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PubMed2003

COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.

Responses to pain and other stressors are regulated by interactions between multiple brain areas and neurochemical systems. We examined the influence of a common functional genetic polymorphism affecting the metabolism of catecholamines on the modulation of responses to sustained pain in humans. Individuals homozygous for the met158 allele of the catechol-O-methyltransferase (COMT) polymorphism (val158met) showed diminished regional mu-opioid system responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in val158 homozygotes. The COMT val158met polymorphism thus influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli.

Adult↗

PubMed2004

Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women.

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

Aged↗

PubMed1997

The effect of COMT inhibition by tolcapone on tolerability and pharmacokinetics of different levodopa/benserazide formulations.

This double-blind, placebo-controlled, randomized, crossover study was designed to evaluate the effects of catechol-O-methyltransferase (COMT) inhibition by tolcapone on the pharmacokinetics of levodopa given as four different formulations of levodopa/benserazide: 50/12.5 mg, 100/25 mg, 200/50 mg (all standard release), or 100/25 mg (controlled release). Sixteen healthy volunteers, in two groups of 8, were given two different levodopa/benserazide formulations with and without tolcapone in random order on 4 days, each separated by a 7-day washout period. On each treatment day, 200 mg tolcapone or placebo (blinded) was taken orally 1 h before and 3 and 7 h after a single (unblinded) dose of levodopa/benserazide. All treatment combinations were well tolerated. Continuous inhibition of erythrocyte COMT activity by approximately 75% was observed over 13 h with tolcapone; this was unaffected by levodopa/benserazide formulation. Tolcapone had similar effects on plasma levodopa concentrations with the standard-release formulations: half-life and bioavailability increased approximately 2-fold compared with placebo, and maximum plasma concentration (Cmax) and time to Cmax (tmax) were unaffected, except for a slight increase in Cmax with the levodopa/benserazide 200/ 50 mg formulation. With the controlled-release formulation, tolcapone increased the levodopa area under the plasma concentration/time curve approximately 2-fold. Although levodopa tmax appeared delayed, the absorption phase was unaffected. Onset of levodopa effect is therefore not likely to be delayed when tolcapone is coadministered with this formulation. Regardless of levodopa/benserazide formulation, 3-O-methyldopa formation was reduced by 90% with tolcapone compared with placebo. These results show that tolcapone could potentiate the antiparkinsonian effects of levodopa independently of levodopa/benserazide formulation.

Adjuvants, Pharmaceutic↗

PubMed2004

No evidence of association between Catechol-O-Methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: a case-control study.

BACKGROUND: Several studies have suggested an association between the functional Val158Met polymorphism in the Catechol-O-Methyltransferase (COMT) gene and neurocognitive performance. Two studies showed that subjects with the low activity Met allele performed better on the Wisconsin Card Sorting Test (WCST) and another study found an effect on processing speed and attention. METHODS: We set out to examine the association between the Val158Met polymorphism and performance on neurocognitive tasks including those tapping working memory, attention and speed, impulsiveness and response inhibition in a sample of 124 children with ADHD. Task performance for each genotypic group was compared using analysis of variance. RESULTS: There was no evidence of association with performance on any of the neurocognitive tasks. CONCLUSIONS: We conclude that Val158Met COMT genotype is not associated with neurocognitive performance in our sample.

Adolescent↗

PubMed2006

Lack of association between COMT gene and deficit/nondeficit schizophrenia.

BACKGROUND: The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients. METHODS: Eighty-six schizophrenia cases that met DSM-IV criteria for schizophrenia were recruited. Additional categorization into deficit and nondeficit syndrome was performed using the Schedule for the Deficit Syndrome (SDS). A healthy comparison group (n = 50) matched to cases on age and ethnicity was recruited. Allele and genotype frequencies of the Val158Met polymorphism were compared among healthy controls, and schizophrenia cases with the deficit (n = 21), and nondeficit syndrome (n = 65). RESULTS: There was a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls (p = 0.004). No significant differences in allele or genotype frequencies were observed between deficit and nondeficit cases. CONCLUSION: Results from this preliminary analysis failed to show an effect of COMT gene on deficit schizophrenia.

Journal Article↗

PubMed1997

No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene. Biomed European Bipolar Collaborative Group.

BACKGROUND: There is compelling evidence for the existence of susceptibility genes for bipolar disorder. Association studies using functional DNA variations are an important approach for identifying these genes. The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamine neurotransmitters and is a candidate for involvement in bipolar disorder. Recently a common functional genetic polymorphism that underlies population variation in COMT activity has been elucidated and a simple assay developed. METHOD: In a collaboration involving seven European centres, we have undertaken an association study of this functional polymorphism in 412 unrelated West European caucasian DSM-III-R bipolar patients and 368 ethnically matched controls. RESULTS: We found no evidence of allelic or genotypic association. CONCLUSIONS: We can conclude that variation at this functional polymorphism does not make an important contribution to bipolar disorder in the Western European population. Future studies using this powerful experimental approach can be expected to contribute to identification of bipolar susceptibility genes.

Adult↗

PubMed1992

[18F]-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.

Adult↗

PubMed2004

COMT inhibitors in Parkinson's disease: can they prevent and/or reverse levodopa-induced motor complications?

COMT inhibitors have historically been used as adjuncts to levodopa in fluctuating PD patients to increase "on" time and reduce "off" time. Evidence that motor complications are related to intermittent or pulsatile stimulation of striatal dopamine receptors has led to the use of long-acting dopaminergic therapies that provide more continuous dopaminergic stimulation (CDS). CDS-based therapies are associated with the prevention and reversal of levodopa-related motor complications in MPTP-lesioned primates and PD patients. However, levodopa remains the most effective and widely used anti-parkinsonian agent and is eventually required in all PD patients. The standard oral formulation of levodopa has a relatively short half-life and is associated with the development of motor complications when used as either initial or supplemental therapy. The CDS concept raises the possibility that administration of levodopa in combination with a COMT inhibitor to extend its half-life might reduce the risk of inducing motor complications. This article considers the possibility that combining levodopa with entacapone may prevent or reverse motor complications.

Animals↗

PubMed2000

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.

Animals↗

PubMed1987

Semisynthetic beta-lactam antibiotics. III. Effect on antibacterial activity and comt-susceptibility of chlorine-introduction into the catechol nucleus of 6-[(R)-2-[3-(3,4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido]-2- phenylacetamido]penicillanic acid.

The resistance of 6-[(R)-2-[3-(3,4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido]-2- phenylacetamido]penicillanic acid (1a) to metabolism by catechol-O-methyl-transferase (COMT) was increased by introduction of the chlorine atom into the catechol moiety. Penicillins (1b-1d) having one or two chlorine atoms at the positions adjacent to the hydroxyl group were found to have greater stability to COMT. This resulted in greater efficiency in vivo in experimental Pseudomonas aeruginosa and Escherichia coli infections. In vitro activities were essentially unchanged.

Animals↗

PubMed2000

Practical issues with COMT inhibitors in Parkinson's disease.

Two inhibitors of catechol-O-methyl transferase (COMT), tolcapone and entacapone, have recently been introduced as adjuncts to levodopa in the treatment of Parkinson's disease patients. Both have been shown to provide PD patients with increased "on" time, decreased "off" time, and improved motor scores. There are, however, a number of practical issues that must be considered in order to achieve maximal benefits with this class of agent. They include dosing and administration, efficacy, adverse events, and patient education. In general, these agents are easy to administer and well tolerated. Both the benefits and the principal side effects of treatment are related to increased dopaminergic activity. Patients must be advised of possible side effects so that they can be reported in a timely manner. Physicians must appreciate that dopaminergic side effects, such as dyskinesia, should be controlled by adjusting the dose of levodopa and not the COMT inhibitor. Explosive diarrhea has been reported with tolcapone and usually necessitates discontinuing the drug. Tolcapone must also be monitored for possible liver dysfunction. This has not been reported with entacapone, and no monitoring is required. Metabolites of tolcapone and entacapone may cause discoloration of the urine. This is harmless but patients should be advised that this may occur.

Benzophenones↗

PubMed2006

[Prevalence of Val158Met polymorphism in COMT gene on non-BRCA1/2 hereditary breast cancer].

OBJECTIVE: To explore the prevalence of Val158Met polymorphism in Catechol-O-methyltransferase (COMT) gene and its effect on genetic susceptibility for breast cancer in Shanghai population. METHODS: A total of 114 patients with BRCA1/BRCA 2 negative hereditary breast cancer from independent families and 121 age-matched healthy controls were analyzed. Genotype analysis was conducted by polymerase chain reaction (PCR) and then DNA direct sequencing. The odd ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression model. RESULTS: The frequency of Val158Met polymorphism GG, GA and AA genotype in case group and control was 0.58 (65), 0.32 (36), 0.10 (11) and 0.60 (66), 0.35 (41), 0.03 (3), respectively. The frequency of allele-containing genotypes is significantly higher in early-onset breast cancer patients (0.57) than in familial ones (0.35). Compared with GG (Val/Val) genotype, AA (Met/Met) genotype confers a significantly increased risk for breast cancer (adjusted OR = 3.15; 95% CI, 0.70 - 14.19), especially among premenopausal women (adjusted OR = 9.98; 95% CI, 1.00 - 99.64). Borderline significantly association was found between AA genotype (adjusted OR = 7.57; 95% CI, 0.57 - 101.28) and susceptibility for breast cancer in BMI < or = 23 kg/m(2) group. CONCLUSIONS: Val158Met polymorphism in COMT gene could be a candidate for low penetrance breast cancer susceptibility in Shanghai population, especially among premenopausal women and early-onset breast cancer patients.

Adult↗

PubMed1989

[The dentistry of Blainville and the positivism of Comte].

COMTE improved BLAINVILLE's acquaintance when he was the secretary of SAINT-SIMON. They became friends. BLAINVILLE aided COMTE in his illness and financial troubles, taught him biology and was one of the first to support his philosophical ideas, through which he became self-conscious of his own value and scientific methods.

Biology↗

PubMed1983

Effect of adrenal medullectomy on the activity of COMT and MAO in adrenal cortex of control and stressed rats.

The effect of bilateral adrenal medullectomy on the activity of catecholamine degrading enzymes--catechol-o-methyl transferase (COMT) and monoamino oxidase (MAO)--in adrenal cortex and on the level of corticosterone in plasma was studied in the rats subjected either to a single (2.5 h) or repeated (2.5 h daily for 150 days omitting Saturdays and Sundays) immobilization stress. After medullectomy a significant increase of COMT activity was found in adrenal cortex of unstressed controls, while the activity of MAO was significantly decreased. Similar results were observed also in medullectomized animals subjected either to a single or repeated stress. The levels of corticosterone remained unchanged in medullectomized controls, but were significantly decreased in medullectomized and stressed animals. Although the mechanism still remains to be elucidated, these results may be considered as a further contribution to the understanding of the functional interrelations between the adrenal medulla and cortex.

Adrenal Cortex↗

PubMed1980

MAO, DBH and COMT: the effect of anxiety.

Anxiety, a common accompaniment of depression, can be a source of confusion in affective disorder research. The present study examined the effect of anxiety on platelet monoamine oxidase, RBC catechol-0-methyltransferase, and serum dopamine-beta-hydroxylase-enzymes frequently implicated in affective disorders. Levels of anxiety, plasma catecholamines and the enzymes mentioned above were quantified in groups of anxious subjects and mentally and physically healthy controls. Anxious subjects were found to have significantly higher levels of blood plasma catecholamines and platelet monoamine oxidase. significant positive correlations were demonstrated between plasma catecholamines and platelet monoamine oxidase, while significant inverse correlations were found between trait anxiety and COMT, norepinephrine and DBH, and COMT and DBH

Adult↗

PubMed2025

The importance of dopamine levels and single-nucleotide polymorphism within COMT, DRD1 and DRD2 genes in obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is a prevalent sleep disorder that contributes to serious cardiovascular comorbidities. While the mechanical aspects of OSA are well-studied, its neurobiological underpinnings remain underexplored. In this study, we investigated the role of dopamine and its genetic modulators in OSA pathophysiology. PATIENTS AND METHODS: Serum dopamine levels were assessed in a cohort of 153 participants (96 OSA patients and 57 controls), and single-nucleotide polymorphisms (SNPs) in dopamine-related genes, including COMT, DRD1 and DRD2, were analysed in a cohort of 286 participants (141 OSA patients and 145 controls). RESULTS: Elevated serum dopamine levels were observed in OSA patients (p = 0.01), with dopamine levels correlating independently with OSA and male gender. Genotypic analysis identified the DRD2 rs1800497 T allele as a potential independent predictor of OSA severity (p = 0.011), hypopnea (p = 0.005) and arousals (p = 0.024). CONCLUSIONS: This study advances the understanding of OSA by identifying elevated dopamine levels and genetic variations in DRD2 rs1800497 as potential modulators of its occurrence and severity. These findings pave the way for personalized diagnostic and therapeutic approaches. By integrating neurobiology, genetics, and clinical practice, this research contributes to the evolving framework for precision medicine in sleep disorders.

Humans↗

PubMed2000

No association between low- and high-activity catecholamine-methyl-transferase (COMT) and attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children.

Biochemical and genetic studies of attention deficit hyperactivity disorder (ADHD) suggest that regulation of catecholamine neurotransmission is a key factor in the aetiology of the disorder. In particular, it is postulated that an underactive dopamine system is associated with the disorder. In this study we have tested this hypothesis by screening a clinical sample of Turkish children with the combined subtype of ADHD with a functional variant of catecholamine-methyl-transferase (COMT) that codes for high- and low-activity variants of the enzyme. Using within-family tests of association and linkage in a sample of 72 children, we found no evidence for a genetic association or linkage. We conclude that altered regulation of catecholamines due to this polymorphism does not have a significant main effect on the risk for ADHD in this population. However, it remains feasible that more minor effects or interacting effects with other genes or environment exist.

Alleles↗

PubMed2000

Long forms of the dopamine receptor (DRD4) gene VNTR are more prevalent in substance abusers: no interaction with functional alleles of the catechol-o-methyltransferase (COMT) gene.

Substance abuse is a complex behavior that is caused by both environmental and genetic factors. Work to understand the genetic factors has focused on genes related to dopamine activity because of its critical role in rewarding and reinforcing behaviors. The DRD3 and other dopamine receptor subtypes are expressed in many areas of the limbic system, and have been the objects of study for their possible roles in several neuropsychiatric disorders. Interest in variants of the D4 gene was heightened by reports that some alleles were more frequent in individuals who score high on Novelty Seeking, an aspect of personality that may be related to drug seeking behavior. We now show that the long form of the DRD4 gene is more frequent in individuals with high quantity/frequency of drug use compared to controls (chi(2) = 5.7, df = 1, P = 0.017, odds ratio = 1.89, CI = 1.1-3.2). There is no difference in DRD3 allele frequencies in these samples, and there is no interaction of DRD4 alleles with those of the catecholamine-o-methyl- transferase gene (COMT) that we previously identified to be more frequent in substance abusers than controls [Vandenbergh, et al.: 1997: Am. J. Med. Gen. 74:439-442].

Alleles↗