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PubMed2005

The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia.

The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. Schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia.

Adult↗
PubMed1998

Catechol-O-methyltransferase and breast cancer risk.

Recent studies suggest that a polymorphism in catechol-O-methyltransferase (COMT) is associated with increased risk of breast cancer. Methylation by COMT is the principal pathway for inactivation of catechol estrogens, which are hypothesized to participate in estrogen-induced carcinogenesis. We examined the association of COMT genotype and breast cancer risk in a population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 654 cases and 642 controls, with approximately equal numbers of African-American and white women and women under the age of 50 and aged 50 or over. Contrary to previous reports, we did not observe an association between one or more copies of the low activity COMT allele (COMT-L) and breast cancer risk. Multivariate relative risks (RRs) were 0.8 (95% confidence interval: 0.6-1.1) for COMT-HL and 0.8 (0.6-1.1) for COMT-LL, compared with the COMT-HH genotype. RRs for COMT did not differ among African-American and white women and we did not observe strong modification of RR estimates by menopausal status, body mass index, physical activity or other covariates. Our results suggest that COMT genotype is not related to breast cancer risk.

Adult↗
PubMed1991

Stress Responses in Alfalfa (Medicago sativa L.): X. Molecular Cloning and Expression of S-Adenosyl-l-Methionine:Caffeic Acid 3-O-Methyltransferase, a Key Enzyme of Lignin Biosynthesis.

S-Adenosyl-l-methionine:caffeic acid 3-O-methyltransferase (COMT, EC 2.1.1.6) catalyzes the conversion of caffeic acid to ferulic acid, a key step in the biosynthesis of lignin monomers. We have isolated a functionally active cDNA clone (pCOMT1) encoding alfalfa (Medicago sativa L.) COMT by immunoscreening a lambdaZAPII cDNA expression library with anti-(aspen COMT) antibodies. The derived amino acid sequence of pCOMT1 is 86% identical to that of COMT from aspen. Southern blot analysis indicates that COMT in alfalfa is encoded by at least two genes. Addition of an elicitor preparation from bakers' yeast to alfalfa cell suspension cultures resulted in a rapid accumulation of COMT transcripts, which reached a maximum level around 19 hours postelicitation. Northern blot analysis of total RNA from different organs of alfalfa plants at various developmental stages showed that COMT transcripts are most abundant in roots and stems. Transcripts encoding ATP: i-methionine-S-adenosyl transferase (AdoMet synthetase, EC 2.5.1.6), the enzyme responsible for the synthesis of the methyl donor for the COMT reaction, were coinduced with COMT transcripts in elicitor-treated cells and exhibited a similar pattern of expression to that of COMT in different organs of alfalfa plants at various stages of development.

Journal Article↗
PubMed1980

Developmental patterns of catechol-O-methyltransferase in genetically different rat strains: enzymatic and immunochemical studies.

Catechol-O-methyltransferase (COMT) activity in the liver and kidneys of adult Fischer-344 (F-344) rats is only half of that in the same organs of Wistar-Furth (W-F) rats. The trait of low COMT activity in these animals is inherited in an autosomal recessive fashion. A comprehensive study of patterns of change in COMT activity during growth and development was performed to determine whether "temporal gene" effects might play a role in the inherited differences in enzyme activity present in adult animals. The COMT activity expressed per mg protein in liver and kidneys of newborn F-344 rats is only 50-60% of that in the same organs of W-F animals. The liver and the kidneys of newborn rats of both strains have COMT activity an order of magnitude higher than those in brain, heart, or blood. In addition, in both strains there are much larger increases in liver and kidney COMT activities during growth and development (5-10 fold) than in blood, brain, or heart (one- to twofold). Immunotitration with antibodies against rat COMT demonstrates that differences in immunoreactive COMT parallel differences in COMT activity, both between strains and within strains during growth and development. However, when the temporal patterns of change in enzyme activities in the liver and the kidneys of the two strains of rat are compared at multiple times during growth and development, no differences in the patterns are present. These results make it unlikely that temporal gene effects can explain the inherited differences in COMT activity in liver and kidneys of F-344 and W-F rats.

Aging↗
PubMed1994

The disposition of the tolcapone 3-O-methylated metabolite is affected by the route of administration in rats.

Catechol-O-methyltransferase (COMT) catalyses the transfer of the methyl group from S-adenyl-L-methionine (SAM) to one of the hydroxy groups of a catechol, usually the hydroxy group in position 3. COMT is present mainly in a soluble form (S-COMT) in the cytosol, but a small fraction is bound to cell membranes (MB-COMT). MB-COMT has higher affinity for the catechol substrate than does S-COMT by a factor of > 10, and high MB-COMT activity is observed in the intestinal muscle layer. The present study investigates the effect of the administration route on the disposition of the tolcapone 3-O-methylated metabolite following intravenous and oral tolcapone administration in rats. Tolcapone is a substrate for COMT although the 3-O-methylated metabolite produced has no pharmacological actions. The 3-O-methylated metabolite was eliminated very slowly following oral administration of tolcapone, and its concentration approached a plateau level, which was in contrast to the situation following intravenous administration of tolcapone. It is thought that the oral dose of tolcapone receives a high exposure to MB-COMT in the intestinal muscle layer during its absorption, and tolcapone seems to form a complex with MB-COMT having a high affinity constant (i.e. a very low Ki). The fraction of the intravenous dose of tolcapone metabolized to the 3-O-methylated metabolite at 10 mg kg-1 was 2.6%, whereas those of the oral doses, which were corrected by the bioavailability, were 5.4% for 20 mg kg-1 and 2.7% for 40 mg kg-1.

Administration, Oral↗
PubMed2002

Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice.

Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake(1), followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake(2), followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO). For dopaminergic neurons, uptake by the high-affinity dopamine transporter (DAT) is the most effective mechanism, and the contribution of glial COMT remains secondary under normal conditions. In the present study we have characterized the role of COMT using COMT-deficient mice in conditions where DAT is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12909) or cocaine. In mice lacking COMT, GBR 12909 results in total brain tissue dopamine levels generally higher than in wild-type mice but no such potentiation was ever seen in striatal extracellular fluid. Dopamine accumulation in nerve endings is more evident in striatum and hypothalamus than in cortex. Both GBR 12909 and cocaine induced hyperlocomotion in mice lacking COMT. Unexpectedly, hyperactivity induced by 20 mg/kg GBR 12909 was attenuated only in male COMT knockout mice, i.e., they had an inability to sustain the hyperactivity induced by DAT inhibition. Furthermore, attenuation of hyperlocomotion was observed also after cocaine treatment in both C57BL/6 (at 5 and 15 mg/kg) and 129/Sv (at 30 mg/kg) genetic background COMT-deficient male mice. Despite the possible interaction between DAT and extraneuronal uptake (and subsequently COMT), the role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited.

Animals↗
PubMed2002

Assay of catechol-O-methyltransferase activity in human erythrocytes using norepinephrine as a natural substrate.

BACKGROUND: Catechol-O-methyltransferase (COMT) catalyses the inactivation of catecholamines. It is widely distnbuted in most tissues in soluble (S-COMT) and membrane-bound (MB-COMT) forms. Recently, we used a new assay for COMT activity and demonstrated that COMT plays an important role in blood pressure regulation in spontaneously hypertensive rats. In order to investigate whether this is true for human hypertension, we have evaluated the erythrocyte COMT assay in humans. METHOD: The assay procedure included the use of norepinephrine (NE) as a natural substrate and the quantification of the reaction product, normetanephrine, followed by high-performance liquid chromatography separation and fluorescence or chemiluminescence detection. RESULTS: After evaluation of the method, the optimum conditions were obtained for the assay of human erythrocyte COMT. The S- and MB-COMT activities obtained were 50.6 (24.5) and 329.8 (179.4) fmol/min/mg protein, respectively [mean (standard deviation); n = 54]. The Km values for NE were 91.3 (14.1) and 11.7 (1.1) micromol/L for S- and MB-COMT, respectively (n = 6). CONCLUSION: The established assay method used to assess S- and MB-COMT activities in human erythrocytes could be useful to elucidate catecholamine metabolism in the normal physiological state as well as in the pathology of certain diseases.

Adult↗
PubMed2006

Departure from multiplicative interaction for catechol-O-methyltransferase genotype and active/passive exposure to tobacco smoke among women with breast cancer.

BACKGROUND: Women with homozygous polymorphic alleles of catechol-O-methyltransferase (COMT-LL) metabolize 2-hydroxylated estradiol, a suspected anticarcinogenic metabolite of estrogen, at a four-fold lower rate than women with no polymorphic alleles (COMT-HH) or heterozygous women (COMT-HL). We hypothesized that COMT-LL women exposed actively or passively to tobacco smoke would have higher exposure to 2-hydroxylated estradiol than never-active/never passive exposed women, and should therefore have a lower risk of breast cancer than women exposed to tobacco smoke or with higher COMT activity. METHODS: We used a case-only design to evaluate departure from multiplicative interaction between COMT genotype and smoking status. We identified 502 cases of invasive incident breast cancer and characterized COMT genotype. Information on tobacco use and other potential breast cancer risk factors were obtained by structured interviews. RESULTS: We observed moderate departure from multiplicative interaction for COMT-HL genotype and history of ever-active smoking (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 0.7, 3.8) and more pronounced departure for women who smoked 40 or more years (aOR = 2.3, 95% CI: 0.8, 7.0). We observed considerable departure from multiplicative interaction for COMT-HL genotype and history of ever-passive smoking (aOR = 2.0, 95% CI: 0.8, 5.2) or for having lived with a smoker after age 20 (aOR = 2.8, 95% CI: 0.8, 10). CONCLUSION: With greater control over potential misclassification errors and a large case-only population, we found evidence to support an interaction between COMT genotype and tobacco smoke exposure in breast cancer etiology.

Journal Article↗
PubMed1994

Ethnic differences in erythrocyte catechol-O-methyltransferase activity in black and white Americans.

Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catecholamine and catechol drugs such as levodopa and methyldopa. Human COMT activity is inherited as an autosomal co-dominant trait; approximately 25% of white individuals have low activity consistent with homozygosity for a low activity allele, about 50% have intermediate activity (i.e., heterozygous genotype) and 25% have high activity. COMT activity has not been characterized in African-Americans or other black populations. To investigate potential ethnic and gender differences in COMT, we measured erythrocyte COMT activity in 195 unrelated black and 202 unrelated white healthy individuals living in the Southeast United States. Overall, the black population had significantly higher COMT activity than the white population (median 15.7 vs. 11.4 U/ml of packed red blood cell volume; P < .001). Maximum likelihood estimation of COMT activity distribution identified significant ethnic differences, with high activity in 23% of whites and 55% of blacks, intermediate activity in 50% of whites and 38% of blacks and low activity in 27% of whites and 7% of blacks. No greater differences in COMT activity were observed in either ethnic group. We conclude that red blood cell COMT activity is significantly higher in black subjects than white subjects. Hardy-Weinberg estimates indicate that this ethnic difference is due to a higher frequency of high activity COMT alleles in blacks vs. whites (0.74 vs. 0.48).

Adolescent↗
PubMed2001

L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase.

High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.

Animals↗
PubMed1993

Inhibition of catechol-O-methyltransferase by 1-vinyl derivatives of nitrocatechols and nitroguaiacols. Kinetics of the irreversible inhibition by 3-(3-hydroxy-4-methoxy-5-nitro benzylidene)-2,4-pentanedione.

It is well known that activated alkene derivatives react with thiol groups according to a Michael's addition reaction. On the basis of the presence of at least one thiol group essential for the activity of catechol-O-methyltransferase (COMT), several 1-vinyl derivatives of nitrocatechol and nitroguaiacol were synthesized and tested as potential irreversible active site-directed inhibitors of COMT. All the synthesized products were potent inhibitors of partially purified pig liver COMT. However, the inhibition was reversible in most cases, with the exception of 3-(3-hydroxy-4-methoxy-5-nitrobenzylidene)-2,4-pentanedione (compound 2) which inhibited COMT in an irreversible manner. When the inhibition of COMT was measured as a function of the length of time of pre-incubation with 2, biphasic kinetics were observed, suggesting the modification of at least two thiol groups which are essential for COMT activity. The analysis of the two parts of the inhibition curve as a function of the inhibitor concentration showed that compound 2 modified the more reactive group in a non-specific manner, while it behaved as an active site-directed inhibitor on the second slow-reacting thiol group. Importantly, a saturating concentration of S-adenosyl-L-methionine (AdoMet) in the pre-incubation mixture gave pseudo-first order kinetics, suggesting total protection of one thiol group. Magnesium ions had no effect on the protection of COMT by AdoMet. In the presence of 3,5-dinitrocatechol (DNC) slight protection of COMT was observed; when the inactivation of both groups was analysed independently, protection of the specifically modified group was detected, while the reaction with the other group was faster in the presence of DNC. When both AdoMet and DNC were present, inactivation of COMT by 2 was not observed, suggesting that both reacting groups are located at or near the active site.

Animals↗
PubMed2004

Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women.

Schizophrenia is a complex disorder with a polygenic inheritance. Catechol-O-methyltransferase (COMT) plays a significant role in the regulation of dopaminergic systems. A polymorphism at COMT Val108/158Met has been identified in association with schizophrenia. We examined the allele and genotype association of the COMT Val108/158Met polymorphism of 297 unrelated schizophrenic patients who strictly met DSM-IV criteria for schizophrenia, and 341 healthy controls. We found significant difference in allele and genotype frequencies between schizophrenic patients and controls (chi2=13.030; P=0.001). The allele frequency of the COMT-L was 45.79% in the total schizophrenic patients, and 41.50% in controls. The genotype frequency of the COM-LL was 21.2% in the total schizophrenic patients, and 11.4% in controls (OR=2.085; 95% CI=1.350-3.219; chi2=11.293; P=0.001). With a separate sex analysis, the frequency of the COMT-L allele was moderately distributed in male schizophrenia (chi2=6.177; df=2; P=0.046). The COMT-LL genotype had a 1.818-fold increased risk for schizophrenia (OR=1.818; 95% CI=1.010-3.273; chi2=4.048; P=0.044). The frequency of the COMT-L allele was even more significantly distributed in women schizophrenia (chi2=7.797; df=2; P=0.020). The COMT-LL genotype had remarkably more increased risk for schizophrenia (OR=2.456; 95% CI=1.287-4.687; chi2=7.710; P=0.005). In conclusion, our results provide strong evidence for a role of the COMT-L allele and LL genotype in the etiopathophysiology of schizophrenia with a sexual difference.

Adult↗
PubMed2003

Effects of peripheral and central catechol-O-methyltransferase inhibition on striatal extracellular levels of dopamine: a microdialysis study in freely moving rats.

Tolcapone is a mixed (peripheral and central) catechol-O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of L-DOPA into 3-O-methyl-DOPA and thereby increase plasma and cerebral levels of L-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of L-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following L-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of L-DOPA and DA compared with saline. The levels of L-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.

Animals↗
PubMed1987

Kinetic reaction mechanism for magnesium binding to membrane-bound and soluble catechol O-methyltransferase.

Catechol O-methyltransferase (COMT, EC 2.1.1.6) from human brain occurs in both a membrane-bound (MB-COMT) and a soluble form (SOL-COMT). While these enzymes appear to be distinct molecular entities, both catalyze the O-methylation of catecholamines through an ordered reaction mechanism in which S-adenosylmethionine (SAM) is the leading substrate [Rivett, A. J., & Roth, J. A. (1982) Biochemistry 21, 1740-1742; Jeffery, D. R., & Roth, J. A. (1985) J. Neurochem. 44, 881-885]. Both MB-COMT and SOL-COMT require the presence of divalent cations for catalytic activity. This series of experiments provides evidence indicating that magnesium ions bind to both MB-COMT and SOL-COMT in a rapid equilibrium sequence prior to the addition of SAM. An equation is presented that predicts the qualitative results obtained in all kinetic experiments carried out with either MB-COMT or SOL-COMT.

Brain↗
PubMed2006

The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures.

The human gene for catechol O-methyltransferase (COMT) contains a common polymorphism that results in substitution of methionine (M) for valine (V) at residue 108 of the soluble form of the protein. While the two proteins have similar kinetic properties, 108M COMT loses activity more rapidly than 108V COMT at 37 degrees C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 degrees C. The 108M allele has been associated with increased risk for breast cancer, obsessive-compulsive disorder, and aggressive and highly antisocial manifestations of schizophrenia. In the current work, we have constructed homology models for both human COMT polymorphs and performed molecular dynamics simulations of these models at 25, 37, and 50 degrees C to explore the structural consequences of the 108V/M polymorphism. The simulations indicated that replacing valine with the larger methionine residue led to greater solvent exposure of residue 108 and heightened packing interactions between M108 and helices alpha2, alpha4 (especially with R78), and alpha5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 A away, leading to a loosening of the active site. At physiological temperature, 108M COMT sampled a larger distribution of conformations than 108V. 108M COMT was more prone to active-site distortion and had greater overall, and SAM binding site, solvent accessibility than 108V COMT at 37 degrees C. Similar structural perturbations were observed in the 108V protein only at 50 degrees C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.

Amino Acid Sequence↗
PubMed2003

Catechol-O-methyltransferase inhibition in erythrocytes and liver by BIA 3-202 (1-[3,4-dibydroxy-5-nitrophenyl]-2-phenyl-ethanone).

The present study evaluated the relationship between the degree of catechol-O-methyltransferase (COMT) inhibition in erythrocytes and liver by BIA 3-202 (1-[3,4-dihydroxy-5-nitrophenyl]-2-phenyl-ethanone) and determined its effects upon the O-methylation of L-DOPA in rats orally treated with L-DOPA plus benserazide. The soluble form of COMT (S-COMT) in erythrocytes was endowed with the same affinity as liver S-COMT for the substrate adrenaline. BIA 3-202 inhibited erythrocytes and liver S-COMT with ED50's of 1.9 (0.7, 3.1) and 1.9 (0.5, 3.2) (95% confidence limits) mg kg(-1), respectively. BIA 3-202 reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation, striatal dialysate levels and striatum, and increased dopamine striatal levels. In BIA 3-202-treated rats the increase in L-DOPA in peripheral blood and striatal dialysates was significantly greater than in vehicle-treated rats. It is concluded that S-COMT activity in erythrocytes may provide important information on the pharmacodynamic profile of COMT inhibitors. The novel COMT inhibitor BIA 3-202 is a potent COMT inhibitor that enhances the availability of L-DOPA to the brain by reducing its O-methylation, which may prove beneficial in patients with Parkinson's disease treated with L-DOPA.

Acetophenones↗
PubMed2005

The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val(108/158)Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMT(VAL/VAL) and COMT(VAL/MET) genotype carriers showed a better response than COMT(MET/MET)-bearing patients in the mirtazapine group. Moreover, carriers of the COMT(VAL/VAL) or COMT(VAL/MET) genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMT(MET/MET) homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Adult↗
PubMed1998

Induction of nuclear catechol-O-methyltransferase by estrogens in hamster kidney: implications for estrogen-induced renal cancer.

Catecholestrogens are postulated to contribute to carcinogenesis by causing DNA damage mediated by reactive oxygen species generated during redox cycling between catechol and quinone estrogens, and by quinone estrogens that can form depurinating adducts. The above hypothesis is based principally on studies of the cancers that develop in renal cortex of hamsters treated with primary estrogens: Hamster kidney can catalyze 2- and 4-hydroxylation of estrogens and support their redox cycling, and the kidneys of estradiol-treated hamsters show evidence of oxidative cellular and DNA damage. Here we used immunocytochemisty to test the postulate that catechol-O-methyltransferase (COMT), the enzyme that can prevent oxidation of catecholestrogens to their quinone derivatives, would be induced in renal cortex of hamsters treated with estradiol or ethinyl estradiol. In kidneys of control hamsters, COMT was localized in cytoplasm of epithelial cells of proximal convoluted tubules, predominantly in the juxtamedullary region where the estrogen-induced cancers arise. After 2- or 4-weeks of treatment with either estrogen, COMT was seen in epithelial cells of proximal convoluted tubules throughout the cortex, and many cells also showed intense nuclear COMT immunoreactivity. Estradiol-induced renal cancers were negative for COMT, but were surrounded by tubules with intense cytoplasmic and nuclear immunostaining. The nucleus-associated COMT was shown by immunoblot analysis to be the soluble form of the enzyme. Using reverse transcription-polymerase chain reaction amplification, hamster kidney COMT was shown to lack the putative nuclear localization signal sequence present in human COMT. A second phase II enzyme, CuZn-superoxide dismutase (CuZnSOD), was shown by immunocytochemistry to remain extranuclear in proximal convoluted tubules of estrogen-treated hamsters, which indicates entry of COMT into the nucleus to be selective. The findings are consistent with the catechol/quinone estrogen hypothesis of estrogen-induced cancer, while the translocation of the enzyme to the nucleus following estrogen treatment suggests a response to a threat to the genome by electrophilic products of catechols.

Amino Acid Sequence↗