Catechol-O-methyltransferase and Pregnancy Outcome: an Appraisal in Rat.
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ABSTRACT:
SUBMITTER: Iqbal K
PROVIDER: S-EPMC8082470 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PURPOSE: Catechol-O-methyltransferase (COMT) inactivates the estradiol metabolites, 2-hydroxy and 4-hydroxy catechols, which have been implicated in the pathogenesis of endometriosis. A COMT valine to methionine polymorphism (G-to-A) in exon 4 of the COMT gene is polymorphic in the human population, with 25% of Caucasians being homozygous for the low-activity allele (COMT-L) of the enzyme. In a case-control study we investigated whether this COMT polymorphism is associated with endometriosis. METHODS: Polymerase chain reaction was performed to analyze the COMT genotype among women with surgically and histologically confirmed endometriosis (study group; n = 91) and in women without evidence of endometriosis confirmed by laparoscopy or laparotomy (control group; n = 92). RESULTS: Allele frequencies for the low-activity allele (COMT-L) among women with endometriosis and controls were 0.50 and 0.50, respectively (p = 0.999; odds ratio = 1.0, 95% CI: 0.66-1.51). CONCLUSIONS: Our results suggest that the valine to methionine polymorphism in exon 4 of the COMT gene is not associated with the risk of endometriosis compared to a surgical control population.
| S-EPMC3455752 | biostudies-other
Project description:Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes.We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women's Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment.COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (?=-0.032% [0.012], p=0.008) and borderline significant in MAGIC (?=-0.006% [0.003], p=0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR=0.98 [0.96-0.998], p=0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR=0.81 [0.65-1.00], p=0.05).COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD.
| S-EPMC4924514 | biostudies-literature
Project description:Background Genetic variation in catechol-O-methyltransferase (COMT), a key enzyme in estrogen and catecholamine metabolism, has plausible physiological links to cardiovascular disease (CVD) and its risk factors. In WHS (Women's Health Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not aspirin, suggesting a possible role of COMT in thrombosis. Methods and Results To evaluate potential pathways linking COMT with CVD, and COMT effect modification of aspirin in prevention, we examined COMT association with CVD risk and subclinical measures, coronary artery calcium, and carotid intima-media thickness in MESA (Multi-Ethnic Study of Atherosclerosis). In 65 957 person-years of follow-up, during which 498 events occurred, COMT rs4818 was associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.74-0.97 [P=0.02]). This association remained virtually unchanged after adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (β, -3.65; SE, 1.35 mg/dL [P=0.007]). Results were directionally similar but not significant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95% CI, 0.65-0.95; P=0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.71-1.13; P=0.34) among more frequent users (Pinteraction=0.39). Neither intima-media thickness nor coronary artery calcium was associated with COMT. Conclusions In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD risk and lower fibrinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible role of COMT in the latter stages of CVD.
| S-EPMC6951085 | biostudies-literature
Project description:3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.
| S-EPMC4360154 | biostudies-literature
Project description:In the rat, the catechol O-methyltransferase (COMT) gene has been found to contain two promoters, P1 and P2. This organization enables the gene to produce a soluble (S-COMT) and a membrane-associated (MB-COMT) protein by using two in-frame ATG initiation codons (S- and MB-ATG). The P1 promoter expresses a 1.6 kb transcript (S-mRNA) which codes for the S-COMT polypeptide only. Here we demonstrate that the P2 promoter controls the expression of alternatively spliced 1.9 kb transcripts (MB-mRNA) which differ by a 27-nucleotide region immediately upstream of the MB-AUG codon. The presence of the 27-base sequence alters the nucleotide at position -3 from G to C, thereby changing the translation initiation context of the MB-AUG codon. Expression experiments in COS-7 cells using full-length COMT cDNAs showed that this alteration affected the initiation of the translation of the MB-AUG and consequently changed the relative amounts of MB- and S-COMT polypeptides produced. No proteolytic cleavage of the MB-COMT form to S-COMT was detected in in vitro or in vivo pulse-chase experiments. We conclude that the bifunctional 1.9 kb mRNAs are able to produce both S-COMT and MB-COMT polypeptide by the leaky scanning mechanism of translation initiation.
| S-EPMC1137739 | biostudies-other
Project description:Background & aimsThe etiology of abdominal pain in postinfectious, diarrhea-predominant irritable bowel syndrome (PI-IBS-D) is unknown, and few treatment options exist. Catechol-O-methyltransferase (COMT), an enzyme that inactivates and degrades biologically active catecholamines, plays an important role in numerous physiologic processes, including modulation of pain perception. Our objective was to determine the mechanism(s) of how decreased colonic COMT in PI-IBS-D patients contributes to the chronic abdominal pain phenotype after enteric infections.MethodsColon neurons, epithelial cells, and macrophages were procured with laser capture microdissection from PI-IBS-D patients to evaluate cell-specific colonic COMT, microRNA-155 (miR-155), and tumor necrosis factor (TNF) α expression levels compared to recovered patients (infection cleared: did not develop PI-IBS-D) and control individuals. COMT-/-, colon-specific COMT-/-, and miR-155-/- mice and human colonoids were used to model phenotypic expression of COMT in PI-IBS-D patients and to investigate signaling pathways linking abdominal pain. Citrobacter rodentium and trinitrobenzene sulfonic acid animal models were used to model postinflammatory changes seen in PI-IBS-D patients.ResultsColonic COMT levels were significantly decreased and correlated with increased visual analog scale abdominal pain ratings in PI-IBS-D patients compared to recovered patients and control individuals. Colonic miR-155 and TNF-α were increased in PI-IBS-D patients with diminished colonic COMT. COMT-/- mice had significantly increased expression of miR-155 and TNF-α in both colon tissues and dorsal root ganglia. Introduction of cV1q antibody (anti-TNF-α) into mice reversed visceral hypersensitivity after C rodentium and trinitrobenzene sulfonic acid.ConclusionsDecreased colonic COMT in PI-IBS-D patients drives abdominal pain phenotypes via the COMT/miR-155/TNF-α axis. These important findings will allow new treatment paradigms and more targeted and personalized medicine approaches for gastrointestinal disorders after enteric infections.
| S-EPMC10038873 | biostudies-literature
Project description:BACKGROUND: Treatment outcome of low back pain (LBP) is associated with inter-individual variations in pain relief and functional disability. Genetic variants of catechol-O-methyltransferase (COMT) gene have previously been shown to be associated with pain sensitivity and pain medication. This study examines the association between COMT polymorphisms and 7-11 year change in Oswestry Disability Index (ODI) and Visual Analog Score (VAS) for LBP as clinical outcome variables in patients treated with surgical instrumented lumbar fusion or cognitive intervention and exercise. METHODS: 93 unrelated patients with chronic LBP for duration of >1 year and lumbar disc degeneration (LDD) were treated with lumbar fusion (N = 60) or cognitive therapy and exercises (N = 33). Standardised questionnaires assessing the ODI, VAS LBP, psychological factors and use of analgesics, were answered by patients both at baseline and at 7-11 years follow-up. Four SNPs in the COMT gene were successfully genotyped. Single marker as well as haplotype association with change in ODI and VAS LBP, were analyzed using Haploview, linear regression and R-package Haplostats. P-values were not formally corrected for multiple testing as this was an explorative study. RESULTS: Association analysis of individual SNPs adjusted for covariates revealed association of rs4633 and rs4680 with post treatment improvement in VAS LBP (p = 0.02, mean difference (?) = 13.5 and p = 0.02, ? = 14.2 respectively). SNPs, rs4633 and rs4680 were found to be genotypically similar and in strong linkage disequilibrium (LD). A significant association was found with covariates, analgesics (p = 0.001, ? = 18.6); anxiety and depression (p = 0.008, ? = 15.4) and age (p = 0.03, mean difference per year (?) = 0.7) at follow-up. There was a tendency for better improvement among heterozygous patients compared to the homozygous. No association was observed for the analysis of the common haplotypes, these SNPs were situated on. CONCLUSIONS: Results suggest an influence of genetic variants of COMT gene in describing the variation in pain after treatment for low back pain. Replication in large samples with testing for other pain related genes is warranted.
| S-EPMC3453507 | biostudies-literature
Project description:We have utilized multiparametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol-water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol-water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its nonlipophilic nature predicted by octanol-water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting a mechanism other than the membrane-mediated mechanism of action for the neurotransmitters at the postsynaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.
| S-EPMC7145343 | biostudies-literature
Project description:The Met allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with increased cortical dopamine and risk behaviors including illicit drug use and unprotected sex. Therefore, we examined whether or not the distribution of the Val158Met genotype differed between HIV-infected and HIV-uninfected women.Cross-sectional analysis using data from the Women's Interagency HIV Study (WIHS), the largest longitudinal cohort study of HIV in women.We conducted an Armitage-Cochran test and logistic regression to compare genotype frequencies between 1848 HIV-infected and 612 HIV-uninfected women in WIHS.The likelihood of carrying one or two Met alleles was greater in HIV-infected women (61%) compared to HIV-uninfected women (54%), Z ?=? -3.60, P ?< 0.001.We report the novel finding of an association between the Val158Met genotype and HIV serostatus that may be mediated through the impact of dopamine function on propensity for risk-taking.
| S-EPMC3897122 | biostudies-literature
Project description:Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of dopaminergic neurons, with consequent reduction in striatal dopamine levels leading to characteristic motor symptoms. The most effective treatment for this disease continues to be the dopamine replacement therapy with levodopa together with an inhibitor of aromatic amino acid decarboxylase (AADC). The efficacy of this therapy, however, decreases with time and most patients develop fluctuating responses and dyskinesias. The last decade showed that the use of catechol-O-methyltransferase inhibitors as adjuvants to the levodopa/AADC inhibitor therapy, significantly improves the clinical benefits of this therapy. The purpose of this article is to review the current knowledge on the enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD as a new therapeutic approach to PD involving conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on nebicapone, presently under clinical development, as well as entacapone and tolcapone, which are already approved as adjuncts in the therapy of PD. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety.
| S-EPMC6494163 | biostudies-literature