cathechol-O-methyltransferase Research Articles

Influences of COMT rs4680 and OPRM1 rs1799971 Polymorphisms on Chronic Postsurgical Pain, Acute Pain, and Analgesic Consumption After Elective Cesarean Delivery.

The main objectives of this study were to assess the effects of cathechol-O-methyl-transferase (COMT) rs4680 and μ-opioid receptor rs1799971 polymorphisms alone or genotype combinations on chronic postsurgical pain (CPSP), acute pain, and analgesic consumption after elective cesarean delivery in a Chinese cohort. Two hundred sixty-six patients undergoing elective cesarean delivery with a Pfannenstiel incision under spinal anesthesia were enrolled in this prospective, observational study. All patients were screened for rs4680 and rs1799971 using a peripheral venous blood sample of DNA. Postoperative pain relief was provided by IV patient-controlled analgesia with sufentanyl and tramadol for 48 hours postoperatively. Postoperative pain scores and analgesic consumption were assessed, and CPSP was evaluated 3 months after surgery in all patients. Twenty-nine patients (29/266; 10.9%) developed CPSP at 3 months after surgery. The risk factors for CPSP included previous cesarean delivery and higher analgesic consumptions at 24 hours and 48 hours postoperatively (P=0.032, 0.015, and 0.008, reapectively). No associations were found between CPSP and a single rs4680 and rs1799971 polymorphism, or their combinations (P>0.05). In contrast, patients with rs1799971 GG required higher patient-controlled analgesics at 24 hours and 48 hours postoperatively compared with those with other genotypes (GG>AG>AA). However, no significant effects of interactions between the 2 single nucleotide polymorphisms on analgesic consumption were observed. Our results indicate that cathechol-O-methyl-transferase rs4860 and μ-opioid receptor rs1799971 may not contribute to CPSP development after cesarean delivery. The genotype of rs1799971 affects postcesarean analgesic requirement, while the rs4680 do not. Additional larger studies are needed to confirm these findings.

Serotonin Transporter and COMT Polymorphisms as Independent Predictors of Health-related Quality of Life in Patients with Panic Disorder.

There is growing evidence of poor health-related quality of life (HRQOL) in patients with panic disorder (PD). However, little is known about the factors affecting HRQOL in patients with PD. The authors examined whether 5-HTTLPR tri-allelic approach and Cathechol-O-methyltransferase (COMT) Val158Met polymorphism can predict HRQOL in patients with PD controlling for sociodemographic factors and disorder-related symptom levels. The sample consisted of 179 patients with PD consecutively recruited from an outpatient clinic and age- and gender ratio-matched 110 healthy controls. The SF-36 was used to assess multiple domains of HRQOL. Hierarchical multiple regression analysis was performed to determine the independent effect of the 5-HTTLPR and COMT Val158Met on the SF-36 in panic patients.Patients with PD showed lowered HRQOL in all sub-domains of the SF-36 compared to healthy controls. The 5-HTTLPR independently and additively accounted for 2.2% of variation (6.7% of inherited variance) of perceived general health and the COMT Val158Met independently and additively accounted for 1.5% of variation (5.0% of inherited variance) of role limitation due to emotional problems in patient group. The present study suggests that specific genetic polymorphisms are associated with certain domains of HRQOL and provides a new insight on exploring the factors that predict HRQOL in patients with PD.

Genetic Polymorphism of the Serotonin Transporter Gene, SLC6A4 rs16965628, Is Associated with Obsessive Compulsive Disorder.

Obsessive compulsive disorder (OCD) is a psychiatric disorder characterized by obsessive ideas and compulsive behaviors. Genetic studies have centered on candidate genes involved in OCD etiology related to serotonergic and dopaminergic systems. In this study, the relationship between cathechol-O-methyltransferase (COMT) -287A/G (rs2097063), serotonin transporters 5-HTTLPR I/D, and SLC6A4 rs16965628 polymorphisms in 80 OCD patients and 100 healthy controls was determined. Patients and controls were genotyped for COMT rs2097063 and SLC6A4 rs16965628 polymorphisms by real-time polymerase chain reaction (PCR). The 5-HTTLPR I/D polymorphism was genotyped using PCR and agarose gel electrophoresis. Severity of symptoms was checked with a Yale-Brown Obsession Compulsion Scale (Y-BOCS). When the OCD group and controls were compared, no significant difference was found between COMT -287A/G (rs2097063), 5-HTTLPR I/D polymorphisms, and OCD. However, a significant difference was found between 5-HTT rs16965628 polymorphism and OCD (p=0.025, OR=3.43, 95% CI 1.41-10.35). In addition, the G allele frequency was found to be higher for rs16965628 in the OCD group. No significant difference was observed between COMT -287A/G (rs2097063), SLC6A4 rs16965628, and 5-HTTLPR I/D polymorphisms and Y-BOCS scores (p>0.05). There was also lack of correlation between Yale-Brown scores and gender of OCD patients. On the other hand, combined genotypes of SLC6A4 rs16965628 GG+GC were found to be risk factors for OCD development (p=0.02, OR=3.464; 95% CI 1.214-9.883) in logistic regression analysis adjusted for age and gender. Our findings suggest that subjects carrying the G allele of rs16965628 have genetic susceptibility to OCD. These data are the first to suggest that polymorphism in serotonin transporter (rs16965628) is associated with the development of OCD in the Turkish population.

Pharmacokinetic study of luteolin, apigenin, chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract in rats

Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone. Furthermore, AUC of luteolin was significantly increased by entacapone, while that of chrysoeriol was decreased by entacapone, which revealed COMT might play an important role in the disposition of luteolin in rats after dosing of FCE. In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo.

The effect of Ecstasy on memory is moderated by a functional polymorphism in the cathechol-O-methyltransferase (COMT) gene

There is ample evidence for decreased verbal memory in heavy Ecstasy users. However, findings on the presence of a dose–response relation are inconsistent, possibly due to individual differences in genetic vulnerability. Catechol-O-methyltransferase (COMT) is involved in the catabolism of Ecstasy. Therefore, COMT gene polymorphisms may moderate this vulnerability. We prospectively assessed verbal memory in subjects with a high risk for future Ecstasy use, and compared 59 subjects after first Ecstasy use with 60 subjects that remained Ecstasy-naive. In addition, we tested the interaction effect of Ecstasy and the functional val 158met polymorphism on verbal memory. Met-allele carriers were somewhat more sensitive to the effects of Ecstasy on verbal learning than homozygous val-subjects. After correction for the use of other substances this effect was no longer statistically significant. The findings suggest that the COMT gene moderates the negative effect of Ecstasy on memory, but also other drug use seems to play a role.

Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy

Alterations in dopamine levels and dopamine receptors in brain are suggested to be associated with treatment response in electroconvulsive therapy (ECT). Dopamine 2 receptor gene (DRD2) polymorphism C957T (rs6277) and cathechol-o-methyltransferase (COMT) polymorphism Val158Met (rs4680) interaction was studied in 118 patients suffering from major depressive disorder (MDD) treated with ECT and 383 healthy controls. It was found that the combination of COMT Met allele and DRD2 T allele predicted more severe depression in those already affected but did not predict the risk of depression when compared to normal population. The genotype modified the response to ECT. The patients with TT genotype of D2 receptor gene C957T polymorphism combined with COMT gene polymorphism Met/Met genotype did not achieve remission as often as those with CC genotype of DRD2 C957T combined with COMT Val/Val genotype. Thus the interaction of these polymorphisms may be associated with response to ECT.

Quantifiable mRNA transcripts for tamoxifen-metabolising enzymes in human endometrium

Tamoxifen has been used in the management of receptor-positive breast cancer for >20 years. Usage confers an elevated risk of developing endometrial carcinoma. Its mechanism of carcinogenicity remains unresolved with controversy as to whether or not this is mediated through a genotoxic mechanism. Usage is not only associated with an elevated occurrence of endometrioid endometrial carcinoma, but also type 2 and mixed epithelial-stromal tumours (MESTs) that have a poorer prognosis. Following hysterectomy, endometrial tissues ( n = 18) classified as benign ( n = 6), non-tamoxifen-associated carcinoma ( n = 6) and tamoxifen-associated carcinoma ( n = 6) were obtained; quantitative gene expression was performed. Employing real-time RT-PCR, the relative gene expressions of phase I/II metabolic enzymes CYP1A2, CYP1B1 and CYP3A4, cathechol- O-methyltransferase ( COMT) and SULT2A1 were ascertained. Measurable mRNA transcripts, especially for those genes associated with tamoxifen bioactivation, were quantifiable in all the tissues examined. Whether this is evidence that generation of genotoxic tamoxifen metabolites may occur in human endometrial tissue remains to be ascertained.

An association study between cathechol- O-methyltransferase gene and mental retardation in the Chinese Han population

Cathechol- O-methyltransferase ( COMT) regulates the amount of dopamine in the prefrontal cortex (PFC). Substantial studies indicate a close relationship between COMT and several human psychotic disorders. The case–control method was used to study the association between mental retardation (MR) and genetic variants of COMT. Three single nucleotide polymorphisms (SNPs: rs4680, rs165656 and rs165774), in the cathechol- O- methyltransferase ( COMT) gene, were genotyped by PCR–RFLP method. Individual SNP analysis shows significant differences only at SNP rs165656 for both genotype and allele frequency when comparing MR cases and controls ( p = 0.023, 0.011, respectively). Further haplotype analysis indicates that there are two haplotype sets, rs165656– rs4680 and rs165656– rs165774, which show statistical differences between MR cases and controls (global p = 0.047, p = 0.033, respectively). Our results suggest a positive association between the genetic variants of the COMT gene and MR in the Chinese Han population in the Qinba region.

Gender-Dependent Association of the Functional Catechol-O-Methyltransferase Val158Met Genotype with Sensation Seeking Personality Trait

The gene encoding cathechol-O-methyltransferase (COMT) contains a common functional missense polymorphism (Val158Met) that regulates dopamine in an allele-dependent manner. A pivotal role of dopamine neurotransmission in the prefrontal cortex has been implicated in drug-seeking behavior and related personality traits, such as sensation seeking, with some evidence for a gender-specific association. Here, we tested the hypothesis that the COMT Val158Met polymorphism modulates the personality dimension, sensation seeking, in a gender-dependent manner. Study sample included 214 male (age 38.1+/-12.6 years) and 218 female (age 36.1+/-13.6 years) healthy volunteers, who were assessed with Zuckerman's sensation-seeking scale and genotyped for the Val158Met polymorphism (dbSNP:rs4680). Univariate analysis of variance showed that the sensation seeking score was significantly affected by a COMT genotype x gender interaction (F=5.330, df=2, p=0.005). The Val158Met polymorphism was associated with the sensation seeking personality trait in women only. The highest scores in the sensation-seeking scale and in three of the four subscales were observed in female subjects with the Val/Val genotype relative to women carrying the Met allele. Our results suggest that high COMT enzyme activity associated with the Val allele predisposes to high sensation seeking scores in female subjects and add to increasing evidence for a gender specific role of COMT in normal and dysfunctional behavior.

Insights into Cephamycin Biosynthesis: the Crystal Structure of CmcI from Streptomyces clavuligerus

Cephamycin C-producing microorganisms use two enzymes to convert cephalosporins to their 7alpha-methoxy derivatives. Here we report the X-ray structure of one of these enzymes, CmcI, from Streptomyces clavuligerus. The polypeptide chain of the enzyme folds into a C-terminal Rossmann domain and a smaller N-terminal domain, and the molecule packs as a hexamer in the crystal. The Rossmann domain binds S-adenosyl-L-methionine (SAM) and the demethylated product, S-adenosyl-L-homocysteine, in a fashion similar to the common binding mode of this cofactor in SAM-dependent methyltransferases. There is a magnesium-binding site in the vicinity of the SAM site with a bound magnesium ion ligated by residues Asp160, Glu186 and Asp187. The expected cephalosporin binding site near the magnesium ion is occupied by polyethyleneglycol (PEG) from the crystallisation medium. The geometry of the SAM and the magnesium binding sites is similar to that found in cathechol O-methyltransferase. The results suggest CmcI is a methyltransferase, and its most likely function is to catalyse the transfer of a methyl group from SAM to the 7alpha-hydroxy cephalosporin in the second catalytic reaction of cephamycin formation. Based on the docking of the putative substrate, 7alpha-hydroxy-O-carbamoyldeacetylcephalosporin C, to the structure of the ternary CmcI-Mg2+-SAM complex, we propose a model for substrate binding and catalysis. In this model, the 7-hydroxy group of the beta-lactam ring ligates the Mg2+ with its alpha-side facing the methyl group of SAM at a distance that would allow methylation of the hydroxyl-group.

Inhibition of Production of Reactive Oxygen Species and Gene Expression Profile by Treatment of Ethanol Extract of Moutan Cortex Radicis in Oxidative Stressed PC12 Cells

Moutan Cortex Radicis (MCR) is one of the most widely used Oriental medicines. In this study, we assessed the reducing effect of ethanol extract of MCR on hydrogen peroxide-induced reactive oxygen production, the main cause of cell damage or death in PC12 cells. The viability of cells treated with 1 mg/ml of MCR was significantly restored from that of oxidative-stressed PC12 cells. Measurement of intracellular reactive oxygen species (ROS) generation was determined using the H(2)DCFDA assay. MCR at 1-0.01 mg/ml concentration inhibited ROS production in oxidative-stressed cells. To identify candidate genes responsible for the anti-oxidative effects of MCR on PC12 cells, an oligonucleotide microarray analysis was performed. The result of gene expression profiles showed that 10 genes were up-regulated and 7 were down-regulated in MCR plus hydrogen peroxide treated cells compared with hydrogen peroxide treated cells. Among them, heme oxygenase (HO) and cathechol-O-methyltransferase (COMT) are related to regulation of ROS generation and the others are known to regulate cell survival and progression. Subsequently, we performed real-time RT-PCR to quantify the ROS related gene. MCR treatment increased the expression of HO by 370% and COMT by 280% at the concentration of 1 mg/ml. These findings suggest that MCR inhibits the production of ROS and cytotoxicity by oxidative-stressed PC12 cells through over-expression of HO and COMT.

Repeated l-DOPA administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat

The “wearing-off” phenomenon is a clinically recognized adverse effect of long-term l-DOPA therapy in Parkinson's disease. Several causes of this phenomenon have been proposed, but no direct evidence has yet been obtained. The present study was therefore conducted to investigate the effects of long-term l-DOPA administration on the dopamine system. We examined in rats the time course of the levels of l-DOPA and its metabolites in the serum and striatum, the activities of tyrosine hydroxylase and cathechol O-methyltransferase, and the D1 and D2 dopamine receptor bindings in the striatum until 12 h after the final dose on the 28th day of repeated oral l-DOPA administration, and compared the results with those after a single l-DOPA administration. The results revealed that long-term l-DOPA administration induced (1) acceleration of DOPA absorption at the gut and the blood-brain barrier, (2) reduction of dopamine retention in the striatum, and (3) loss of “supersensitive response” of dopamine receptors. “Supersensitive response” induced by single l-DOPA administration was preceded by the increase of D1 messenger RNA. We suggest that these changes after long-term l-DOPA administration are causes of the “wearing-off” phenomenon in Parkinson's disease.

18 F]‐6‐Fluorodopa PET scanning in Parkinson's disease after selective COMT inhibition with nitecapone (OR‐462)

PET studies were performed to investigate the effects of a new cathechol-O-methyltransferase (COMT) inhibitor, nitecapone (OR-462 [3-(3,4-dihydroxy-5-nitrobenzylidene)- 2,4-pentadione]), on the accumulation of dopamine in the striatum and whether it is able to improve [18F]6-fluorodopa imaging of the brain. Altogether, three patients with Parkinson's disease (PD) and three normal volunteers were examined, first without nitecapone and then with an oral dose of 100 mg of nitecapone 1 hour before the IV injection of 3 mCi of [18F]6-fluorodopa. High-pressure liquid chromatography analysis of arterial plasma samples showed a significant reduction in the metabolic conversion rate from [18F]6-fluorodopa to [18F]3-O-methylfluorodopa after the administration of nitecapone. PET studies showed that nitecapone significantly (p less than 0.05) increased the [18F]6-fluorodopa accumulation in the striatum both in PD patients and normal controls; the magnitude of this increase was 20.0 +/- 5.5% (mean +/- SEM). The ratio of radioactivity in the striatum and arterial plasma was increased 39.0 +/- 5.0% (mean +/- SEM) after the administration of nitecapone. Consequently, the quality of PET images after OR-462 was better, which has implications for future [18F]6-fluorodopa studies. In addition, COMT inhibition may have clinical advantages by improving levodopa treatment in PD.

Additions and Corrections-Synthesis and Evalutaion of Some Stable Multisubstrate Adducts as Inhibitors of Cathechol O-Methyltransferase

Additions and Corrections-Synthesis and Evalutaion of Some Stable Multisubstrate Adducts as Inhibitors of Cathechol O-Methyltransferase

Enzymes for epinephrine synthesis and metabolism in the myometrium, endometrium, red blood cells, and plasma of pregnant human subjects

The enzyme phenylethanolamine-N-methyl transferase (PNMT) converts norepinephrine (NE) to epinephrine (E), and cathechol-O-methyl transferase (COMT) and monoamine oxidase (MAO) both metabolize NE and E. We were able to measure the activity of these enzymes in myometrial and endometrial samples obtained from 27 pregnant women between 32 and 40 weeks' gestation at the time of cesarean section. In addition, these enzymes were measured in red blood cells and plasma obtained from 45 normal pregnancies between 10 and 40 weeks' gestation. PNMT activity was significantly higher in myometrium than in endometrium. During labor myometrial and red blood cell PNMT activity is significantly lower than in specimens from patients at term not in labor, while myometrial PNMT activity is significantly elevated in patients with dystocia. Under these conditions no significant alterations in myometrial, red blood cell, or plasma COMT or myometrial MAO activities were observed. This study identifies for the first time the presence of PNMT in myometrium, endometrium, and red blood cells and provides the necessary step for the conversion of NE to E, a concept previously limited to the adrenal bland, brain, and heart. This could provide an important physiologic mechanism for the control of uterine activity during pregnancy and parturition.

S-adenosylmethionine and catechol-O-methyl-transferase in schizophrenia.

The authors examined the hypothesis of disordered transmethylation in schizophrenia by comparing S-adenosylmethionine (SAMe) concentration and cathechol-O-methyltransferase (COMT) activities in venous blood of schizophrenic and nonschizophrenic patients. While they did not find a difference in blood SAMe concentration between the groups, they did find a significant correlation between blood COMT activity and SAMe concentration. This suggests that some schizophrenics may methylate biogenic amines more actively than others.