Disease relevance of Comt

• Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes [1].
• The kinetic parameters of monoamine oxidase (MAO; E.C 1.4.3.4) and catechol-O-methyltransferase (COMT; EC 2.1.1.6) were evaluated in extracts of adrenergic and non-adrenergic mouse neuroblastoma cells and in rat glioma cells [2].
• Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3',4'-dihydroxybenzyl)-1,2,3, 4-tetrahydroisoquinoline [3].
• However, hyperthermia was induced even at the lowest methamphetamine dose, the COMT-deficient mice being most sensitive [4].
• Furthermore, comparison of the contents of these melanin-related metabolites between highly pigmented and less pigmented B16 melanomas suggests that 5-S-CD may be accumulated in pigmented melanoma by virtue of binding to melanin and that catechol-O-methyltransferase (COMT) may play a regulatory role in pigmentation [5].

Psychiatry related information on Comt

• Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice [6].
• Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome [6].
• METHODS: We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice [7].

High impact information on Comt

• By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced [6].
• The conserved linkage between human chromosome 22 and mouse chromosome 16 includes two closely linked loci, Comt and IgI-1 [8].
• Monoamine oxidase, catechol-O-methyltransferase, and norepinephrine levels in mice with the hereditary obese-hyperglycemic syndrome [9].
• Inherited differences of brain and erythrocyte soluble catechol-o-methyltransferase activity in two mouse strains [10].
• The significantly lower COMT activity in the hamster liver and red blood cells suggests that under chronic estrogen treatment at high doses, the concentration of catechol estrogens in these tissues may exceed the capacity of COMT to effectively catalyse their O-methylation into inactive metabolites [11].

Chemical compound and disease context of Comt

• Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease [12].
• These results show that peripherally acting entacapone, unlike the brain-penetrating tolcapone, is a safe catechol-O-methyltransferase inhibitor for the treatment of Parkinson's disease, since it does not interfere with mitochondrial energy metabolism at pharmacologically effective concentrations [13].
• Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson's disease, does not impair mitochondrial energy production [13].
• Catechol-O-methyltransferase decreases levodopa toxicity in vitro [14].
• In this study we examine whether the use of COMT inhibitor, which reduced the levels of 3-O-methyldopa, affect levodopa toxicity [14].

Biological context of Comt

• Finally, we have assigned the mouse TrxR2 gene to chromosome 16 mapping at 11.2 cM from the centromer and linked to the catechol-o-methyltransferase (comt) gene [15].
• CONCLUSIONS: Mice with reduced or absent COMT activity have altered metabolism of catecholamines and are unable to increase renal DA activity and produce normal natriuresis in response to acute sodium loading [16].
• Adrenal dopamine-beta-hydroxylase was also inhibited by NLCAs [3'O-methylnorlaudanosolinecarboxylic acid (MNLCA) Kj = 1.2 x 10(-4) M] and NLCA is a competitive inhibitor of norepinephrine methylation by hepatic catechol-O-methyltransferase (NLCA Kj = 5.6 x 10(-5) M) [17].
• Lack of increased oxidative stress in catechol-O-methyltransferase (COMT)-deficient mice [4].
• Macroscopic pathology and histopathology revealed no abnormal findings in any COMT genotype [18].

Anatomical context of Comt

• Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake(1), followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake(2), followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO) [19].
• However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid [7].
• In red blood cells, the level of COMT activity is 4- and 12-fold lower in the hamster compared to mouse and rat, respectively [11].
• In contrast, the COMT activity in the forestomach and small intestinal mucosa of the mouse was increased with increasing concentration of dietary BHA [20].
• Assignment of the catechol-O-methyltransferase gene to human chromosome 22 in somatic cell hybrids [21].

Associations of Comt with chemical compounds

• Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites [1].
• In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations [1].
• Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites [1].
• Inhibition of monoamine oxidases (MAOs) by pargyline, but not of catechol-O-methyltransferase (COMT) by tolcapone, slowed down DA elimination in knockout mice [22].
• In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine [7].

Other interactions of Comt

• The activities of three other catecholaminergic enzymes, DOPA decarboxylase, catechol O-methyltransferase, and monoamine oxidase, were generally elevated in Ts16 brain, as were their daily increments [23].
• Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly [7].
• Ado + Hcy treatment resulted in decreased activities of catechol-O-methyltransferase, histamine-N-methyltransferase, and AdoHcy hydrolase in vitro [24].
• The results demonstrated that curcumin had no effect on the catalytic activities of ovarian aromatase, hepatic catechol-O-methyltransferase or hepatic UDP-glucuronosyltransferase [25].

Analytical, diagnostic and therapeutic context of Comt

• In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal [1].
• In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed [26].
• Entacapone, a novel mainly peripherally acting catechol-O-methyltransferase inhibitor used in the treatment of Parkinson's disease, was evaluated for its possible uncoupling activity in cell culture, in rat liver mitochondria, and in isolated guinea-pig heart [13].
• Following the administration of nontoxic doses of EGCG and ECG, aromatase (CYP19), CYP3A, CYP1A, and catechol O-methyltransferase (COMT) were measured [27].
• The product of the COMT reaction has been characterized by thin-layer chromatography [28].

References