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PubMed2000

The activity of catechol-O-methyltransferase in parkinsonian patients with "on-off fluctuations".

Motor fluctuations complicate therapy in Parkinson's disease (PD). The mechanisms responsible for motor fluctuations such as the on-off type, are poorly understood. Differences of activity of various enzymes, such as Catechol-O-Methyltransferase (COMT, E.C.2.1.1.6.) may influence the appearance of motor fluctuations and the quantity of metabolic products of levodopa. Aim of this study was to compare erythrocyte COMT-activity in Parkinsonian patients without and with motor fluctuations from the on-off type. No significant differences in COMT-activity appeared in both groups. We conclude that activity differences in COMT-activity do not contribute to the appearance of motor fluctuations in Parkinson's disease.

Aged↗

PubMed2001

The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in L-DOPA/carbidopa treated rats.

Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with L-DOPA (L-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of L-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with L-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. L-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 microl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with L-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Animals↗

PubMed2004

Evidence for the existence of PAH-quinone reductase and catechol-O-methyltransferase in Mycobacterium vanbaalenii PYR-1.

Polycyclic aromatic hydrocarbon (PAH) quinone reductase (PQR) and catechol-O-methyltransferase (COMT), from the PAH-degrading Mycobacterium vanbaalenii PYR-1, were demonstrated to be constitutive enzymes located in the soluble fraction of cell extracts. PQR activities for the reduction of 9,10-phenanthrenequinone and 4,5-pyrene- quinone were 1.40+/-0.13 and 0.12+/-0.01 micromol min(-1) mg-protein(-1), respectively. The exogenous catechols alizarin, anthrarobin, 2,3-dihydroxynaphthalene and esculetin inhibited PQR activity. Anthrarobin (100 microM) and esculetin (100 microM) inhibited 4,5-pyrenequinone reduction by 64-92%. COMT was involved in the O-methylation of 1,2-dihydroxyphenanthrene to form 1-methoxy-2-hydroxyphenanthrene and 1,2-dimethoxyphenanthrene. Both pyrene and 1-hydroxypyrene were metabolized by M. vanbaalenii PYR-1 to form 1-methoxypyrene, 1-methoxy-2-hydroxypyrene, 1-hydroxy-2-methoxypyrene and 1,2-dimethoxypyrene. Among the catechols tested, anthrarobin showed the highest COMT activity (1.06+/-0.04 nmol/30 min(-1) mg-protein(-1)). These results suggest that the PQR and COMT activities of M. vanbaalenii PYR-1 may play an important role in the detoxification of PAH catechols.

Biotransformation↗

PubMed2006

Meta-analysis of association between a catechol-O-methyltransferase gene polymorphism and attention deficit hyperactivity disorder.

There have been conflicting reports on the association between the Val158/108Met polymorphism of the catechol-O-methyltransferase (COMT) gene and attention deficit hyperactivity disorder (ADHD). Therefore we would like to perform a meta-analysis of previous studies to assess the overall magnitude and significance of the association. Family-based and case-control studies of the association between the COMT gene polymorphism and ADHD were searched systematically and comprehensively. Odds ratios (OR) of association were pooled by the fixed effects model if no significant heterogeneity was present among different studies. Subgroup analysis by gender and ADHD subtypes were also performed. Eleven family-based and two case-control studies were identified. After pooling the results, no significant association between the COMT Vall58/108Met polymorphism and ADHD was found (OR 0.99 (95% CI: 0.88-1.12), P = 0.87). There was also no significant association when the results were stratified by gender or ADHD subtype. There was no significant statistical heterogeneity (chi2 = 12.27, P = 0.2) although clinical heterogeneity was present in the studies, especially the ethnicity of subjects. Sensitivity analysis demonstrated absence of undue influence of any single study. Standard regression analysis showed no significant publication bias. We concluded that no significant association was present between the most common COMT gene polymorphism and ADHD. Further studies should employ larger sample size in more homogeneous subjects. Further investigations in moderator variables and gene-gene and gene-environment interactions are also warranted.

Amino Acid Substitution↗

PubMed2005

Estrogen metabolizing polymorphisms and breast cancer risk among older white women.

OBJECTIVE: To investigate breast cancer risk according to metabolizing genes polymorphisms in older women. METHODS: A subset (43.8%) of 4248 older, white women from the Study of Osteoporotic Fractures (SOF) were genotyped for the catechol-O-methyltransferase (COMT) Val108Met polymorphism and the CYP1A1*2C locus. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between genotypes and breast cancer while controlling for potential confounders. RESULTS: During a mean follow up of 12.4 years, 252 women (5.9%) developed breast cancer. The HR (95% CI) for breast cancer was 1.24 (0.87-1.75) for COMT(Val/Met) and 1.35 (0.93-1.97) for COMT(Met/Met). No interactions with lifestyle and reproductive factors were found. The HR associated with the CYP1A1*2C Val allele was 0.80 (0.46, 1.39) with little evidence for interactions with lifestyle or reproductive factors. CONCLUSIONS: Among older white women, neither the COMT Val108/158Met polymorphism nor the CYP1A*2C Val allele plays a major role in breast cancer risk either alone or in combination with lifestyle and reproductive factors.

Aged↗

PubMed2006

Catechol-O-methyltransferase haplotypes and breast cancer among women on Long Island, New York.

The gene encoding catechol-O-methyltransferase (COMT), critical to the inactivation of reactive catechol estrogens, has several single nucleotide polymorphisms (SNPs) that influence enzyme activity. A 3-SNP haplotype (IVS1+255 C>T; Ex4-12 G>A; 3'UTR-521 A>G), which has been shown to reduce COMT expression in the human brain, has been identified. To evaluate the influence of genetic variation of COMT on breast cancer risk, these 3-SNPs were genotyped in 1052 cases and 1098 controls. We estimated the associations between breast cancer and individual SNPs, as well as, multilocus haplotypes. We also examined surrogates of hormone exposure as potential modifiers of the putatively functional Ex4-12 SNP-breast cancer association. Odds ratios (OR) and 95% confidence intervals (CI) were based on age-adjusted unconditional logistic regression models. We found no association between the individual SNPs alone and breast cancer. When examining the association between breast cancer and the 3-SNP haplotypes, we observed a 19% increase in risk associated with each copy of the TGG haplotype (OR=1.19, 95% CI 0.96-1.49), relative to the common TAA haplotype, which was statistically significant when assuming a dominant model (OR=1.32, 95% CI 1.05-1.67, p-value=0.02). In this report of COMT haplotypes and breast cancer, we found some evidence that additional genetic variability beyond the Ex4-12 G>A SNP contributes to risk of breast cancer among a small subgroup of women; however, these results need to be replicated in additional studies.

Adult↗

PubMed1979

Catechol-O-methyltransferase activity in erythrocytes of women taking oral contraceptive steroids.

We have measured catechol-O-methyltransferase (COMT) activity in erythrocytes (red blood cells, RBCs) obtained from 64 women taking oral contraceptives steroids and compared these values with those found in RBCs obtained from 73 women using nonsteroidal contraceptives. The COMT activity in the RBCs of women taking oral contraceptives steroids and of women not taking contraceptive steroids was 9.1 +/- 0.28 (mean and standard error) and 8.8 +/- 0.26 nmoles 2-methoxyestrone X ml-1 RBC X hr-1, respectively. This difference in the COMT activity in RBCs from these two groups of women was not statistically significant. This finding differs from that of others who found that COMT activity in RBCs of women taking oral contraceptive steroids was greater than that of women not taking such drugs.

Adult↗

PubMed1987

Effects of anoxia and ischemia on uptake2 of catecholamines in perfused rat heart.

The effects of 30 min periods of either anoxia or ischemia (stop-flow) on the uptake2 of isoprenaline and on the production of O-methyl-isoprenaline, a major metabolite of isoprenaline formed by catechol-O-methyltransferase (COMT), were examined in the perfused rat heart. After either glucose deprivation or anoxia, the uptake2 of isoprenaline in hearts subsequently perfused with isoprenaline and 3',4'-dihydroxy-2-methyl-propiophenone, a COMT inhibitor, was similar to control values. However, uptake2 was decreased following either anoxia in association with glucose deprivation or ischemia. In the absence of the COMT inhibitor, neither glucose deprivation nor anoxia alone had any effect on the production of [3H]3-O-methyl-isoprenaline from [3H]isoprenaline, but both anoxia together with glucose deprivation and stop-flow ischemia decreased it. These findings indicate that both anoxia coupled with glucose deprivation and ischemia inhibit both uptake2 and COMT activity and suggest that such inhibition may be responsible for the high concentration of catecholamines released locally following myocardial infarction.

Animals↗

PubMed1983

Possible mechanism of action of 2-hydroxylated estradiol on the positive feedback control for LH release in the rat.

Evidence was given to support a positive role of 2-hydroxyestradiol on the LH surge. The catecholestrogen may act by its catechol A ring on the nucleus arcuatus COMT, consequently leaving the noradrenaline free. The result may be a longer action on the peptidergic terminal in the median eminence and an increase in the LH secretion by the pituitary. This assumption is supported by the observations that the catecholestrogen effect can be mimicked by homocystein, an aminoacid able also to inhibit COMT activity, having neither a steroid nor a catechol structure. The fact that alpha-MIT is able to prevent homocystein-induced increase in LH suggests that it is acting by protecting the local increase of the catecholamine. After ten years of intensive effort to understand the possible physiological role of the catecholestrogens, attention was mostly paid to its structural similarity to estrogen and a great deal of effort was made to understand its function by acting upon the estrogen receptor in the cytosol. The evidence for catecholestrogen action upon COMT, an outside membrane enzyme involved in the process of catecholamine degradation, supports the idea of a catechol action for 2-OHE2. The present evidence strongly supports the physiological importance of the catechol group in the 2-OHE2 in its action mechanism. However, a true physiological role for the catecholestrogens remains to be solved. The evidence we bring confirms once more that catecholestrogens may have a function and explains a new mechanism of action. However, the basic question concerning the true amount of catecholestrogen existing in the hypothalamic nuclei, either brought by the blood stream or locally produced, still needs to be solved: we cannot say whether the mechanism we described is a functioning one, whether it is just brought about by the experimental increase of the catecholestrogen or the artificial blockage of COMT.

Animals↗

PubMed1988

Properties of novel effective and highly selective inhibitors of catechol-O-methyltransferase.

Novel bisubstituted catechols were found to be potent and highly selective COMT inhibitors in vitro. One of them, OR-462 (3-(3,4-dihydroxy-5-benzylidene)-2,4-pentanedione), was studied also in vivo. When administered to rats orally together with levodopa and carbidopa, OR-462 greatly improved the bioavailability of levodopa and effectively reduced the formation of 3OMD. The levels of levodopa and dopamine were increased also in the striatum, and the 3OMD levels were decreased. The metabolic profile of dopamine demonstrated that COMT inhibition occurred in the peripheral tissues but not in the striatum. OR-462 thus resembled the peripheral inhibitors of dopadecarboxylase. These potent, selective and orally active COMT inhibitors offer a new tool for interfering in the metabolism of various COMT substrates.

Animals↗

PubMed1988

Extraneuronal accumulation of isoproterenol in atria and ventricle of perfused rat heart.

Extraneuronal accumulation of isoproterenol in atria and ventricle of perfused rat heart was investigated. Rat hearts were perfused with various concentrations of 3H-isoproterenol for 30 min in the absence and the presence of catechol-O-methyltransferase (COMT) inhibitor (tropolone). When COMT was intact, the accumulation of 3H-isoproterenol in both atria and ventricle after perfusion with low concentration of 3H-isoproterenol (0.01 to 1 mumol/l) was less than that of perfusing concentration; the tissue/medium ratio (T/M) of isoproterenol for artia was lower than that for ventricle. The T/M of isoproterenol after perfusion with 10 and 20 mumol/l of 3H-isoproterenol were 0.94 and 1.76 for atria and 3.25 and 2.95 for ventricle, respectively. When COMT was inhibited by tropolone, the T/M increased 6.3-9.0 folds for atria and 5.1-6.7 folds for ventricle after perfusion with 3H-isoproterenol (0.01 to 1 mumol/l). From these results, it was concluded that both atria and ventricle of the rat heart have an extraneuronal O-methylating system as reported in rat whole heart, and was suggested that there might be different capacities of extraneuronal uptake and COMT between them.

Animals↗

PubMed1986

beta-phenylethylamine effect on brain and blood catechol-O-methyltransferase activity.

A significant decrease in catechol-o-methyltransferase (COMT) activity has been found in the striatum (77% of control) and hippocampus (63% of control) of gerbils treated with daily injections of beta-phenylethylamine (50 mg/kg) for 10 days. This treatment group also exhibited increased (204% above control) COMT activity in a lysed red blood cell preparation. There were no changes in COMT activity in groups receiving 10 mg/kg beta-phenylethylamine or haloperidol (0.5 mg/kg). In vitro beta-phenylethylamine has no demonstrable effect on COMT activity.

Animals↗

PubMedDate not supplied

Effect of oestrogens and progesterone on the metabolic inactivation of noradrenaline in the human placenta.

The enzymatic inactivation of noradrenaline was investigated in 25 fresh human placentae in vitro. Oxidative deamination by monoamine oxidase (MAO) was greater than enzymic O-methylation by catechol-O-methyltransferase (COMT). The addition of oestriol (E3) or progesterone to the organ bath significantly decreased (P less than 0.001) the activity of placental MAO. Oestrone (E1) and oestradiol (E2) showed no inhibitory effect. In addition, E3 significantly inhibited the activity of COMT (P less than 0.001), whereas oestrone and oestradiol had no effect on COMT activity. COMT was also inhibited by progesterone (P less than 0.05). The decrease in enzymic inactivation of noradrenaline caused by oestriol and progesterone suggests an activated adrenoceptor function.

Catechol O-Methyltransferase↗

PubMed1980

Catechol-O-methyltransferase and catecholamines in anxiety and relaxation.

Levels of anxiety, plasma epinephrine and norpinephrine, and red blood cell (RBC) catechol-O-methyltransferase (COMT) activity were measured before and after 4 weeks of relaxation training in a group of 15 drug-free, anxious subjects and at a similar interval in a group of 15 drug-free, healthy controls. The index group showed significant decreases in levels of anxiety and plasma epinephrine and norepinephrine after treatment. No changes were observed in the control values. RBC COMT did not show any significant differences in activity between the index and control groups and between the pre- and posttreatment values. Similarly, COMT activity levels failed to correlate with levels of anxiety and catecholamines before or after treatment. These findings indicate that anxiety is unlikely to have an effect on RBC COMT activity, whereas it has a direct effect on plasma catecholamines.

Adult↗

PubMed1992

Expression of enzymatically active rat liver and human placental catechol-O-methyltransferase in Escherichia coli; purification and partial characterization of the enzyme.

To produce sufficient amounts of recombinant catechol-O-methyltransferase (COMT) for structural and functional studies the coding regions of the rat liver and human placental COMT genes have been introduced into a bacterial expression vector pKEX14. Recombinant COMT was produced in Escherichia coli up to 10% of total bacterial protein after the induction of the T7 RNA polymerase gene with isopropyl-beta-D-thiogalactopyranoside. Both the rat and human enzymes were enzymatically active, soluble and reacted with anti-COMT antiserum in Western blotting. Both enzymes were purified from E. coli cells and partially characterized by determining their specific activity, apparent molecular weight and pI.

Animals↗

PubMed1991

Immunoaffinity purification and partial amino acid sequence analysis of catechol-O-methyltransferase from pig liver.

Monoclonal antibodies (mAbs) against the soluble form (S-COMT) of catechol-O-methyltransferase (COMT, EC 2.1.1.6) were produced using a purified preparation of the enzyme from pig liver as antigen. The selected monoclonal antibodies recognized the enzyme with different capacities. One of them (Co60-1B/7) showed a significant cross reaction with S-COMT from rat and human liver. A protein band of 23 kDa was recognized by the mAbs on Western blots of the soluble fraction of pig liver. The mAbs were also able to recognize the membrane-bound form of the enzyme, which was found to be mainly localized in the microsomal fraction of pig and rat liver as well as of the human hepatoma cell line Hep G2. The protein bands detected in microsomes had a molecular mass of 26 kDa in pig and rat liver and displayed a slightly higher molecular mass (29 kDa) in the Hep G2 cell line. A single step method for the immunoaffinity purification of pig liver S-COMT was developed by using a Sepharose 4B column to which the mAb Co54-5F/8 was covalently coupled. Acid elution conditions were optimized to obtain the enzyme in active form with a good yield. SDS-PAGE analysis of the purified preparation revealed a single protein band with a molecular mass of 23 kDa with 154-fold enrichment in enzyme activity over the starting material. Since the N-terminus was blocked, purified enzyme preparations were cleaved with trypsin. Two fragments of 22 and 33 amino acids in length could be sequenced by Edman degradation.

Amino Acid Sequence↗

PubMed1992

Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2.

Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a physiologically important enzyme in the metabolism of catecholamine neurotransmitters and catechol drugs. Using primers derived from the known rat cDNA sequence for COMT, we have used the polymerase chain reaction to produce an amplified DNA fragment corresponding to the complete coding region of the rat gene. With this fragment as a probe, we have hybridized DNAs from two panels consisting of human/rodent and human/hamster somatic cell hybrids carrying various translocations and deletions to refine the chromosomal location of human COMT. Southern blot analysis indicates that the human COMT gene is localized to 22q11.1----q11.2, a region to which several anonymous DNA sequences, but until now, no structural genes, have been assigned.

Catechol O-Methyltransferase↗