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PubMed2005

Characterization of two new variants of human catechol O-methyltransferase in vitro.

Catechol O-methyltransferase (COMT) plays an important role in the inactivation of biologically active and toxic catechols. It has been shown that human soluble COMT (S-COMT) is genetically polymorphic with a wild type and at least one variant in which a valine has been substituted with a methionine at codon 108. This polymorphism has been the subject of intense molecular epidemiological studies because of the important role of COMT in the metabolism of catecholamines and catechol estrogens. Several epidemiological studies have shown that women, homozygous with the Val108Met variant, have an increased risk of developing estrogen-associated cancers. However, some other studies have shown that this COMT polymorphism is not associated with increased risk of developing cancers. These conflicting data suggest that additional COMT genetic variants might contribute to the increased risk of developing cancers. Although two new single nucleotide polymorphisms (SNP) that cause amino acid substitutions Ala22Ser and Ala52Thr have been identified recently, they have not been fully characterized. In the present study, Ala22Ser and Ala52Thr variants of human S-COMT were produced using recombinant DNA techniques, and then COMT properties were measured including enzymatic activity, thermostability, and sensitivity to inhibition mediated by 4-hydroxyequilenin (4-OHEN). The Ala22Ser variant showed lower methylation capacity and higher thermolability. In addition, this variant is sensitive to 4-OHEN mediated irreversible inhibition. Our data indicate that the Ala22Ser polymorphism might also be of functional significance and might play a role in susceptibility to estrogen-associated cancers.

Alanine↗
PubMed2004

O-Methylation of benzaldehyde derivatives by "lignin specific" caffeic acid 3-O-methyltransferase.

Although S-adenosyl-l-methionine (SAM) dependent caffeic acid/5-hydroxyferulic acid 3/5-O-methyltransferase (COMT) is one of the key enzymes in lignin biosynthesis, the present work demonstrates that alfalfa COMT methylates benzaldehyde derivatives more efficiently than lignin pathway intermediates. 3,4-Dihydroxy, 5-methoxybenzaldehyde and protocatechuic aldehyde were the best in vitro substrates for OMT activity in extracts from developing alfalfa stems, and these compounds were preferred over lignin pathway intermediates for 3-O-methylation by recombinant alfalfa COMT expressed in Escherichia coli. OMT activity with benzaldehydes was strongly reduced in extracts from stems of transgenic alfalfa down-regulated in COMT. However, although COMT down-regulation drastically affects lignin composition, it does not appear to significantly impact metabolism of benzaldehyde derivatives in alfalfa. Structurally designed site-directed mutants of COMT showed altered relative substrate preferences for lignin precursors and benzaldehyde derivatives. Taken together, these results indicate that COMT may have more than one role in phenylpropanoid metabolism (but probably not in alfalfa), and that engineered COMT enzymes could be useful for metabolic engineering of both lignin and benzaldehyde-derived flavors and fragrances.

Amino Acid Substitution↗
PubMed2003

Human catechol-O-methyltransferase down-regulation by estradiol.

Catechol-O-methyltransferase (COMT) is a crucial enzyme in dopamine and levodopa metabolism. Previously we reported that physiological concentrations of 17beta-estradiol (E2) down-regulated steady-state 1.3-kb COMT mRNA levels in MCF-7 cells. In this study, we investigated whether similar reductions occurred in a glial cell line (U138MG) and whether COMT protein and activity levels paralleled the reduction in COMT mRNA levels in MCF-7 cells. In addition, we explored the mechanism of E2 action. E2 had no effect on COMT mRNA levels in U138MG cells, but significantly reduced COMT protein and activity in MCF-7 cells (activity by 53% at 10(-7) M of E2, by 45% at 10(-8) M, and by 28% at 10(-9) M relative to non-E2-treated cells). A specific estrogen receptor antagonist (ICI 182780) blocked these estrogenic effects. Estrogen receptor in nuclear extracts of MCF-7 cells, which were pretreated with E2 (10(-9) M) for 48 h, bound to the whole proximal and distal promoter regions, as determined by electrophoretic mobility shift analysis (EMSA). We propose that E2 decreased COMT activity through down-regulation of its gene and protein expression mediated via ER interaction with response elements in the promoter region of the gene. Our findings may explain the lower of COMT activity in women compared to that in men, and, in part, the beneficial effects of E2 therapy in post-menopausal Parkinson's disease patients.

Antibody Specificity↗
PubMed2002

Separation methods for catechol O-methyltransferase activity assay: physiological and pathophysiological relevance.

Catechol O-methyltransferase (COMT) transfers a methyl group from S-adenosyl-L-methionine to the catechol substrate in the presence of magnesium. After the characterisation of COMT more than four decades ago, a wide variety of COMT enzyme assays have been introduced. COMT activity analysis usually consists of the handling of the sample and incubation followed by separation and detection of the reaction products. Several of these assays are validated, reliable and sensitive. Besides the studies of the basic properties of COMT, the activity assay has also been applied to explore the relation of COMT to various disease states or disorders. In addition, COMT activity analysis has been applied clinically since COMT inhibitors have been introduced as adjuvant drugs in the treatment of Parkinson's disease.

Catalysis↗
PubMed2002

Catechol-O-methyltransferase polymorphism and endometriosis.

PURPOSE: Catechol-O-methyltransferase (COMT) inactivates the estradiol metabolites, 2-hydroxy and 4-hydroxy catechols, which have been implicated in the pathogenesis of endometriosis. A COMT valine to methionine polymorphism (G-to-A) in exon 4 of the COMT gene is polymorphic in the human population, with 25% of Caucasians being homozygous for the low-activity allele (COMT-L) of the enzyme. In a case-control study we investigated whether this COMT polymorphism is associated with endometriosis. METHODS: Polymerase chain reaction was performed to analyze the COMT genotype among women with surgically and histologically confirmed endometriosis (study group; n = 91) and in women without evidence of endometriosis confirmed by laparoscopy or laparotomy (control group; n = 92). RESULTS: Allele frequencies for the low-activity allele (COMT-L) among women with endometriosis and controls were 0.50 and 0.50, respectively (p = 0.999; odds ratio = 1.0, 95% CI: 0.66-1.51). CONCLUSIONS: Our results suggest that the valine to methionine polymorphism in exon 4 of the COMT gene is not associated with the risk of endometriosis compared to a surgical control population.

Adolescent↗
PubMed1993

Catechol-O-methyltransferase mRNA in the kidney and its appearance during ontogeny.

Catechol-O-methyltransferase (COMT), primarily present as a soluble cytosolic form (S-COMT), inactivates catechols. The recent cloning of the rat and human S-COMT from placenta has allowed us to synthesize complementary oligonucleotide probes to study the localization of COMT mRNA during development in the rat kidney and in the adult human kidney using in situ hybridization histochemistry. In the adult rat kidney, COMT mRNA was detected in segment S3 of proximal tubule cells in the outer stripe of the outer medulla, and thick ascending limb of loop of Henle (TAL) in the inner stripe. COMT mRNA was detected in the prenatal rat kidney as early as on day 18. In the human kidney, strong hybridization signal was seen in the medulla and in tubule segments of the cortex. In the adult rat kidney, COMT mRNA was in addition demonstrated in the transitional epithelium of the ureter. The results suggest synthesis of COMT and inactivation of catechols along the distal parts of proximal tubules, in TAL cells, and in the epithelium of the ureter.

Aging↗
PubMed2004

Association between catechol-O-methyltransferase functional polymorphism and male suicide completers.

Suicide has been suggested to involve catecholaminergic dysfunction and to be related to genetics. Catechol-O-methyltransferase (COMT) 158Val/Met polymorphism (GenBank Accession No. Z26491) is a polymorphism of the gene encoding COMT, a major enzyme in catecholamine inactivation. The COMT 158Val/Met polymorphism affects COMT activity, that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. In this study, we hypothesized that the COMT 158Val/Met polymorphism is associated with suicide. The study population consisted of 163 suicide completers (112 males and 51 females). We found that the genotype distribution of the COMT 158Val/Met polymorphism was significantly different between male suicide completers and male controls (p=0.036), while the frequency of the Val/Val genotype, a high-activity COMT genotype, was significantly less in male suicide completers than in male controls (OR: 0.52; 95% CL: 0.31-0.89; p=0.016). However, this was not the case in females. Our results suggest that the Val/Val genotype is a protective factor against suicide in males.

Adult↗
PubMed1989

Variations in catechol O-methyltransferase activity in rodent tissues: possible role in estrogen carcinogenicity.

Catechol-O-methyltransferase (COMT) [EC 2.1.1.6] is a ubiquitous cytosolic enzyme which has a pertinent role in the inactivation of both natural and synthetic catechol estrogens in mammalian tissues. We have compared the COMT activity in mouse, hamster and rat kidney, liver and red blood cells and examined the kinetic characteristics of this enzyme in the latter two species using various catechol estrogens as substrates. Results presented here indicate that the ratios of COMT activity in the kidney versus the liver of the rat and mouse are nearly identical, 0.48-0.52, whereas there is a 29-fold ratio between the level of COMT activity in these two tissues in the hamster. In red blood cells, the level of COMT activity is 4- and 12-fold lower in the hamster compared to mouse and rat, respectively. When the kinetic characteristics of this enzyme were assessed in the hamster and rat kidney and liver, except for 2-hydroxymoxestrol which had an apparent Km value of 15-48 microM, the other catechol estrogen substrates exhibited Km values ranging from 1-10 microM. Generally, the Vmax values were markedly higher in the rat kidney and liver than those observed in corresponding hamster tissues. The significantly lower COMT activity in the hamster liver and red blood cells suggests that under chronic estrogen treatment at high doses, the concentration of catechol estrogens in these tissues may exceed the capacity of COMT to effectively catalyse their O-methylation into inactive metabolites. The resulting accumulation of catechol estrogens may contribute to the estrogen carcinogenicity observed in the hamster liver and kidney. Additionally, when 2-hydroxyestrone was used as a substrate, the estrogen-induced renal carcinoma exhibited only 8.6% of the COMT activity found in the normal kidney.

Animals↗
PubMed1997

Alterations in dopamine clearance and catechol-O-methyltransferase activity by dopamine infusions in children.

OBJECTIVE: To determine the role of catechol-O-methyltransferase (COMT) in the biodisposition of pharmacologic concentrations of dopamine. DESIGN: The study was an open-label dose escalation trial in which dopamine was employed as the sole exogenous catecholamine. The dosage was adjusted to achieve improvements in cardiac output or to augment renal function. SETTING: A 16-bed pediatric intensive care unit serving both medical and surgical patients. PATIENTS: The study was performed using 14 dopamine-treated and five untreated control patients. Children ranged in age from 16 days to 12 yrs; five of the treated patients and two of the untreated controls were female. All but one of the study patients were enrolled within 24 hrs of palliative or corrective surgery for congenital heart disease. Control patients had noncardiac surgical procedures. Both treated and control groups were similar with respect to severity of illness, as judged by Therapeutic Intervention Scoring System score. INTERVENTIONS: All treated patients received dopamine as a continuous intravenous infusion. Infusion rates were determined by caregivers and ranged from 3.0 to 20 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Serial, timed blood samples were obtained from patients and control subjects for the determination of plasma dopamine concentrations and for the determination of mononuclear cell COMT activity. Measured rates of dopamine infusion (3.0 to 18.3 micrograms/kg/min) were consistently less than the nominal rates (3.0 to 20.0 micrograms/kg/min) of infusion (p < .0001) due in part to calculations based on the hydrochloride salt rather than dopamine base. At similar steady-state infusion rates, plasma dopamine concentrations varied over a four-fold range, with steady-state concentrations at even the lowest infusion rate exceeding endogenous concentrations by at least ten-fold. Variations in steady-state plasma dopamine concentration reflected large age-associated variations in dopamine clearance, which was found to be saturable at concentrations of > 200 ng/mL. Mononuclear cell COMT activity was assessed simultaneously in these patients. Baseline COMT activity varied over a six-fold range and was unrelated to dopamine clearance or patient age. COMT activity increased two- to six-fold in dopamine-treated patients with plasma steady-state dopamine concentrations of > 100 ng/mL. CONCLUSIONS: These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates. While concomitant variability in COMT activity is observed, the lack of correlation between dopamine clearance and COMT activity suggests that COMT is not rate-limiting for the clearance of exogenously administered dopamine.

Catechol O-Methyltransferase↗
PubMed2002

Down-regulation of caffeic acid o-methyltransferase in maize revisited using a transgenic approach.

Transgenic maize (Zea mays) plants were generated with a construct harboring a maize caffeic acid O-methyltransferase (COMT) cDNA in the antisense (AS) orientation under the control of the maize Adh1 (alcohol dehydrogenase) promoter. Adh1-driven beta-glucuronidase expression was localized in vascular tissues and lignifying sclerenchyma, indicating its suitability in transgenic experiments aimed at modifying lignin content and composition. One line of AS plants, COMT-AS, displayed a significant reduction in COMT activity (15%-30% residual activity) and barely detectable amounts of COMT protein as determined by western-blot analysis. In this line, transgenes were shown to be stably integrated in the genome and transmitted to the progeny. Biochemical analysis of COMT-AS showed: (a) a strong decrease in Klason lignin content at the flowering stage, (b) a decrease in syringyl units, (c) a lower p-coumaric acid content, and (d) the occurrence of unusual 5-OH guaiacyl units. These results are reminiscent of some characteristics already observed for the maize bm3 (brown-midrib3) mutant, as well as for COMT down-regulated dicots. However, as compared with bm3, COMT down-regulation in the COMT-AS line is less severe in that it is restricted to sclerenchyma cells. To our knowledge, this is the first time that an AS strategy has been applied to modify lignin biosynthesis in a grass species.

Coumaric Acids↗
PubMed1999

Tobacco O-methyltransferases involved in phenylpropanoid metabolism. The different caffeoyl-coenzyme A/5-hydroxyferuloyl-coenzyme A 3/5-O-methyltransferase and caffeic acid/5-hydroxyferulic acid 3/5-O-methyltransferase classes have distinct substrate specificities and expression patterns.

The biosynthesis of lignin monomers involves two methylation steps catalyzed by orthodiphenol-O-methyltransferases: caffeic acid/5-hydroxyferulic acid 3/5-O-methyltransferases (COMTs) and caffeoyl-coenzyme A (CoA)/5-hydroxyferuloyl-CoA 3/5-O-methyltransferases (CCoAOMTs). Two COMT classes (I and II) were already known to occur in tobacco (Nicotiana tabacum) and three distinct CCoAOMT classes have now been characterized. These three CCoAOMT classes displayed a maximum level of expression at different stages of stem development, in accordance with their involvement in the synthesis of lignin guaiacyl units. Expression profiles upon tobacco mosaic virus infection of tobacco leaves revealed a biphasic pattern of induction for COMT I, COMT II, and CCoAOMTs. The different isoforms were expressed in Escherichia coli and our results showed that CCoAOMTs and, more surprisingly, COMTs efficiently methylated hydroxycinnamoyl-CoA esters. COMT I was also active toward 5-hydroxyconiferyl alcohol, indicating that COMT I that catalyzes syringyl unit synthesis in planta may operate at the free acid, CoA ester, or alcohol levels. COMT II that is highly inducible by infection also accepted caffeoyl-CoA as a substrate, thus suggesting a role in ferulate derivative deposition in the walls of infected cells. Tobacco appears to possess an array of O-methyltransferase isoforms with variable efficiency toward the diverse plant o-diphenolic substrates.

Acyl Coenzyme A↗
PubMed1994

Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters.

Human genomic DNA fragments containing catechol O-methyltransferase (COMT) sequences were isolated and the exon-intron structure analysed by sequencing, PCR and comparing to the human COMT cDNA sequences. The gene contains six exons, of which exons 1 and 2 are noncoding. MB-ATG and S-ATG codons, responsible for the initiation of translation of the membrane-bound (MB) and soluble (S) forms of the enzyme, are located in exon 3. Two distinct COMT-specific transcripts, 1.3 kb and 1.5 kb, were detected in various human tissues and cell lines. Different quantities of the shorter COMT-specific mRNA in the tissues studied suggest a tissue-specific regulation of the COMT gene at transcriptional level. Mapping of the 5' ends of the COMT mRNAs showed that transcription initiates at multiple sites in two separate DNA regions, which are preceded by functional promoter sequences. The proximal promoter (P1), located between the two translation initiation codons and extending approximately 200 bp upstream of the MB-ATG initiation codon, apparently gives rise to the 1.3-kb S-COMT mRNA (S-mRNA). The distal promoter (P2) is located in a DNA fragment in front of and partly overlapping the transcription-start region of the 1.5-kb transcript, suggesting that it controls the expression of this MB-mRNA. Similarities between the rat and human COMT gene promoters are analyzed.

Animals↗
PubMed1992

Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat.

1. We compared three new catechol O-methyltransferase (COMT) inhibitors (OR-611, Ro 40-7592 and CGP 28014; 10 and 30 mg kg-1, i.p.) in male rats given levodopa (L-DOPA, 50 mg kg-1, i.p.) and carbidopa ((-)-L-alpha-methyl dopa, 50 mg kg-1, i.p.). In some studies pretreatment with pargyline (80 mg kg-1, i.p.) was used to block the function of monoamine oxidase (MAO). 2. Decreases of hypothalamic and striatal 3-O-methyl-dopa (3-OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3-methoxytyramine (3-MT; after pargyline) levels. 3. The three COMT inhibitors studied had different individual characteristics. OR-611 was primarily a peripherally acting COMT inhibitor, decreasing 3-OMD levels in the striatum (to 31-52%) and in the hypothalamus (to 16-27%) both in the control and pargyline-treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3-MT. 3. Ro 40-7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3-OMD (always to less than 30%), HVA (to less than 50%) and 3-MT levels (to less than 23%) significantly both at 1 and 3 h. It was more potent than OR-611. 4. CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3-OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3-MT levels at 1 h (to 37-22% and 42-35% in the striatum, and to 57-33% and 64-35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR-611 and Ro 40-7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor.

Amidines↗
PubMed2003

Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat.

Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t(1/2 beta)) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after the last dose of entacapone. In tolcapone-treated animals, there was still extensive COMT inhibition present in peripheral tissues, and the degree of inhibition was higher than that attained after a single dose. The pharmacokinetic-pharmacodynamic modeling revealed that a plateau of COMT inhibition near the maximal attainable inhibition was reached already by plasma concentrations below 2000 ng/ml, both with entacapone and tolcapone. Entacapone and tolcapone inhibited equally rat liver COMT in vitro with K(i) values of 10.7 and 10.0 nM, respectively. In conclusion, tolcapone has a longer duration of action and a better brain penetration than entacapone. The results also suggest that peripheral COMT is inhibited continuously when tolcapone is dosed at 12-h intervals, but this was not seen with entacapone.

Administration, Oral↗
PubMed1980

Immunocytochemical localization of catechol-O-methyltransferase in the pregnant rat uterus.

Light microscopic immunocytochemical observations of catechol-O-methyl-transferase (COMT) localization in the pregnant rat uterus were made with a specific antibody to soluble rat liver COMT and the peroxidase-antiperoxidase technique. The changes in cellular localization of COMT were followed from the onset of pregnancy to 12 h after delivery of the last fetus. COMT first appeared on day 5 of pregnancy in endometrial epithelial cells of the uterus. On day 7, COMT appeared in the decidual cells on the antimesometrial side of the uterus close to the implanting blastocyst. Two morphologically distinct, COMT-positive, decidual cells were observed: polygonal cells and stellate cells. After parturition, COMT-positive decidual cells remained in the decidua basalis. The possible physiological roles of COMT in the pregnant uterus are discussed.

Animals↗
PubMed2003

Val158Met Polymorphism in catechol-O-methyltransferase gene associated with risk factors for breast cancer.

Extensive mammographic density is heritable, strongly associated with increased breast cancer risk, and is influenced by sex hormone exposure. In a cross-sectional study of 181 pre- and 171 postmenopausal women without breast cancer, we examined the relationship of a functional polymorphism in catechol-O-methyltransferase (COMT; VAL-->MET) to mammographic density and other risk factors for breast cancer. We hypothesized that individuals who inherited the low-activity form of COMT (COMT*2 allele) would have higher levels of breast density, presumably because of reduced inactivation/detoxification of catecholestrogens. Subjects were recruited across five categories of breast density. Risk factor information, anthropometric measures, and blood samples were obtained; sex hormone and growth factor levels were measured, and COMT genotypes determined. Mammograms were digitized and measured using a computer-assisted method. After adjustment for age and ethnicity, among pre- but not postmenopausal subjects, each low-activity COMT*2 allele was associated with lower levels of percentage breast density. The statistical significance of this association was lost after further adjustment for serum growth factors [growth hormone, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3)], hormones [follicle-stimulating hormone (FSH) and progesterone], and body size (body mass index and waist:hip ratio). The low-activity COMT*2 allele was also associated, after adjustment for age and ethnicity in premenopausal women, with lower serum levels of IGF-1, higher levels of FSH and progesterone, and with a larger waist:hip ratio, body mass index, and subscapular skinfold. After adjustment for body size, the associations of genotype with IGFBP-3 and FSH were no longer significant. These findings indicate that COMT genotype is associated with several risk factors for breast cancer and suggest that the low-activity COMT*2 allele is associated with a reduced risk of breast cancer among premenopausal women.

Breast↗
PubMed1990

The interaction of transport mechanisms and intracellular enzymes in metabolizing systems.

The life span of extracellular catecholamines is limited by the combination of uptake and subsequent intracellular metabolism by either monoamine oxidase (MAO) and/or catechol-O-methyl transferase (COMT). Three such "metabolizing systems" are involved in the inactivation of noradrenaline: 1) Neuronal uptake (high-affinity uptake1) in association with neuronal MAO (and vesicular uptake), 2) extraneuronal uptake (low affinity uptake2) in association with intracellular COMT and MAO (in smooth muscles, myocardial cells, glands), and 3) uptake1 of non-neuronal cells in association with intracellular COMT and/or MAO (in vascular endothelium of rat lung). Such systems function as "pump and leak systems with enzyme(s) inside". The analysis of either uptake or enzyme fails to reveal the characteristics of such systems; they are determined by the interaction of both components. Because of the high activity of these intracellular enzymes, it is unlikely that either COMT or MAO is ever saturated in vivo. However, in vitro saturation of extraneuronal COMT and MAO reveals that extraneuronal COMT is a high-affinity, but extraneuronal MAO a low-affinity enzyme. Hence, membrane-bound COMT appears to be responsible for the extraneuronal O-methylation of noradrenaline. If intracellular enzymes remain unsaturated, the determination of the rate constants describing the unsaturated enzyme (KENZYME = Vmax/Km) is of particular interest. KENZYME can be determined for metabolizing systems, since this rate constant is not affected by the (usually unknown) fractional size of the metabolizing system.

Animals↗
PubMed1993

The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anaesthetized rabbit.

The present study, carried out in anaesthetized rabbits, aimed at determining the effects of catechol-O-methytransferase (COMT) inhibition on the plasma kinetics of infused 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylalanine (DOPA) as well as on endogenous plasma noradrenaline, DOPEG, DOPA and 3-methoxy-4-hydroxyphenylglycol (MOPEG). The plasma kinetics of infused MOPEG were also evaluated. To block the function of COMT, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) was given intravenously. Dose-finding experiments, in which the drug-induced fall in endogenous plasma MOPEG was used to quantify COMT inhibition, indicated that a Ro 40-7592 dose of 3 mg/kg followed by 1.5 mg/kg every 30 min was sufficient to obtain a virtually complete inhibition of COMT. More than 150 min of COMT inhibition were required for endogenous MOPEG to disappear from plasma, since the plasma half-life of MOPEG was 54 min. COMT inhibition produced marked increases in the plasma levels of endogenous DOPA (1.7-fold) and DOPEG (3.9-fold) and did not alter endogenous plasma noradrenaline. The results concerning the effect of COMT inhibition on the plasma kinetics of infused DOPA and DOPEG were as follows: the plasma clearance of DOPA was not altered, whereas that of DOPEG fell by 41%; the plasma half-life of DOPA increased from 4.9 to 13.0 min and that of DOPEG from 4.8 to 31.0 min; there was an increase in the volume of distribution of DOPA (2 to 3-fold) and DOPEG (4 to 5-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗