Inhibition Of catechol-O-methyltransferase Activity Research Articles

Catechol-O-Methyltransferase (COMT) Enzyme Level In Preoperative Anxiety Patients

Background: Incidence of perioperative anxiety is very high, many preoperative patient experience anxiety . Thiamine acts as an essential nutrition funtionate as cofactor enzyme in most of mitochondria in brain. Brain is very susceptible to thiamine deficiency because its dependency on mitochondrial ATP production. Decreased ATP production result in inhibition of COMT activity. Low COMT levels indicated tendency for anxiety. The aim of this study is to determine the effect of thiamine in increasing COMT enzyme levels in patient with preoperative anxiety
 Methods : A true experiment with pretest-posttest control group and double-blind design conducted at the Department of Anesthesia and Intensive Care of University of North Sumatra in August 2019. The 60 patients were analyzed which were planned for and done an elective surgery under general anesthesia. Preoperative anxiety was measured with Amsterdam Preoperative Anxiety and Information Scale (APAIS) and COMT enzyme level measured by ELISA assays. 
 Results : The results showed that from 64 patients had incidence of preoperative anxiety in this study was 48.3%. We found that there is significant differences in COMT enzyme levels in thiamine group compared to control (p value = 0.001). In addition, it was seen that in thiamine group had an increased COMT levels from 0.96 ng/dL to 1.78 ng/dL, while in control group there also slight increasing from 0.44 ng/dL to 0.78 ng/dL. This show that increase in COMT levels is greater in thiamine group than control group. 
 Conclusion : Thiamine can cause increasing COMT enzyme levels in patients scheduled for elective surgery with preoperative anxiety under general anesthesia

Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity

Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity

Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity

The subcutaneous and systemic injection of serotonin reduces cutaneous and visceral pain thresholds and increases responses to noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT) receptors are suggested to be associated with different types of pain responses. Here we show that serotonin also inhibits catechol O-methyltransferase (COMT), an enzyme that contributes to modultion the perception of pain, via non-competitive binding to the site bound by catechol substrates with a binding affinity comparable to the binding affinity of catechol itself (Ki = 44 μM). Using computational modeling, biochemical tests and cellular assays we show that serotonin actively competes with the methyl donor S-adenosyl-L-methionine (SAM) within the catalytic site. Binding of serotonin to the catalytic site inhibits the access of SAM, thus preventing methylation of COMT substrates. The results of in vivo animal studies show that serotonin-induced pain hypersensitivity in mice is reduced by either SAM pretreatment or by the combined administration of selective antagonists for β2- and β3-adrenergic receptors, which have been previously shown to mediate COMT-dependent pain signaling. Our results suggest that inhibition of COMT via serotonin binding contributes to pain hypersensitivity, providing additional strategies for the treatment of clinical pain conditions.

Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17β-estradiol (E 2). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E 2-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E 2 pellets, co-exposure to quercetin did not protect rats from E 2-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E 2-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E 2 group relative to those in the E 2 group. Catechol- O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F 2α (8-iso-PGF 2α) levels as a marker of oxidant stress showed that quercetin did not decrease E 2-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E 2-induced oxidant stress and may exacerbate breast carcinogenesis in E 2-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E 2 and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E 2 and chronic exposure to oxidant stress as a result of metabolic redox cycling to estrogen metabolites, and thus quercetin may exacerbate E 2-induced breast tumors in female ACI rats.

Catechol-O-methyltransferase inhibition increases striatal L-dopa and dopamine: an in vivo study in rats.

We administered Ro 40-7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of l-dopa. Acute administration of Ro 40-7592 increased basal levels of l-dopa and dihydroxyphenylacetic acid (DOPAC) and decreased basal homovanillic acid (HVA) levels, but did not affect basal dopamine levels. In rats treated with Ro 40-7592, l-dopa administration produced a greater increase in striatal levels of l-dopa, dopamine, and DOPAC than it did in controls, while HVA formation was attenuated. We conclude that inhibition of COMT activity promotes central dopamine synthesis and release following administration of pharmacologic doses of l-dopa.

Augmentation of the Sterilizing Effect of Neonatal Androgenization with Tropolone, a Catechol-O-Methyltransferase Inhibitor, in Female Rats

The influence of tropolone, a catechol-O-methyltransferase (COMT) inhibitor, on the sterilizing effect of neonatal testosterone propionate (TP) has been studied in Wistar female rats. Tropolone-induced changes in COMT activity and noradrenaline (NA) and dopamine (DA) contents in the hypothalamus have been evaluated. Inhibition of COMT activity was maximal 3 h after a single injection of 0.6 mg tropolone on postnatal day 5. An increase in DA level was observed 6 h after drug injection, whereas the NA content was elevated 24 h after tropolone administration. A sexual dimorphism in hypothalamic NA content in rats was found on postnatal day 10: it was higher in males than in females. The rise of catecholamines in the hypothalamus of 10-day-old female rats induced by COMT inhibition with tropolone (0.3 mg on postnatal days 5 and 7) was unable to masculinize developing neuroendocrine regions responsible for sexual cyclicity. At the same time, combined administration of tropolone (0.1 mg daily on postnatal days 4-10) and TP (0.025 mg on day 4) enhanced the sterilizing effect of the androgen. An anovulatory sterility appeared in all experimental animals. It is suggested that a cooperative interaction occurs between catecholamines and sex steroids as determinants of brain sexual differentiation.

Relationship Between Catechol‐O‐Methyltransferase and Phenolsulfotransferase in the Metabolism of Dopamine in the Rat Brain

The relationship between phenolsulfotransferase (PST) and catechol-O-methyltransferase (COMT) in the metabolism of free 3,4-dihydroxyphenylethylamine (DA, dopamine) in the rat brain was studied. In rats not pretreated with a monoamine oxidase (MAO) inhibitor a huge increase of free DA in the brain, following an intraperitoneal injection of L-3,4-dihydroxyphenylalanine (L-DOPA) or an intraventricular injection of free DA, did not lead to any noticeable change in DA sulfate or 3-methoxytyramine (3-MT), which remained undetectable by the present HPLC method. However, in rats previously treated with the MAO inhibitors pargyline or tranylcypromine, the same L-DOPA or free DA treatment resulted in significant increases in both 3-MT and DA sulfate in the hypothalamus, brainstem, and striatum. This response of COMT and PST was not affected by prior treatment of the rats with 6-hydroxydopamine, which suggests that O-methylation and sulfoconjugation occur outside adrenergic neurons not destroyed by the neurotoxin. Inhibition of COMT activity did not lead to any increase in DA sulfate, which showed that despite their common mode of action (both enzymes react preferentially at the same hydroxyl group in the DA molecule), the two enzymes are not competitive. After MAO inhibition there were strong correlations between an increase in DA sulfate and 3-MT on the one hand, and between free DA and 3-MT on the other. Because 3-MT is a marker of central DA release, these data suggest that inhibition of MAO activity not only affects DA metabolism by this enzyme but also influences DA release in the rat brain.

The role of metabolism in temperature-dependent supersensitivity of guinea-pig atria to sympathomimetic amines

The role of enzymatic metabolism in the temperature-dependent supersensitivity to noradrenaline has been investigated at 37°C and at 26°C in isolated guinea-pig atria. In vitro monoamine oxidase (MAO) activity was found to be decreased at 26°C as compared to 37°C. However, 17–22 hr after treatment of guinea-pigs with paragyline, the degree of temperature-induced supersensitivity in isolated atria was unaltered although in vitor MAO activity was 93% inhibited at both incubation temperatures. The temperature-dependent supersensitivity of isolated atria-α methylnoradrenaline, a sympathomimetric amine not metabolized by MAO 2 was greater than that found for noradrenaline. In vitro catechol-O-methyl transferase (COMT) activity also was greater at 37°C than 26°C. In isolated atria, concentration of 3,4-dimethoxy-5-hydroxybenzoic acid which produced 33% inhibition of COMT activity in vitro, did not abolish the temperature-dependent supersensitivity to noradrenaline. However, sensitivity of isolated atria to nylidrin, a sympathomimetic amine not metabolized by COMT, is identical at the two bath temperatures. The data suggest that temperatures. The data suggets that temperature-dependent supersensitivity of isolated guinea-pig atria to sympathomimetic amines may be due to decreased COMT activity at the lower bath temperature.