.

Aryl Hydrocarbon Hydroxylases↗
PubMed1992

Application of an organic solvent extraction to the determination of catechol-O-methyltransferase activity by high-performance liquid chromatography in human mononuclear cells.

We report here a method for measuring mononuclear cell catechol-O-methyltransferase (COMT) activity which is ideally adapted to clinical studies. The method measures the O-methylation of dopamine to 3-methoxytyramine and 4-methoxy-3-hydroxyphenethylamine. Whole mononuclear cell sonicate is incubated with saturating concentrations of dopamine, S-adenosyl-L-methionine and magnesium chloride in sodium-potassium phosphate buffer at pH 7.3. An organic solvent extraction using ethyl acetate is then used for product separation, followed by high-performance liquid chromatography with electrochemical detection for product separation and quantification. This method allows both O-methylated products, 3-methoxytyramine and 4-methoxy-3-hydroxyphenethylamine, to be isolated and quantified separately. The apparent Michaelis constants for dopamine and S-adenosyl-L-methionine using this method are similar to values reported previously (0.51 and 14 microM, respectively). The optimal concentration of magnesium chloride is eight to ten times higher than previously reported. No endogenous inhibitors were apparent using this assay. The within-day coefficient of variation using this method is 7% when measuring 3-methoxytyramine and 5% when measuring 4-methoxy-3-hydroxyphenethylamine. The between-day coefficient of variation is 11%. Mononuclear cell COMT activity can be detected using protein concentrations as low as 0.75 mg/ml, corresponding to 2-3 ml of whole blood. The small amount of blood required per sample allows multiple sample analysis from a single patient, including infants.

Adult↗
PubMedDate not supplied

Psychoses in twins. A 10 year clinical and biochemical follow-up study.

An unbiased sample of monozygotic and dizygotic twins with psychotic or pre-psychotic symptoms has been followed during a 10 year period. The sample was based on 9000 patients, both born in 1930-1946, and hospitalized in Scania, Sweden, during the 1960s. 23 complete pairs were examined in 1972 with regard to a variety of clinical, genetic, and biochemical parameters. A fairly young sample was chosen in order to include a sufficient number of discordant pairs to be followed prospectively, thus making it possible to study a group of individuals with a very high risk of developing psychosis. 18 of the 23 pairs were re-examined by the same clinician 10 years later. The biochemical methods were both partly the same as those used 10 years earlier and partly extended. Very few changes in the clinical diagnoses of the twins were noted during the follow-up period. A highly significant correlation was found between 1972 and 1982 activity both for catechol O-methyltransferase (COMT) and for monoamine oxidase (MAO). The basal levels of MAO, COMT, dopamine beta-hydroxylase (DBH) and serotonin (5-HT) did not show correlations to the presence of pre-psychotic or psychotic symptoms.

Adult↗
PubMed1996

A study of enzymes involved in catecholamine metabolism in parents of patients with schizophrenia.

The concentrations of serum homovanillic acid (HVA), norepinephrine (NE), tyrosine (Tyr), phenylalanine (Phe) and tryptophan (Trp), and the activities of serum dopamine-beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyl transferase (COMT) were measured in 68 healthy parents who had schizophrenic offspring. The results show a significant correlation between the parents of schizophrenic patients in serum HVA (r=0.38, n=34, p<0.05), NE (r=0.40, n=33, p<0.02), Phe (r=0.44, n=34, p<0.0l), Tyr (r=0.43, n = 34, p <0.02) and DBH activity (r=0.51, n = 30, p <0.005), but do not show a significant correlation in erythrocyte COMT (r=0.01, n=27), platelet MAO (r=0.04, n=23) or serum Trp (r=0.10, n=34). There were no significant correlations in these measurements between randomly matched parents. The present study suggests that both parental sides of schizophrenic patients are likely to have similar alleles associated with the catecholamine pathway, and their ill offspring may possess a double dose of the schizophrenogenic alleles.

Adult↗
PubMed1996

Effects of testosterone and its metabolites on aromatase-immunoreactive cells in the quail brain: relationship with the activation of male reproductive behavior.

The enzyme aromatase converts testosterone (T) into 17 beta-estradiol and plays a pivotal role in the control of reproduction. In particular, the aromatase activity (AA) located in the preoptic area (POA) of male Japanese quail is a limiting step in the activation by T of copulatory behavior. Aromatase-immunoreactive (ARO-ir) cells of the POA are specifically localized within the cytoarchitectonic boundaries of the medial preoptic nucleus(POM), a sexually dimorphic and steroid-sensitive structure that is a necessary and sufficient site of steroid action in the activation of behavior. Stereotaxic implantation of aromatase inhibitors in but not around the POM strongly decreases the behavioral effects of a systemic treatment with T of castrated males. AA is decreased by castration and increased by aromatizable androgens and by estrogens. These changes have been independently documented at three levels of analysis: the enzymatic activity measured by radioenzymatic assays in vitro, the enzyme concentration evaluated semi-quantitatively by immunocytochemistry and the concentration of its messenger RNA quantified by reverse transcription-polymerase chain reaction (RT-PCR). These studies demonstrate that T acting mostly through its estrogenic metabolites regulates brain aromatase by acting essentially at the transcriptional level. Estrogens produced by central aromatization of T therefore have two independent roles: they activate male copulatory behavior and they regulate the synthesis of aromatase. Double label immunocytochemical studies demonstrate that estrogen receptors(ER) are found in all brain areas containing ARO-ir cells but the extent to which these markers are colocalized varies from one brain region to the other. More than 70% of ARO-ir cells contain detectable ER in the tuberal hypothalamus but less than 20% of the cells display this colocalization in the POA. This absence of ER in ARO-ir cells is also observed in the POA of the rat brain. This suggests that locally formed estrogens cannot control the behavior and the aromatase synthesis in an autocrine fashion in the cells where they were formed. Multi-neuronal networks need therefore to be considered. The behavioral activation could result from the action of estrogens in ER-positive cells located in the vicinity of the ARO-ir cells where they were produced (paracrine action). Alternatively, actions that do not involve the nuclear ER could be important. Immunocytochemical studies at the electron microscope level and biochemical assays of AA in purified synaptosomes indicate the presence of aromatase in presynaptic boutons. Estrogens formed at this level could directly affect the pre-and post-synaptic membrane or could directly modulate neurotransmission namely through their metabolization into catecholestrogens (CE) which are known to be powerful inhibitors of the catechol- omicron - methyl transferase (COMT). The inhibition of COMT should increase the catecholaminergic transmission. It is significant to note, in this respect, that high levels of 2-hydroxylase activity, the enzyme that catalyzes the transformation of estrogens in CE, are found in all brain areas that contain aromatase. On the other hand, the synthesis of aromatase should also be controlled by estrogens in an indirect, transynaptic manner very reminiscent of the way in which steroids indirectly control the production of LHRH. Fibers that are immunoreactive for tyrosine hydroxylase (synthesis of dopamine), dopamine beta-hydroxylase (synthesis of norepinephrine) or vasotocine have been identified in the close vicinity of ARO-ir cells in the POM and retrograde tracing has identified the origin of the dopaminergic and noradrenergic innervation of these areas. A few preliminary physiological experiments suggest that these catecholaminergic inputs regulate AA and presumably synthesis.

Androgens↗
PubMed1995

Positron emission tomography in drug evaluation: influence of three different catechol-O-methyltransferase inhibitors on metabolism of [NCA] 6-[18F]fluoro-L-dopa in rhesus monkey.

We compared the influence of three different catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on the metabolism of no-carrier-added (NCA) 6-[18F]fluoro-L-dopa (6-FDOPA) in one Rhesus monkey. All three COMT inhibitors improved 6-FDOPA availability in plasma, increased the specific uptake in the brain and thus improved 6-FDOPA uptake measurements using positron emission tomography (PET). Best results were obtained with Ro 40-7592.

Amidines↗
PubMed2005

2,3,7,8-tetrachlorodibenzo-p-dioxin induces CYP1B1 expression in human luteinized granulosa cells.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a reproductive toxicant in multiple species; however, mechanisms and direct ovarian effects are poorly understood. DNA microarrays were used to characterize gene expression profiles of human luteinized granulosa cells (HLGCs) exposed to TCDD in primary cultures. Exposure to 10 nM TCDD for 24 h induced a significant increase in CYP1B1, while few other genes responded. TaqMan PCR and Western immunoblotting demonstrated that induction was dose-dependent. Additionally, the microsomal form of catechol-O-methyltransferase (COMT) was highly expressed in HLGCs, along with only fractional amounts of the soluble form. This is the first report of CYP1B1 and COMT expression, and CYP1B1 induction, in cells from the human ovary. The role of CYP1B1 in the oxidative metabolism of estrogens and potential generation of DNA adducts in the ovary may have significant consequences for oocyte quality, corpus luteum function, and ovarian carcinogenesis.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

Quantitative structure-activity relationships in prooxidant cytotoxicity of polyphenols: role of potential of phenoxyl radical/phenol redox couple.

The aim of this work was to characterize the role of the potential of phenoxyl radical/phenol redox couple, E(7)(2), in the cytotoxicity of polyphenols. The cytotoxicity of polyphenols in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK), and human promyelocytic leukemia cells (line HL-60) was partly inhibited by catalase, by the antioxidant N,N'-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis-(2-chloro-ethyl)-1-nitrosourea, thus showing its prooxidant character. Dapsone, an inhibitor of myeloperoxidase, did not affect the cytotoxicity of polyphenols in HL-60 cells, whereas dicumarol, an inhibitor of DT-diaphorase, showed controversial effects on their cytotoxicity in FLK cells. Inhibitors of cytochromes P-450, alpha-naphthoflavone and izoniazide, decreased the cytotoxicity of several polyphenols, whereas 3,5-dinitrocatechol, an inhibitor of catechol-o-methyltransferase (COMT), increased it. The cytotoxicity of 13 polyhydroxybenzenes was described by the equations: logcL50 (microM) = -0.67 + 5.46E(7)(2) (V) - 0.16 logD (FLK), and logcL50 (microM) = -1.39 + 6.90E(7)(2) (V) - 0.20logD (HL-60), where cL50 is compound concentration for 50% cell survival, and D is octanol/water distribution coefficient at pH 7.0. The flavonoids comprise a separate series of compounds with lower cytotoxicity. The correlations obtained quantitatively confirm the parallelism between the polyphenol cytotoxicity and the rates of their single-electron oxidation, and point to the leading role of formation of the reactive oxygen species in their cytotoxicity. Depending on the examined system, this parallelism may be distorted due to the cytochrome P-450 and COMT-catalyzed transformation of polyphenols.

Animals↗
PubMed2004

Assessment of O-methylated catecholamine levels in plasma and urine for diagnosis of autonomic disorders.

The term 'metanephrines' is used to indicate the two catechol 3-O-methylated metabolites of epinephrine (E) and norepinephrine (NE): metanephrine and normetanephrine (NMN). The corresponding 3-O-methylated metabolite of dopamine is usually referred to as 3-methoxytyramine rather than 3-methoxydopamine and is not generally considered a "metanephrine". O-Methylation occurs outside the sympathetic neuron and neuroeffector junction. Metanephrines are products of the enzyme catechol-O-methyltransferase (COMT). Subsequent conjugation with sulfate or deamination by monoamine oxidase (MAO) followed by reduction to vanilmandelic acid (VMA) facilitates urinary excretion. For the clinician, measurement of normetanephrine provides an index of norepinephrine released during sympathetic nervous system activity, whereas metanephrine concentration provides an indication of adrenal medullary metabolism of epinephrine prior to its discharge into the circulation. Plasma epinephrine concentration is the preferable index of adrenal medullary epinephrine discharge. Pheochromocytomas, with their protean clinical manifestations, may be diagnostic challenges, but assay of metanephrines, especially plasma metanephrine, can be particularly helpful in diagnosis. These COMT metabolites may also help in elucidation of still undiscovered genetic and acquired disorders of catecholamine metabolism.

Animals↗
PubMed2004

Pyridoxine 5'-phosphate oxidase is a candidate gene responsible for hypertension in Dahl-S rats.

To identify candidate genes responsible for hypertension in Dahl salt-sensitive rats (Dahl-S), an oligonucleotide microarray analysis was performed to find differentially expressed genes in kidneys of Dahl-S and Lewis rats. We obtained 101 F2 male rats from Dahl-S and Lewis rats and performed precise measurements of blood pressure (BP) and heart rate by telemetric monitoring at 14 weeks of age after 9 weeks of salt-loading. The correlation analysis between genotypes of differentially expressed genes and BP in F2 rats indicated that pyridoxine 5'-phosphate oxidase (Pnpo) and catecholamine-O-methyltransferease (Comt) showed a highly significant association with BP. However, in the case of Comt, the Dahl-S genotype correlated with low BP. Short/branched chain acyl-CoA dehydrogenase and Sah also showed a significant association with systolic blood pressure. The present study provided evidence that Pnpo is a candidate gene responsible for hypertension in Dahl-S rats.

Alcohol Oxidoreductases↗
PubMed2005

Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction.

BACKGROUND: Recent evidence documents that cannabis use by young people is a modest statistical risk factor for psychotic symptoms in adulthood, such as hallucinations and delusions, as well as clinically significant schizophrenia. The vast majority of cannabis users do not develop psychosis, however, prompting us to hypothesize that some people are genetically vulnerable to the deleterious effects of cannabis. METHODS: In a longitudinal study of a representative birth cohort followed to adulthood, we tested why cannabis use is associated with the emergence of psychosis in a minority of users, but not in others. RESULTS: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele. CONCLUSIONS: These findings provide evidence of a gene x environment interaction and suggest that a role of some susceptibility genes is to influence vulnerability to environmental pathogens.

Adolescent↗
PubMed2004

A colormetric assay for catechol-O-methyltransferase.

A series of catechol diazo dyes were synthesized and tested as substrates for the enzyme catechol-O-methyltransferase (COMT) with the aim of developing a sensitive HPLC assay method using visible wavelength light detection. A method was developed which allowed for the determination of the two regioisomeric methylated products of the COMT catalyzed reaction of 4-[(3,4-dihydroxyphenyl)azo]benzenesulfonate with S-adenosylmethionine (AdoMet). Separation of the assay components was achieved by reverse phase chromatography using an isocratic mobile phase. No pre-preparation of the assay samples was required.

Azo Compounds↗
PubMed2005

Synthesis and evaluation of bifunctional nitrocatechol inhibitors of pig liver catechol-O-methyltransferase.

Bifunctional compounds were tested in vitro as potential inhibitors of pig liver catechol-O-methyltransferase (COMT) with respect to the catechol substrate 4-[(3,4-dihydroxyphenyl)azo]benzenesulfonate. The bifunctional compounds were a composite of either two nitrocatechols or one nitrocatechol and one phenol, linked by amide bonds to a spacer unit comprising two to five methylene groups. The unsymmetrical compounds N-[2-(4-hydroxybenzoylamine)ethyl]-3,4-dihydroxy-5-nitrobenzamide], N-[3-(4-hydroxybenzoyl-amine)propyl]-3,4-dihydroxy-5-nitrobenzamide] and N-[5-(4-hydroxybenzoylamine)pentyl]-3,4-dihydroxy-5-nitrobenzamide] demonstrated strong inhibitory action against COMT with K(i) values in the 100 nM range. In comparison, the monofunctional nitrocatechol analogues of these compounds had K(i) values that were significantly higher.

Animals↗
PubMed2006

Identification of first candidate genes for creativity: a pilot study.

Studies from behavioral genetics have demonstrated the high heritability of intelligence. However, the endeavor to detect the genes forming the molecular basis of intelligence has been rather unsuccessful until now. Pharmacological studies have demonstrated the influence of the dopaminergic (DA) and the serotonergic (5-HT) system on subcomponents of cognitive functioning, and first studies from molecular genetics have demonstrated that genes related to the DA metabolism are associated with mental abilities. However, candidate genes for creativity have not been identified so far. Therefore, the influence of the catechol-O-methyltransferase (locus: COMT VAL158MET) gene and the dopamine D2 receptor gene (locus: DRD2 TAQ IA) on creativity was tested in addition to a serotonergic gene, TPH1 (locus: TPH-A779C), in a sample of N = 92 healthy Caucasian subjects while controlling for intelligence. Results showed that the DRD2 gene and the TPH gene were both associated with total creativity, explaining 9% of the variance, while COMT was not related to creativity at all. With respect to the subcomponents, the A1+ allele of DRD2 was related to higher verbal creativity as compared to the A1- allele, and carriers of the A allele of TPH1 showed significantly higher scores in figural and in numeric creativity, indicating that the two gene loci discriminate between higher cortical functions according to the organization of cognitive functions in the respective hemispheres.

Adolescent↗
PubMed2004

Polymorphisms of estrogen-metabolizing genes and risk of hepatocellular carcinoma in Taiwan females.

Estrogen has been related to the development of hepatocellular carcinoma (HCC). In this molecular epidemiological study, we used logistic regression to compare the genotype frequencies of estrogen-metabolizing genes that are involved in estrogen biogenesis (CYP17), hydroxylation (CYP1A1) and inactivation of the reactive metabolites (catechol-O-methyltransferase, COMT) in HCC patients and control subjects, and determined their relationship with the risk of female HCC. The heterozygous or homozygous variants of high activity CYP17 (A2), high inducibility CYP1A1(m1), and low activity COMT (L) alleles were considered as high-risk genotypes. We found that the risk of HCC was elevated in women harboring either heterozygous or homozygous variants of the CYP1A1 gene and the respective OR (and 95% confidence interval) were 6.61 (1.35, 32.43) and 12.00 (1.73, 83.46). Moreover, we found that the risk of HCC was increased in the female subjects harboring higher numbers of high-risk genotypes, but not in male subjects. The OR for female HCC associated with two putative high-risk genotypes was 12.63 (1.50, 106.37), and the OR for three putative high-risk genotypes was 16.67 (1.82, 152.77). These findings strongly suggest that estrogen play a critical role in female hepatocarcinogenesis.

Carcinoma, Hepatocellular↗
PubMed2005

Genetic mechanisms of psychosis: in vivo and postmortem genomics.

BACKGROUND: The Clinical Brain Disorders Branch Sibling Study data set was initiated in 1996 to examine genetic associations and to identify biological traits associated with susceptibility gene effects. Characterizing genes--and translating their effects on brain development and function--has potential implications for improving the prevention and treatment of schizophrenia. OBJECTIVE: The goal of this article was to discuss the relationship between genetic variation and schizophrenia using in vivo and postmortem genomics. CONCLUSIONS: Over the past 2 years, several specific genes have been convincingly associated with schizophrenia risk in a number of populations around the world. Some of the genes that have been studied more extensively include: catechol O-methyltransferase (COMT) (chromosome 22q), dysbindin-1 (chromosome 6p), neuregulin 1 (chromosome 8p), metabotropic glutamate receptor 3 (GRM-3) (chromosome 7q), glutamate decarboxylase 1 (chromosome 2q), and disrupted-in-schizophrenia 1 (DISC1) (chromosome 1q). A functional polymorphism in the COMT gene, which affects prefrontal cortical function by changing dopamine signaling in the prefrontal cortex, has been studied extensively. This gene impacts the regulation of dopamine neuronal activity in the brainstem, which is associated with psychosis. GRM-3 shows similar results on prefrontal function; in postmortem tissue, it has an effect on expression of various glutamate synaptic markers. DISC1 affects hippocampal anatomy and function, whereas dysbindin-1 appears to be a general cognitive capacity gene that is underexpressed in the schizophrenic cortex. Data suggest that these susceptibility genes influence the cortical information processing which characterizes the schizophrenic phenotype. These data add to the evidence that such genes contribute to the pathophysiology of schizophrenia and provide insights into their mechanisms. Thus, genetic variation and its influence on the biological processes underlying schizophrenia may be key to developing future prevention strategies and new treatments.

Carrier Proteins↗