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PubMed1975

Activity of catecholamine degrading enzymes in rat adrenal medulla and cortex after acute and repeated stress.

The activity of catecholamine degrading enzymes (catechol-O-methyltransferase--COMT and monoamine oxidase--MAO) in separated adrenal cortex and medulla was measured in rats stressed by a singel or repeated immobilization. In controls, the activity of both enzymes was higher in adrenal cortex than in adrenal medulla. After stress, the activity of COMT in adrenal cortex was significantly decreased, while that in adrenal medulla was significantly increased. Moreover, the animals repeatedly immobilized showed lower COMT activity in both parts of adrenals when compared to first time stressed rats. The activity of MAO was not remarkably changed, but was increased only in adrenal medulla when expressed per mg protein, the decrease of which resulted from acute stress. It was concluded that the findings of changed activity of catecholamine degrading enzymes, namely a decreased activity of COMT in both adrenal cortex and medulla in repeatedly stressed rats, might show a possible participation of these enzymes in increased catecholamine content in adrenals of repeatedly stressed animals.

Adrenal Cortex↗

PubMed2002

Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer.

Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer. From a population-based study of ovarian cancer, we analyzed DNA from a total of 480 cases and controls. PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT). Digestion of the PCR products was performed. Genotypes identified by gel electrophoresis were assigned as homozygous wild type (WW), heterozygous variant (Wv), and homozygous variant (vv). Frequencies were compared using chi(2) or Fisher's exact tests. Logistic regression was used to calculate crude and adjusted relative risks (RRs) for ovarian cancer associated with possession of any variant allele overall, and within demographic, weight, and smoking history categories, and by histological subtype of ovarian cancer. A portion (68.9%) of cases either carried or was homozygous for the A2 variant of CYP17 compared with 53.9% of controls, for a RR (and 95% confidence interval) of 1.86 (1.26, 2.75; P = 0.003), adjusted for age, parity, oral contraceptive use, site of study, and family history of breast or ovarian cancer. The increased risk was most apparent for women >50 and women with invasive serous cancers. A portion (71.9%) of cases either carried or was homozygous for the Val/Met variant of COMT, compared with 76.9% of controls (P = 0.27). Although the inverse association of ovarian cancer with possession of a Val/Met variant was not significant overall, it was for mucinous tumors of the ovary, with an adjusted RR of 0.28 (0.13, 0.61; P = 0.0012). Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors. Confirmation in other populations and further exploration of potential pathogenetic mechanisms will be necessary.

Alleles↗

PubMed2003

[Association analysis between attention-deficit hyperactivity disorder and Val158Met polymorphism of catechol-O-methyltransferase gene].

OBJECTIVE: To investigate the association between attention-deficit hyperactivity disorder (ADHD) in Han Chinese children and Val158Met polymorphism of catechol-O-methyltransferase (COMT) gene caused by the missense mutation of G158A in exon 4. METHODS: By using polymerase chain reaction-restriction fragment length polymorphisms the Val158Met polymorphism of COMT gene was tested in 117 children with the diagnosis of ADHD as defined by DSM-IV and in 105 healthy controls living in Shanghai. RESULTS: The frequencies of A allele were 25.21% and 23.81% in the ADHD group and the health controls respectively, which showed no significant difference between the two groups (Chi2=0.5197, P>0.05). There was also no significant difference in the distribution of all genotypes of COMT gene between the ADHD patients and the controls (P>0.05). CONCLUSION: It was suggested that for the Han Chinese children with ADHD in this study, there was no association between ADHD and Val158Met polymorphism of COMT gene.

Adolescent↗

PubMed2005

Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma.

Estrogens are a known risk factor for breast cancer. Studies indicate that initiation of breast cancer may occur by metabolism of estrogens to form abnormally high levels of catechol estrogen-3,4-quinones, which can then react with DNA to form depurinating adducts and, subsequently, induce mutations that lead to cancer. Among the key enzymes metabolizing estrogens are two activating enzymes: cytochrome P450 (CYP)19 (aromatase), which converts androgens to estrogens, and CYP1B1, which converts estrogens predominantly to the 4-catechol estrogens that are further oxidized to catechol estrogen-3,4-quinones. Formation of the quinones is prevented by methylation of the 4-catechol estrogens by the enzyme, catechol-O-methyltransferase (COMT). In addition, catechol estrogen quinones can be reduced back to catechol estrogens by NADPH quinone oxidoreductase 1 (NQO1) and/or are coupled with glutathione, preventing reaction with DNA. Thus, COMT and NQO1 are key deactivating enzymes. In this initial study, we examined whether the expression of these four critical estrogen activating/deactivating enzymes is altered in breast cancer. Control breast tissue was obtained from four women who underwent reduction mammoplasty. Breast tissues from five women with breast carcinoma, who underwent mastectomy, were used as cases. The level of expression of CYP19, CYP1B1, COMT and NQO1 mRNAs was quantified from total RNA using a real time RT-PCR method in an ABI PRISM 7700 sequence detection system. The control breast tissues showed lower expression of the activating enzymes, CYP19 and CYP1B1, and higher expression of the deactivating enzymes, COMT and NQO1, compared to the cases. In the cases, the reverse pattern was observed: greater expression of activating enzymes and lower expression of deactivating enzymes. Thus, in women with breast cancer, estrogen metabolism may be related to altered expression of multiple genes. These unbalances appear to be instrumental in causing excessive formation of catechol estrogen quinones that, by reacting with DNA, initiate the series of events leading to breast cancer.

Adipose Tissue↗

PubMed2006

[The relationship between gene polymorphism of catechol-O-methyltransferase and survival of oral pesticides suicide attempters].

OBJECTIVE: To understand the association between gene polymorphism of catechol-O-methyltransferase (COMT) and suicide attempters taking pesticides orally and to provide a scientific base for the prevention of suicidal behavior. METHODS: 107 suicide attempters taking pesticides orally were collected from The People's Hospitals in Shandong Province from January 2003 through December 2003. The informations of all the attempters were obtained and 1 ml whole blood from of them were collected. Molecular biological techniques were used to study the gene type of each subject. RESULTS: In the 107 suicide attempters, the ratio of male to female is 1:1.55; 67.3% of them were in age range of 20 - 44 years; 59.8% of them had education level of elementary school or lower. 13 suicide attempters (12.1% of all the attempters) had psychiatric disorders. 84 suicide attempters (78.5% of all the attempters) had affective conflicts with others in the recent year. 30 suicide attempters (28.0% of the suicide attempters) had impulsive behavior. Multivariate logistic regression model analysis showed that suicide impulsion and psychiatric disorders were significantly associated with COMT Val/Val, their OR values were 0.052 (95% CI: 0.006 - 0.437), 2.917 (95% CI: 1.097 - 7.760). CONCLUSION: In this population, more attention should be paid to young female people with psychiatric disorders or having affective conflicts with others in the recent year so as to prevent suicide. This study supported that there is heterogeneity in COMT gene in suicide attempters and there is interaction between COMT Val/Val and suicide impulsion and psychiatric disorders.

Adolescent↗

PubMed2006

[Dopamine system genes interaction and neurocognitive traits in patients with schizophrenia, their relatives and healthy controls from general population].

To elucidate main effects of dopamine receptor D4 (DRD4) and cathecol-O-methyltransferase (COMT) genes as well as their interaction effect on neurocognitive traits, DRD4 gene polymorphisms (-809G/A, -521C/T) and the COMT gene Val158Met polymorphism, along with characteristics of verbal memory, executive functions and peculiarities of associative processes, have been studied in 150 patients with schizophrenia, 83 their relatives and 118 mentally healthy subjects without positive family history of psychosis. A main effect of -521C/T polymorphism and DRD4 (-521C/T).Vall58Met polymorphisms interaction were found for verbal fluency, carriers of the Val/Val+CC and the Met/Met+TT genotypes performing better on this task as compared to other genotypes. An interaction DRD4 (-521C/T).Val158Met effect on originality of speech associations was observed in the combined group of unaffected individuals (relatives and controls), with lower scores of the trait in those with the Met/Met+CC genotype. The COMT-DRD4 (-809G/A) interaction effect on working memory was demonstrated for patients and unaffected individuals, homozygotes for the Val and the G alleles having the best results and homozygotes for the Met and the A alleles--the worst ones. The data obtained suggest the relationship of DRD4 and COMT genes with different characteristics of executive functions but not with verbal memory.

Adult↗

PubMedDate not supplied

[Association of functional genes polymorphisms of key enzymes in the metabolism of biogenic amines with paranoid schizophrenia susceptibility and the influence of these polymorphisms on PANSS results in antipsychotic treatment].

AIM: The genetic components of the schizophrenia susceptibility are calculated as being 50%. We evaluated the frequency of alleles and genotypes of COMT and MAO-A genes polymorphisms in patients with schizophrenia and in the healthy population. We searched for the associations between genotypes and PANSS results among patients in a three month antipsychotic therapy. METHOD: The study comprised 72 unrelated patients who met ICD-10 criteria for schizophrenia, and 187 unrelated healthy controls. The analysis of COMT and MAO-A genes polymorphisms were performed using the polymerase chain reaction technique (RFLP-restriction fragments length polymorphism and VNTR-variable number tandem repeats). The severity of psychopathological symptoms was measured by the PANSS (Positive and Negative Schizophrenia Scale). RESULTS: We did not find an association between the genotype of COMT and MAO-A genes polymorphisms and schizophrenia. We found statistically significant different allele distribution in MAO gene polymorphism: alleles with three tandem repeats in the promoter region were more frequent among females with schizophrenia. We did not find any association between the genotype of COMT and MAO-A genes polymorphisms and PANSS results in any time periods. Due to a small number of patients in this study the obtained results should be regarded as preliminary.

Adult↗

PubMed1985

Comparative study of mechanical responses of hepatic arteries strips to adrenalin in presence of pyridoxine and pyridoxal-5'-phosphate.

Since it is known that PLP inhibits "in vitro" the COMT much more than pyridoxine; the influence of pyridoxine to the response of hepatic arteries isolated to AD has been compared to the influence of PLP to the same arteries. As for as the increase in percent is concerned, the result is that PLP gives rise to a greater answer to AD than pyridoxine. Such effects lacked when pyrogallol, a powerful COMT inhibitor, was present. Taking such results as a basis, it has been concluded that the mechanism of action of pyridoxine and of PLP was metabolic and that it was based on the COMT inhibition, even for the hepatic arteries. It was been also deduced that the higher efficiency of PLP compared to the pyridoxine's was due to its greater capacity to inhibit the COMT.

Animals↗

PubMed1984

Hypothalamic nuclei catechol-O-methyl-transferase and the process of brain sexual differentiation.

The present review focuses on some aspects of the function of catechol-O-methyl-transferase (COMT) in the hypothalamic control of gonadotrophin release by the pituitary gland. The in situ influence of a catecholestrogen (2 OH.E2) on the amount of COMT in the hypothalamic nuclei involved in such control as well as on the process of sexual differentiation of the brain is also discussed. Catecholestrogens do not play a significant role in the induction of sexual differentiation and the observed action is probably a pharmacological one. It is difficult to understand why a substance whose structure is so closely related to that of estrogen is so much less active. Most probably the estrogen receptor in the cytosol at this stage of development is not able to recognize the catecholestrogen. Since catecholestrogens are not true virilizing substances they may be used to assess the critical levels of enzymes which are required to determine the sexual pattern of hypothalamic activity. The fact that the extent of the changes in COMT content of the hypothalamus is related to the amount of hormone used to induce virilization strengthens the view that sexual differentiation is the consequence of a genomic change during the critical period, which will induce an enzymatic pattern characteristic of the male acyclic pattern of gonadotrophin control. The finding that the COMT content of the hippocampus also changes in parallel to sexual differentiation leads us to speculate that perhaps sexual behavior may also be differentiated in the same way.

Animals↗

PubMed1978

Studies on the monoamine oxidase and catechol-O-methyltransferase of the rat cerebral microvessels.

The rat cerebral microvessels were isolated and assayed both for monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT) activities. Cerebral microvessels and brain filtrate were found to contain both forms (A & B) of MAO. On a per mg protein basis, the cerebral microvessels contained the greatest activity of MAO and COMT than that of brain filtrate and mesenteric artery. Chemical sympathectomy using 6-hydroxydopamine neither decreased total MAO activity, nor the A form of the enzyme, nor did it have any effect on COMT activity in the brain microvessels. These results suggest that COMT and both forms of MAO in the rat brain microvessels are extraneuronal in origin.

Animals↗

PubMed1993

Influence of estradiol-17 beta and progesterone on catechol-O-methyltransferase and monoamine oxidase activities in uterine artery and myometrium of ovariectomized pigs.

Activities of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) were determined in uterine artery and myometrium of uterine horn in ovariectomized pigs. It was considered that in uterine artery COMT activity increased after estradiol (E2) by 91.4% (p < 0.01), after progesterone (P) by 194.3% (p < 0.001) and after simultaneous administration of E2+P by 109.3% (p < 0.01). In myometrium this activity rose after E2 by 56.3% (p < 0.01) and after simultaneous using E2+P rose by 64.3% (p < 0.01) in relation to COMT activity determined in ovariectomized animals (Control). MAO activity in uterine artery decreased by 55.4% after P (p < 0.01) and also after simultaneous administration of E2+P by 58.7% (p < 0.01). In myometrium this activity decreased after E2 by 35.5% (p < 0.05) and after E2+P by 51.2% (p < 0.01), whereas increased after P by 30.6% (p < 0.05) in relation to MAO activity determined in control. Changes of MAO and COMT activities after E or P administration in ovariectomized animals denote that the hormones can participate in regulation of NA concentration in adrenergic synapse by the way of qualitative and quantitative changes of this mediator decomposition rate. E2 causes decrease of NA concentration in adrenergic synapse of uterine artery, whereas P operates the opposite way, as increaser.

Animals↗

PubMed1977

The effect of monoamine oxidase and catechol O-methyltransferase inhibitors on the accumulation and metabolism of [l-3H] norepinephrine by the adventitia and media of rabbit aorta.

The effects of catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) inhibitors on the accumulation and metabolism of [l-3H] norepinephrine ([l-3H]NE) were studied in the isolated adventitia and media of rabbit aorta. The COMT inhibitors produced a greater inhibition of O-methylation in the isolated media than in the isolated adventitia. In addition, exposure to these drugs was associated with an increased level of [l-3H]NE and increased formation of the catechol deaminated metabolites by the isolated media but not by the isolated adventitia. The effects of these drugs on the balance of the oxidized vs. reduced forms of the deaminated metabolites was interpreted to mean that 3-methoxy-4-hydroxyphenylethylglycol is formed from normetanephrine rather than from 3,4-dihydroxyphenylethylglycol whereas 3-methoxy-4-hydroxymandelic acid is formed from 3,4-dihydroxymandelic acid. 3,4-Dihydroxyphenylethylglycol does not seem to serve as a substrate for 3-methoxy-4-hydroxyphenylethylglycol becuase it rapidly passes out of the tissue after it is formed. Parglyline and iproniazid markedly decreased deamination of [l-3H]NE and increased the tissue level of [l-3H]NE. However, these drugs produced little if any compensatory increase in O-methylation of [l-3H]NE. The effects of these drugs are compatible with the hypothesis that adrenergic nerves contain MAO and vascular smooth muscle contains MAO and COMT. Harmaline seemed to block both MAO and COMT. Based on the effects of clorgyline and deprenyl and the other MAO inhibitors tested, the isolated adventitia seems to contain primarily type A MAO and the isolated media seems to contain primarily type B MAO.

Animals↗

PubMedDate not supplied

Cathechol-O-methyl transferase activity in the individual human platelet populations.

COMT activity is present in many animal tissues, but there is no evidence on the presence or the functional role of COMT activity in platelets. The present work reports the results obtained on COMT activity in the individual platelet populations separated by a discontinuous sucrose density gradient. In the young platelet populations the activity is remarkable higher than in the old and light populations. Low values of COMT activity in the old platelets may reflect platelet senescence.

Blood Platelets↗

PubMed1998

NSF function in neurotransmitter release involves rearrangement of the SNARE complex downstream of synaptic vesicle docking.

The SNARE hypothesis has been proposed to explain both constitutive and regulated vesicular transport in eukaryotic cells, including release of neurotransmitter at synapses. According to this model, a vesicle targeting/docking complex consisting primarily of vesicle- and target-membrane proteins, known as SNAREs, serves as a receptor for the cytosolic N-ethylmaleimide-sensitive fusion protein (NSF). NSF-dependent hydrolysis of ATP disassembles the SNARE complex in a step postulated to initiate membrane fusion. While features of this model remain tenable, recent studies have challenged fundamental aspects of the SNARE hypothesis, indicating that further analysis of these components is needed to fully understand their roles in neurotransmitter release. We have addressed this issue by using the temperature-sensitive Drosophila NSF mutant comatose (comt) to study the function of NSF in neurotransmitter release in vivo. Synaptic electrophysiology and ultrastructure in comt mutants have recently defined a role for NSF after docking in the priming of synaptic vesicles for fast calcium-triggered fusion. Here we report that an SDS-resistant neural SNARE complex, composed of the SNARE polypeptides syntaxin, n-synaptobrevin, and SNAP-25, accumulates in comt mutants at restrictive temperature. Subcellular fractionation experiments indicate that these SNARE complexes are distributed predominantly in fractions containing plasma membrane and docked synaptic vesicles. Together with the electrophysiological and ultrastructural analyses of comt mutants, these results indicate that NSF functions to disassemble or otherwise rearrange a SNARE complex after vesicle docking and that this rearrangement is required to maintain the readily releasable pool of synaptic vesicles.

Adenosine Triphosphatases↗

PubMed2026

Environmentally relevant concentrations of DCOIT impaired lifespan and healthspan in Caenorhabditis elegans.

DCOIT (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one) is an antifouling biocide widely used as an alternative to organotin compounds. While previous studies had focused on its effects on energy production, endocrine disruption, and lipid metabolism, its impact on aging and underlying mechanisms remained unclear. Here, we demonstrated that environmentally relevant concentrations of DCOIT (37, 370 and 3700 ng/L) significantly impaired both lifespan and healthspan in Caenorhabditis elegans. RNA-seq and validation assays revealed that DCOIT upregulated comt-4, a key gene in dopamine metabolism, leading to dopamine depletion and subsequent induction of oxidative stress. This redox imbalance critically contributed to accelerated aging phenotypes. Importantly, both genetic (comt-4 RNAi) and pharmacological (opicapone) interventions restored dopamine levels, alleviated oxidative stress, and reversed DCOIT-induced aging deficits. Our study established the comt-4/dopamine/oxidative stress axis as a central mechanism in DCOIT toxicity, suggesting dopamine modulation as a potential countermeasure against environmental toxicant-induced aging.

Animals↗

PubMed1978

Activities of types A and B MAO and catechol-o-methyltransferase in blood cells and skin fibroblasts of normal and chronic schizophrenic subjects.

We assayed activities of monoamine oxidase (MAO) type B in blood platelets and type A (and B) in fibroblasts cultured from punch biopsy specimens of skin, as well as of catechol-O-methyltransferase (COMT) in erythrocytes and fibroblasts. Fibroblasts contained moderate amounts of both forms of MAO (types A and B) found in human brain and large amounts of COMT activity. Activities of both enzymes correlated poorly between fibroblasts and blood cells. Comparing carefully diagnosed chronic schizophrenics with age-matched normal young men, we found no difference in these biochemical variables, nor could we distinguish patients with paranoid symptoms. In contrast, we confirmed markedly lower MAO activities in platelet samples from chronic patients provided by colleagues at the National Institute of Mental Health. Results concerning MAO and COMT activities are now sufficiently inconsistently characteristic of schizophrenics as to question their clinical applicability and to indicate a need for further critical evaluation, with special attention to diagnosis, matching of subjects, and effects of possible spurious environmental variables.

Adolescent↗

PubMed2006

Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.

CONTEXT: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking. DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes. RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility. CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

Adult↗

PubMed1999

Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder is the most common child psychiatric disorder with a prevalence rate in an Ontario study of 9% in boys and 3% in girls [Szatmari et al., 1989]. This disorder is characterized by problems in the areas of attention, overactivity, impulse control, and distractibility. Strong evidence for a genetic component has been provided from twin, family, and adoption studies [for review see Levy et al., 1998] and molecular genetic studies are in progress by several groups worldwide. The Catechol-O-Methyltransferase (COMT) gene is an interesting candidate for ADHD as it is involved in the breakdown of dopamine and norepinephrine, neurotransmitters strongly implicated in the etiology of ADHD. In addition, children with velo-cardio-facial syndrome, a deletion syndrome of the chromosomal region 22q11 where the COMT gene has been localized, often have symptoms of ADHD suggesting this gene may have an etiological role in ADHD. In this study, we have tested for linkage in ADHD families using the functional polymorphism at codon 158 that determines COMT activity [Lachman et al., 1996] and analyzed the data with the transmission disequilibrium test (TDT). A total of 77 nuclear families collected from Toronto were genotyped. We find no evidence for linkage of this polymorphism and ADHD in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:710-713, 1999.

Adolescent↗