Showing papers on "Catechol-O-methyl transferase published in 2014"

Common Variants in Psychiatric Risk Genes Predict Brain Structure at Birth

Abstract: Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ɛ3ɛ4 vs. ɛ3ɛ3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensorbased morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk.

Medicinal chemistry of catechol O-methyltransferase (COMT) inhibitors and their therapeutic utility.

Abstract: Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.

Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain

Abstract: SUMMARYGenetic interactions between catechol-O-methyltransferase val158met with estrogen receptor 1 and guanosine-5-triphosphate cyclohydrolase 1 polymorphisms modulate downstream catechol-O-methyltransferase effects, including enzymatic activity, pain sensitivity, disease risk, and psychological pr

Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans

Abstract: Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls.

Abstract: Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.

Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders

Abstract: Catechol-O-methyltransferase (COMT) is of great importance in pharmacology because it catalyzes the metabolism (methylation) of endogenous and xenobiotic catechols. Moreover, inhibition of COMT is the drug target in the management of central nervous system (CNS) disorders such as Parkinson's disease due to its role in regulation of the dopamine level in the brain. The X-ray crystal structures for COMT have been available since 1994. The active sites for cofactor and substrate/inhibitor binding are well resolved to an atomic level, providing valuable insights into the catalytic mechanisms as well as the role of magnesium ions in catalysis. Determination of how the substrates/inhibitors bind to the protein leads to a structure-based approach that has resulted in potent and selective inhibitors. This review focuses on the design of two types of inhibitors (nitrocatechol-type and bisubstrate inhibitors) for COMT using the protein structures.

β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines

Abstract: Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2- and β3-adrenergic receptors (β2ARs and β3ARs). Here we investigated molecules downstream of β2- and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2- and β3AR stimulation, we hypothesized that nitric oxide (NO) and proinflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 in the presence or absence of the β2AR antagonist ICI118,551+β3AR antagonist SR59320A. We also assessed whether the NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) and cytokine-neutralizing antibodies block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) in a β2- and β3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked the development of COMT-dependent pain. Finally, we found that NO influences TNFα, IL-1β, IL-6, and CCL2 levels, whereas TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2- and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2- and β3ARs, NO, and proinflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.

Catechol-o-methyltransferase polymorphisms predict opioid consumption in postoperative pain.

Abstract: BACKGROUND:Previous studies have associated the catechol-O-methyltransferase (COMT) enzyme rs4680 polymorphism with opioid consumption in the treatment of chronic cancer pain. In this study, we evaluated the association between COMT rs4680 and rs4818 polymorphisms and opioid consumption in the acute

Factors affecting cognitive remediation response in schizophrenia: The role of COMT gene and antipsychotic treatment

Abstract: Cognitive remediation is the best available tool to treat cognitive deficits in schizophrenia and has evidence of biological validity; however results are still heterogeneous and significant predictors are lacking. Previous studies showed that cognitive remediation is able to induce changes in PFC function and dopaminergic transmission and thus the study of possible sources of variability at these levels (i.e. antipsychotic treatments and genetic variability) might help to gain a deeper understanding of neurobiological correlates and translate into optimization and personalization of interventions. In the present study, we analyzed the interaction between pharmacological treatment (clozapine vs typical/atypical D2 blockers) and COMT rs4680 polymorphism on cognitive changes after cognitive remediation therapy, in a sample of 98 clinically stabilized patients with schizophrenia. The General Linear Model showed a significant interaction of pharmacological treatment and COMT polymorphism on the improvement in “Symbol Coding” subtest, a global measure of speed of processing. Post-hoc analysis revealed a significant difference between COMT genotypes, when treated with D2 blockers, with worse results among Val/Val patients. These preliminary results suggest that genetic variability, influencing prefrontal dopamine, might affect individual capacity to improve with different patterns, depending on antipsychotic treatment.

Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.

Abstract: Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy individuals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippocampus-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype.

Comprehensive interrogation of CpG island methylation in the gene encoding COMT, a key estrogen and catecholamine regulator

Abstract: The catechol-O-methyltransferase (COMT) enzyme has been widely studied due to its multiple roles in neurological functioning, estrogen biology, and methylation metabolic pathways. Numerous studies have investigated variation in the large COMT gene, with the majority focusing on single nucleotide polymorphisms (SNPs). This body of work has linked COMT genetic variation with a vast array of conditions, including several neurobehavioral disorders, pain sensitivity, and multiple human cancers. Based on COMT’s numerous biological roles and recent studies suggesting that methylation of the COMT gene impacts COMT gene expression, we comprehensively interrogated methylation in over 200 CpG dinucleotide sequences spanning the length of the COMT gene. Using saliva-derived DNA from a non-clinical sample of human subjects, we tested for associations between COMT CpG methylation and factors reported to interact with COMT genetic effects, including demographic factors and alcohol use. Finally, we tested associations between COMT CpG methylation state and COMT gene expression in breast cancer cell lines. We interrogated >200 CpGs in 13 amplicons spanning the 5’ UTR to the last exon of the CpG dinucleotide-rich COMT gene in n = 48 subjects, n = 11 cell lines and 1 endogenous 18S rRNA control. With the exception of the CpG island in the 5’UTR and 1st exon, all other CpG islands were strongly methylated with typical dynamic ranges between 50-90%. In the saliva samples, methylation of multiple COMT loci was associated with socioeconomic status or ethnicity. We found associations between methylation at numerous loci and genotype at the functional Val 158 Met SNP (rs4680), and most of the correlations between methylation and demographic and alcohol use factors were Val 158 Met allele-specific. Methylation at several of these loci also associated with COMT gene expression in breast cancer cell lines. We report the first comprehensive interrogation of COMT methylation. We corroborate previous findings of variation in COMT methylation with gene expression and the Val 158 Met genotype, and also report novel associations with socioeconomic status (SES) and ethnicity at several methylated loci. These results point to novel mechanisms for COMT regulation, which may have broad therapeutic implications.

Polymorphisms in Catechol-O-Methyltransferase Modify Treatment Effects of Aspirin on Risk of Cardiovascular Disease

Abstract: Objective— Catechol- O -methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. Approach and Results— We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women’s Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51–0.84]; P =0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P =2.4×10 −5 ). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05–3.25]; P =0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39–0.93]; P =0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83–2.70]; P =0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34–0.84]; P =0.006) women. Rs4818 results were similar. Conclusions— Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

Mapping the conformational space accessible to catechol-O-methyltransferase.

Abstract: Methylation catalysed by catechol-O-methyltransferase (COMT) is the main pathway of catechol neurotransmitter deactivation in the prefrontal cortex. Low levels of this class of neurotransmitters are held to be causative of diseases such as schizophrenia, depression and Parkinson's disease. Inhibition of COMT may increase neurotransmitter levels, thus offering a route for treatment. Structure-based drug design hitherto seems to be based on the closed enzyme conformation. Here, a set of apo, semi-holo, holo and Michaelis form crystal structures are described that define the conformational space available to COMT and that include likely intermediates along the catalytic pathway. Domain swaps and sizeable loop movements around the active site testify to the flexibility of this enzyme, rendering COMT a difficult drug target. The low affinity of the co-substrate S-adenosylmethionine and the large conformational changes involved during catalysis highlight significant energetic investment to achieve the closed conformation. Since each conformation of COMT is a bona fide target for inhibitors, other states than the closed conformation may be promising to address. Crystallographic data for an alternative avenue of COMT inhibition, i.e. locking of the apo state by an inhibitor, are presented. The set of COMT structures may prove to be useful for the development of novel classes of inhibitors.

Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype.

Abstract: Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported. This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment. A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol. MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P = 0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients (P = 0.009), but not among males (P = 0.07). Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients.

Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders.

Abstract: Catechol-O-methyltransferase (COMT) is the enzyme which catalyzes the transfer of a methyl group from S-adenosylmethionine to catechols and catecholamines, like the neurotransmitters dopamine, epinephrine and norepinephrine. COMT has implications in many neurological and psychiatric disorders like schizophrenia, Parkinson's disease (PD), bipolar disorders, etc. and therefore, it serves as an important drug target. Since its characterization in 1957, many inhibitors were designed where the first generation inhibitors were found to be highly toxic, short acting and had poor bioavailability. Currently, two of the second generation inhibitors, tolcapone and entacapone have been used for treatment of PD but are associated with various dopaminergic and gastro-intestinal side-effects. There have been several approaches for the design of novel COMT inhibitors with a good and safe therapeutic profile. The focus of this article is to review the current knowledge on COMT and the role of COMT inhibitors in the treatment of neurological disorders. The inhibitors have been classified into six different classes based on the structural framework. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on new generation of inhibitors till date.

Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum.

Abstract: A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val(158) allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val(158) allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val(158) allele, stimulus-response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans.

Catechol-O-methyltransferase Val158Met polymorphism and altered COMT gene expression in the prefrontal cortex of suicide brains

Abstract: Catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamine neurotransmitters within the brain. A functional polymorphism COMT Val158Met has been associated with psychiatric disorders including suicidal behavior. In the present study we examined whether this polymorphism was related to COMT mRNA expression in frontal cortical regions, and whether the expression of COMT differed between depressed suicide victims and psychiatric healthy controls. The Val158Met polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) analysis. The levels of COMT mRNA expression in the frontopolar cortex (FPC; 29 suicides vs. 27 controls) and orbital frontal cortex (OFC; 19 suicides vs. 15 controls) were significantly increased among depressed individuals that died by suicide relative to those of controls, being up-regulated by approximately 60% and 65% in the FPC and OFC, respectively. Furthermore, among individuals with the Met allele (Met/Met and Met/Val genotypes) who died by suicide COMT mRNA expression was elevated relative to that of the nondepressed Met allele carriers. However, significant differences were not detected between suicides (n = 49) and controls (n = 72) with respect to the Val158Met genotypic distribution and allelic frequencies. These results are consistent with the perspective that altered COMT mRNA expression in frontal cortical brain regions might contribute to suicide and/or depression, further supporting the role of dysregulation of catecholaminergic pathway genes in the pathophysiology of suicide behaviors.

Synergistic inhibition of lung cancer cell lines by (−)-epigallocatechin-3-gallate in combination with clinically used nitrocatechol inhibitors of catechol-O-methyltransferase

Abstract: (−)-Epigallocatechin-3-gallate (EGCG) has exhibited been studied for lung cancer inhibitory activity in vitro and in animal models, but it is rapidly methylated and inactivated by catechol-O-methyltransferase (COMT). Entacapone and tolcapone, COMT inhibitors, are used to mitigate the symptoms of Parkinson’s disease. We investigated the synergistic effects of entacapone/tolcapone and EGCG against lung cancer cell lines in culture. EGCG, entacapone and tolcapone inhibited the growth of H1299 human lung cancer cells (IC50 = 174.9, 76.8 and 29.3 µM, respectively) and CL-13 murine lung cancer cells (IC50 = 181.5, 50.7 and 19.7 µM, respectively) as single agents following treatment for 72 h. Treatment with 1:10, 1:5, 1:2.5 and 1:1 combinations of EGCG and tolcapone or entacapone resulted in synergistically enhanced growth inhibition. The growth inhibitory effect of the combinations was mediated by induction of intracellular oxidative stress, cell cycle arrest and decreased nuclear translocation of nuclear

Genetic Polymorphisms of Catechol-O-Methyltransferase Modify the Neurobehavioral Effects of Mercury in Children

Abstract: Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8–12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene–Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

Estradiol 17β and its metabolites stimulate cell proliferation and antagonize ascorbic acid-suppressed cell proliferation in human ovarian cancer cells

Abstract: Estradiol 17β (E2β) and ascorbic acid (AA) have been implicated in cancer progression However, little is known about the actions of biologically active metabolites of E2β, 2-hydroxyestradiol (2OHE2), 4-hydroxyestradiol (4OHE2), 2-methoxyestradiol (2ME2), and 4-methoxyestradiol (4ME2) synthesized sequentially by cytochrome P450, family 1, subfamily A (CYP1A1) and B (CYP1B1), polypeptide 1, and catechol-O-methyltransferase (COMT) on ovarian cancer Herein, we examined the expression of CYP1A1, CYP1B1, COMT, and estrogen receptor α (ERα) and β (ERβ) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432) We also investigated the roles of E2β, 2OHE2, 4OHE2, 2ME2, and 4ME2 in cell proliferation, and their interactive effects with AA on ovarian cells We found the expression of CYP1A1, CYP1B1, COMT, ERα, and ERβ in most cell lines tested Treating cells with physiological concentrations of E2β and its metabolites promoted (13%-42% of the control) IOSE-385 and OVCAR-3 proliferation The ER blockade inhibited IOSE-385 (∼76%) and OVCAR-3 (∼87%) proliferative response to E2β but not to its metabolites The ERα blockade inhibited (∼85%) E2β-stimulated OVCAR-3 proliferation, whereas ERβ blockade attenuated (∼83%) E2β-stimulated IOSE-385 proliferation The AA at ≥250 μmol/L completely inhibited serum-stimulated cell proliferation in all cell lines tested; however, such inhibition in IOSE-385, OVCAR-3, and OVCA-432 was partially (∼10%-20%) countered by E2β and its metabolites Thus, our findings indicate that E2β and its metabolites promote cell proliferation and antagonize the AA-suppressed cell proliferation in a subset of ovarian cancer cells, suggesting that blocking the actions of E2β and its metabolites may enhance AA’s antiovarian cancer activity

Analysis of oxidative stress status, catalase and catechol-O-methyltransferase polymorphisms in Egyptian vitiligo patients.

Abstract: Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT) and catechol-O-Methyltransferase (COMT) gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population.

Cognitive ability, intraindividual variability, and common genetic variants of catechol-O-methyltransferase and brain-derived neurotrophic factor: a longitudinal study in a population-based sample of older adults.

Abstract: Genetic differences play a significant role in generating individual differences in cognitive abilities. Studies have linked common polymorphisms (valine to methionine substitution; VAL/MET) in the catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) to cognitive differences between individuals. However, not all studies support these associations and hence, the impact of these polymorphisms on cognition is unclear. Here, we investigated the effect of COMT VAL158MET and BDNF VAL66MET polymorphisms and their interaction on cognitive performance measured longitudinally over 8 years in a population-based sample of older adults (60-64 years at baseline; n = 400). We used multilevel models to examine differences between individuals with different genotypes in performance on psychometric tests while controlling for age, sex, and education. We observed significant main and interaction effects of COMT and BDNF genotypes on reaction time (RT) and intraindividual variability in RT (IIV-RT). Subjects with at least one copy of the COMT*MET allele (which is associated with higher prefrontal dopamine) had significantly faster RT (both simple and choice RT) and less IIV-RT in both tasks than those without the COMT*MET allele when they also carried one or more BDNF*MET alleles (which is associated with lower activity-dependent BDNF secretion). However, RT and IIV-RT did not differ significantly between the COMT genotypes in the absence of the BDNF*MET allele. These polymorphisms had no significant effect on within person change in RT or IIV-RT. Our findings indicate that the interaction between common variants of COMT and BDNF explain individual differences in RT and IIV-RT but do not explain age-related decline in these abilities.

Tolcapone suppresses ethanol intake in alcohol-preferring rats performing a novel cued access protocol.

Abstract: Background Dopamine (DA) has been shown to play a central role in regulating motivated behavior and encoding reward. Chronic drug abuse elicits a state of hypodopaminergia in the mesocorticolimbic (MCL) system in both humans and preclinical rodent models of addiction, including those modeling alcohol use disorders (AUD). Methods Working under the hypothesis that reductions in the bioavailability of DA play an integral role in the expression of the excessive drinking phenotype, the catechol-O-methyltransferase (COMT) inhibitor tolcapone was used as a means to amplify cortical DA concentration and drinking behaviors were then assessed. Sucrose and ethanol (EtOH) consumption were measured in P and Wistar rats in both a free choice drinking protocol and a novel cued access protocol. Results Tolcapone attenuated the consumption of EtOH, and to a lesser extent sucrose, in P rats in the cued access protocol, while no effect was observed in the free choice drinking protocol. Tolcapone also decreased EtOH consumption in high drinking Wistar rats. A follow-up experiment using the indirect DA agonist d-amphetamine showed no change in EtOH consumption. Conclusions Collectively, these data suggest that COMT inhibitors may be capable of alleviating the extremely motivating or salient nature of stimuli associated with alcohol. The hypothesis is put forth that the relative specificity of tolcapone for cortical DA systems may mediate the suppression of the high seeking/drinking phenotype.