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PubMed2007

High systolic blood pressure is associated with Val/Val genotype in the catechol-o-methyltransferase gene. The Nord-Trøndelag Health Study (HUNT).

BACKGROUND: The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met. A few studies on animals have shown a relationship between the COMT gene and BP, but whether this exists in human beings is unclear. The aim of this study was to evaluate the relationship between codon 158 COMT gene polymorphism and BP in a population-based cohort. METHODS: In the 1995-97 Nord-Trøndelag Health Study (HUNT), the association between Val/Met polymorphism at the COMT gene and BP was evaluated in a group of 2966 nondiabetic individuals. RESULTS: Among the 2591 individuals without current use of antihypertensive drugs, systolic BP > or =140 mm Hg was more likely among persons with Val/Val genotype compared with the other genotypes (44.8% v 39.1%, P = .02). In the multivariate analysis the prevalence odds ratio for having the Val/Val genotype was 1.63 (95% CI = 1.18 to 2.24) among individuals with systolic BP > or =160 mm Hg compared with those with systolic BP <140 mm Hg. Val/Val genotype was also more likely (OR = 1.30, 95% CI = 1.04 to 1.63) among individuals with hypertension (as defined by use of antihypertensive medication, systolic BP > or =140 mm Hg, or diastolic BP > or =90 mm Hg) than among those with normal BP. CONCLUSIONS: Based on the study findings, the Val/Val genotype appears to be associated with a higher prevalence of increased systolic BP compared with the Met/Met or Met/Val genotypes at the COMTgene.

Adult↗
PubMed2004

In vivo assessment of catechol O-methyltransferase activity in rabbit skeletal muscle.

With the use of microdialysis technique in the anesthetized rabbit, we examined the catechol O-methyltransferase (COMT) activity at the skeletal muscle interstitium. We implanted a dialysis probe into the adductor muscle, and monitored dialysate catecholamines and their metabolites with chromatogram-electrochemical detection. Administration of COMT inhibitor (entacapone) decreased dialysate 3-methoxy 4-hydroxyphenylglycol (MHPG) levels. Local administration of dihydroxyphenylglycol induced increases in dialysate MHPG levels. These increases in dialysate MHPG levels were suppressed by the addition of entacapone. The concentration of MHPG in the skeletal muscle dialysate corresponded to the COMT activity in the skeletal muscle. Furthermore, local administration of norepinephrine or epinephrine increased normetanephrine or metanephrine levels in dialysate but not MHPG levels. Skeletal muscle microdialysis with local administration of catecholamine offers a new method for in vivo assessment of regional COMT activity.

Animals↗
PubMed2005

The influence of the dopaminergic system on cognitive functioning: A molecular genetic approach.

Many pharmacological and clinical studies have demonstrated the importance of the dopaminergic (DA) system for cognitive functioning but little is known about the genetic basis of general cognitive ability that has been demonstrated to be highly heritable. Attempts to detect associations between certain gene loci and endophenotypes of general cognitive ability have turned out to be more promising. Therefore, the aim of the present study was to investigate two dopaminergic candidate genes (COMT VAL158MET and DRD2 TAQ IA) for endophenotypes of cognitive functioning i.e. attention, vigilance, interference, time estimation and sensoric and motoric reaction times. Out of a gene data bank of more than 600 healthy Caucasian participants, 96 subjects (n = 48 males and n = 48 females) were recruited according to their genotype/allele pattern, resulting in six independent groups (COMT: VAL/VAL, VAL/MET, MET/MET)x(DRD2: A1-, A1+) of n = 16 subjects each. Results showed associations of the COMT gene with attention and with time estimation but most noteworthy was an interaction effect DRD2xVAL on interference performance as measured by the STROOP-test explaining 13% of the variance. Findings suggest that a balance between DA related catabolic enzyme activity and receptor density are good predictors for the endophenotype of cognitive interference and that the COMT gene is in accordance with previous studies related to cognitive functioning.

Analysis of Variance↗
PubMed2006

Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents.

BACKGROUND: The catechol-O-methyltransferase (COMT) gene codes for an enzyme that degrades prefrontal cortex (PFC) synaptic dopamine. Of two identified alleles (Met and Val), the Met allele results in COMT activity that is up to 4 times less pronounced than that conferred by the Val allele, resulting in greater PFC dopamine concentrations. Met-Met homozygotes perform better than individuals who possess the Val allele on PFC-mediated cognitive tasks. These genotypic variations and their associations with executive functions have been described in adults and prepubescent children, but there is a paucity of research assessing these relations in adolescent samples. METHODS: In this study, 70 children aged 9-17 were genotyped for COMT and completed measures of working memory, attention, fine motor coordination, and motor speed. RESULTS: COMT genotype modulated all but the motor speed measures. The Val-Met genotype was optimal for performance in this adolescent sample. CONCLUSIONS: Results are discussed within the context of developmental changes in the dopaminergic system during adolescence.

Adolescent↗
PubMed2006

Genotype distribution of estrogen receptor-alpha, catechol-O-methyltransferase, and cytochrome P450 17 gene polymorphisms in Caucasian women with uterine leiomyomas.

OBJECTIVE: To evaluate the association between the presence of uterine leiomyomas and three functional single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ESR1), catechol-O-methyltransferase (COMT), and cytochrom P450 17 (CYP17A) genes, which have been described to modify the estrogen metabolism. DESIGN: Prospective case control study. SETTING: Academic research institution. PATIENT(S): One hundred thirty women with clinically and surgically diagnosed uterine leiomyomas and 139 population controls. INTERVENTION(S): Peripheral venous puncture. MAIN OUTCOME MEASURE(S): Polymerase chain reaction and pyrosequencing were performed to genotype women with respect to the ESR1 IVS1-397 T/C (PvuII), COMT G158A, and the CYP17A 34T-->C SNPs. RESULT(S): Comparing women with uterine leiomyomas and controls, no statistically significant differences with respect to allele frequency and genotype distribution were ascertained for ESR1 IVS 1-397 T/C (PvuII) (P=0.9 and P=0.6, respectively), COMT G158A (P=0.3 and P=0.6, respectively), and CYP17A 34T-->C (P=0.1 and P=0.5, respectively). When all two-way interactions of investigated SNPs were ascertained, no significant interactions were observed. In a multivariate model, no SNP was significantly associated with leiomyomas. CONCLUSION(S): Carriage of the ESR1 IVS1-397 T/C (PvuII), COMT G158A, and the CYP17A 34T-->C SNPs is not associated with the susceptibility to uterine leiomyoma in a Caucasian population.

Adenine↗
PubMed2006

Influence of the catechol-O-methyltransferase Val108/158Met polymorphism on the plasma concentration of catecholamine metabolites and on clinical features in type I bipolar disorder--a preliminary report.

BACKGROUND: The activity of catechol-O-methyltransferase (COMT) may be related to psychosis susceptibility. The Val108/158Met polymorphism of the COMT gene influences its enzymatic activity and may result in altered concentrations of monoamine metabolites and different clinical responses of patients to pharmacological treatments. METHODS: We examined in a sample of 42 bipolar patients if the Val108/158Met polymorphism influences: (a) the presence of psychosis in type I bipolar patients; (b) the blood plasma concentration of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), which are metabolites of dopamine and noradrenaline respectively and (c) the severity of the clinical characteristics of these patients and their response to pharmacological treatment. RESULTS: No significant associations were found between the studied COMT genotypes and the studied parameters. However, a non-significant aggregation of bipolar patients presenting with psychosis was found in the homozygous Val-Val group. Clinical improvement was found to significantly correlate with the levels of plasma MHPG prior to treatment. Moreover, a significant difference was found between the standard deviations of the concentrations of HVA in the three genotypes, but not in their mean values. Significant associations were not detected between COMT polymorphisms and the initial severity of the disorder, or the clinical response to pharmacological treatment. LIMITATIONS: The size of the studied sample is somewhat small and comparisons have been made with a previously studied control group. CONCLUSIONS: The Val108/158Met polymorphism does not appear to be a crucial determinant in type I bipolar disorder.

Adult↗
PubMed2001

Prefrontal neurons and the genetics of schizophrenia.

This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness.

Alleles↗
PubMed1997

No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene.

Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample.

Adult↗
PubMed1997

Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly.

OBJECTIVES: The multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving concomitant carbidopa and levodopa. METHODS: Thirty-six volunteers from 55 to 75 years old participated in this double-blind, placebo-controlled, ascending multiple-dose study. Tolcapone was studied at dosages of 100, 200, 400, or 800 mg three times daily (t.i.d.) in four sequential groups. Each group consisted of nine participants who had been randomized to receive either placebo (n = 3) or tolcapone (n = 6). Tolcapone or placebo was coadministered with carbidopa and levodopa (25 and 100 mg, respectively) for 7 days. Assessments included tolerability, pharmacokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes. RESULTS: By inhibiting COMT, tolcapone reduced levodopa metabolism to 3-O-methyldopa, resulting in a twofold increase in levodopa exposure (area under the curve) and elimination half-life, without changing levodopa peak plasma concentration. These effects were similar on days 1 and 7 of treatment. Development of tolerance to COMT inhibition was not observed. Onset of effect was rapid (day 1 of treatment), and the maximum effect on levodopa pharmacokinetics was already observed with 100 or 200 mg tolcapone t.i.d. At these dosages, tolcapone pharmacokinetics were linear and stable; accumulation occurred with 800 mg t.i.d. The combination of tolcapone and carbidopa-levodopa was generally well tolerated, although more nausea and vomiting were observed at higher dosages (400 to 800 mg t.i.d.), particularly in women. CONCLUSION: Tolcapone shows promise as an effective adjunct to levodopa in the treatment of Parkinson's disease. Clinical pharmacology data indicate that the therapeutic regimen should be 100 or 200 mg t.i.d.

Administration, Oral↗
PubMed2002

Effects of entacapone and tolcapone on mitochondrial membrane potential.

Catechol-O-methyl transferase (COMT) inhibitors, entacapone and tolcapone, are used as an adjunctive treatment to L-dopa in Parkinson's disease. Based on their catechol structure, both inhibitors are potential uncoupling agents, but only tolcapone shows this effect in vitro at clinically relevant concentrations. This study was designed to evaluate the direct uncoupling effects of the two COMT inhibitors in vitro and in vivo. In isolated rat liver mitochondria, entacapone had no effect on the membrane potential at therapeutical concentrations, but both tolcapone and the reference compound 2,4-dinitrophenol disrupted the potential at low microM concentrations. Since protein binding is speculated to decrease the uncoupling effects in vivo, the COMT inhibitory effect of entacapone and tolcapone as a surrogate for the overall activity of these inhibitors was evaluated in vitro with or without serum. The COMT inhibitory activity of entacapone was reduced to half, while tolcapone had only about 1/10 of its activity left in the presence of serum. Further, uncoupling is known to induce an increase in the body temperature in vivo, and these effects were evaluated in the rat by a possible hyperthermic response to the treatment with entacapone or tolcapone in combination with L-dopa (10 mg/kg) and carbidopa (20 mg/kg). This combination with entacapone (400 mg/kg) had no effect on the rectal body temperature. In contrast, tolcapone (50 mg/kg) caused an elevation in the body temperature together with L-dopa and carbidopa (P < 0.01). Both in vitro and in vivo results indicate that entacapone does not impair energy metabolism related to uncoupling of oxidative phosphorylation.

Animals↗
PubMed2001

Repression of O-methyltransferase genes in transgenic tobacco affects lignin synthesis and plant growth.

Among the different enzymatic steps leading to lignin biosynthesis, two methylation reactions introduce the methyl groups borne by guaiacyl (G) and syringyl (S) units. Tobacco possesses a complex system of methylation comprising three classes of CCoAOMTs (caffeoyl-CoA-O-methyltransferases) and two classes of COMTs (caffeic acid OMTs). Antisense plants transformed with the CCoAOMT sequence alone or fused to COMT I sequence have been produced and compared to ASCOMT I plants in order to study the specific role of each OMT isoform in lignin biosynthesis, plant development and resistance to pathogens. Tobacco plants strongly inhibited in OMT activities have been selected and analyzed. Whereas antisense COMT I plants exhibited no visual phenotype, CCoAOMT repression was shown to strongly affect the development of both single and double transformants: a reduction of plant growth and the alteration of flower development were observed in the most inhibited plants. Lignin analysis performed by Klason and thioacidolysis methods, showed a decrease in the lignin quantity and changes in the lignin structure of ASCCoAOMT and ASCCoAOMT/ASCOMT I transgenics but not in ASCOMT I plants. Inhibition of COMT I in single as well as in double transformed tobacco was demonstrated to decrease S unit synthesis and to provoke the accumulation of 5-hydroxyguaiacyl lignin units. ASCCoAOMT/ASCOMT I tobacco was affected in lignin amount and composition, thus demonstrating additive effects of inhibition of both enzymes. The changes of lignin profiles and the phenotypical and molecular alterations observed in the different transgenic lines were particularly prominent at the later stages of plant development.

Lignin↗
PubMed1999

New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson's disease.

Levodopa remains the most effective drug for Parkinson's disease (PD). However, its benefits are limited owing to extensive metabolism by catechol-O-methyltransferase (COMT), especially if levodopa is used in combination with peripheral dopa-decarboxylase inhibitors. A new generation of potent, orally active, selective, and reversible COMT inhibitors has become available recently. Among these, tolcapone and entacapone have been best characterised. Preclinical and clinical studies have shown that COMT inhibitors markedly enhance levodopa availability and prolong its plasma half-life. In recent large clinical trials they proved to be able to ameliorate motor fluctuations, reduce disability, and decrease levodopa requirements in PD patients. The tolerability profiles of entacapone and tolcapone are good. COMT inhibition promises to become an important means of extending the benefits of levodopa therapy in PD.

Animals↗
PubMed2001

Association between a catechol-o-methyltransferase polymorphism and obsessive-compulsive disorder in the Afrikaner population.

BACKGROUND: It has been proposed that the catechol-o-methyl transferase gene (COMT) may play a role in the pathogenesis of obsessive-compulsive disorder (OCD). Whereas studies in a North American population showed that the low activity (L) allele of a functional polymorphism in COMT was associated with OCD in male patients, this result was not supported by studies in a Japanese population. The present association study assessed the risk for OCD conferred by this COMT polymorphism in a geographically different patient group, namely, the relatively genetically homogeneous Afrikaner population of South Africa. METHODS: Fifty-four unrelated OCD patients and fifty-four sex-matched controls were recruited from the same Afrikaner community. Patients and controls were phenotyped (DSM-IV) and genotyped for a NlaIII polymorphism with H (high activity) or L (low activity) alleles in the COMT gene. RESULTS: The H/L genotype was significantly more common than expected in the OCD patient group (P = 0.0017). LIMITATIONS: Replication studies with related individuals may be useful in discovering factors underpinning the H/L genotype abundance in the Afrikaner population. CONCLUSIONS: These results emphasise the need for further studies in genetically homogeneous populations to help define the complex etiology of this disease.

Adult↗
PubMed2002

Eye movement disturbances in schizophrenia and a polymorphism of catechol-O-methyltransferase gene.

Previous studies suggested an association between the catechol-O-methyltransferase (COMT) Val/Met polymorphism and the performance on neuropsychological tests, measuring prefrontal function in schizophrenia. The aim of this study was to examine the relationship between this polymorphism and performance on oculomotoric tests in schizophrenic patients. The intensity of eye movement disturbances on fixation and smooth pursuit tests and the Val/Met polymorphism of COMT gene were studied in 117 schizophrenic patients (74 male and 43 female). In male schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was lower in subjects who had the Met/Met genotype, with significant difference compared to other genotypes. Also, a significantly higher frequency of the Met allele and the Met/Met genotype was found in male schizophrenic patients exhibiting a lower intensity of smooth pursuit disturbances, and a trend in this direction was observed for the intensity of fixation disturbances. No such relationship was found in female schizophrenic patients. The results obtained suggest that, in male schizophrenic patients the Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye movement disturbances. They also point to possible gender differences as to the role of COMT in brain function in schizophrenia.

Adolescent↗
PubMed1998

No association between anxiety disorders and catechol-O-methyltransferase polymorphism.

Several studies have shown that the morbidity risk for anxiety disorders is increased among the relatives of patients with obsessive-compulsive disorder (OCD). Recently, it was reported that a polymorphism of the catechol-O-methyltransferase (COMT) gene is significantly associated with OCD. The purpose of this study was to determine the association, if any, between the COMT polymorphism and anxiety disorders. We undertook an association study of the COMT polymorphism in 108 patients who met DSM-IV criteria for anxiety disorders and 135 healthy controls. All subjects were unrelated Japanese. The subdiagnostic groups did not differ significantly from the control group in either the genotypic or allelic frequencies. There were no statistically significant differences between the genotype and males, females, or a family history. The mean age of onset did not significantly differ among the genotypes. Our results suggest this functional COMT polymorphism does not make an important contribution to anxiety disorders in the Japanese population.

Adult↗
PubMed2001

Genotypes of catechol-O-methyltransferase and response to levodopa treatment in patients with Parkinson's disease.

A single nucleotide polymorphism at the nucleotide 1947 in the catechol-O-methyltransferase (COMT) gene encodes the high and low activity forms of the enzyme. We investigated COMT genotypes of 73 Korean patients with Parkinson's disease (PD), 29 with multiple system atrophy (MSA), and 49 controls, and analyzed the response to levodopa challenge in the PD patients. We found no significant difference in the distribution of the COMT genotypes among the three groups. The frequencies of the G- and A-alleles in the total population were 75 and 25%, respectively. The levodopa response was determined by a single oral levodopa challenge test with Sinemet (25/250 mg) in the patients with PD. The motor response evaluated by the time to peak response, the duration and magnitude of the response in the motor part of the Unified Parkinson's Disease Rating Scale; tapping or walking times showed no significant difference between the genotypes. Thus, pharmacokinetic or pharmacodynamic factors other than the investigated genetic variant of the COMT enzyme seem to determine the response to levodopa in PD.

Adult↗
PubMed2002

Metabolism of caffeic acid by isolated rat hepatocytes and subcellular fractions.

Caffeic acid (CA) is found in a wide variety of foods such as vegetables, fruits, tea, coffee, and wine. However, enzymes involved in its metabolism have not been identified. In the following, caffeic (CA), chlorogenic (CGA), and dihydrocaffeic (DHCA) acids were incubated with hepatocytes and shown to undergo metabolism by cytochrome P450, catechol-O-methyltransferase (COMT), and beta-oxidation enzymes. Ferulic (FA) or dihydroferulic (DHFA) acids, formed as the result of CA- or DHCA-O-methylation by COMT, were also O-demethylated by CYP1A1/2 but not CYP2E1. DHCA or DHFA also underwent side chain dehydrogenation to form CA and FA, respectively, which was prevented by thioglycolic acid, an inhibitor of the beta-oxidation enzyme acyl CoA dehydrogenase. The rates of glutathione conjugate formation catalyzed by NADPH/microsomes (CYP2E1) in decreasing order DHCA>CA>CGA trend which was in reverse order to the rates of their O-methylation by COMT. The CA- and DHCA-o-quinones formed by NADPH/P450 likely inhibited COMT but can readily form glutathione conjugates. CA, DHCA and DHFA were inter-metabolized to each other and to FA by isolated rat hepatocytes whereas FA was metabolized only to CA but not to DHCA or DHFA. CA, DHCA, FA, DHFA and CGA showed a dose-dependent hepatocyte toxicity and the LD(50) (2 h), determined were in decreasing order of effectiveness DHCA>CA>DHFA>CGA>FA. In summary, evidence has been provided that O-methylation, GSH conjugation, hydrogenation and dehydrogenation are involved in the hepatic metabolism of CA and DHCA. The O-methylation pathway for CA and DHCA is a detoxification route whereas o-quinones formation catalyzed by P450 is the toxification route.

Animals↗
PubMed2002

Quercetin metabolism in the lens: role in inhibition of hydrogen peroxide induced cataract.

Oxidative stress is implicated in the initiation of maturity onset cataract. Quercetin, a major flavonol in the diet, inhibits lens opacification in a lens organ culture oxidative model of cataract. The aim of this research was to investigate the metabolism of quercetin in the lens and show how its metabolism affects the ability to prevent oxidation-induced opacity. The LOCH model (Free Radical Biology & Medicine 26:639; 1999) was employed, using rat lenses to investigate the effects of quercetin and metabolites on hydrogen peroxide-induced opacification. High-performance liquid chromatography analysis showed that the intact rat lens is capable of converting quercetin aglycone to 3'-O-methyl quercetin (isorhamnetin). Over a 6 h culture period no further metabolism of the 3'-O-methyl quercetin occurred. Loss of quercetin in the lens was accounted for by the increase in 3'-O-methyl quercetin. Incubation with 3,5-dinitrocatechol (10 microM), a catechol-O-methyltransferase (COMT) inhibitor, prevented the conversion of quercetin to 3'-O-methyl quercetin. The presence of both membrane-bound and soluble COMT was confirmed by immunoblotting. The results demonstrate that in the rat lens COMT methylates quercetin and that the product accumulates within the lens. Quercetin (10 microM) and 3'-O-methyl quercetin (10 microM) both inhibited hydrogen peroxide- (500 microM) induced sodium and calcium influx and lens opacification. Incubation of lenses with quercetin in the presence of COMT inhibitor revealed that the efficacy of quercetin is not dependent on its metabolism to 3'-O-methyl quercetin. The results indicate dietary quercetin and metabolites are active in inhibiting oxidative damage in the lens and thus could play a role in prevention of cataract formation.

Animals↗