Characteristics of catechol O-methyltransferase (COMT) and properties of selective COMT inhibitors

Männistö, Pekka T.; Ulmanen, Ismo; Lundström, Kenneth; Taskinen, Jyrki; Tenhunen, Jukka; Tilgmann, Carola; Kaakkola, Seppo

doi:10.1007/978-3-0348-7144-0_9

Cited by 109 publications

(112 citation statements)

References 167 publications

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“…This isoform dominates over the MB-COMT in peripheral rat and human tissues, with the exception of adrenals and pheochromocytomas [7,29,30]. The analysis of adrenaline O-methylation kinetics in mouse and rat liver homogenates showed that the K m value obtained for the rat COMT was in agreement with the values described in the literature for the methylation of catecholamines by S-COMT.…”

Section: Discussionsupporting

confidence: 80%

“…The analysis of adrenaline O-methylation kinetics in mouse and rat liver homogenates showed that the K m value obtained for the rat COMT was in agreement with the values described in the literature for the methylation of catecholamines by S-COMT. However, the Km value obtained for the mouse COMT was within the range of values described for MB-COMT [10,29,30]. Actually, the affinities of adrenaline O-methylation by mouse liver S-COMT and MB-COMT were found to be, respectively, 242 and 12 µM [7].…”

Section: Discussionsupporting

confidence: 66%

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Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

Bonifácio¹,

Loureiro²,

Torrão³

et al. 2009

Biochemical Pharmacology

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The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of nebicapone in rats and mice. Upon oral administration of nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat.Nebicapone was rapidly absorbed reaching plasma C max within 30 min and being completely eliminated by 8 h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K cat values, respectively 7.3 and 6.4 min -1 ), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83).Furthermore, nebicapone inhibited rat liver COMT with a lower K i than mouse liver COMT (respectively 0.2 versus 1.2 nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by nebicapone. The more pronounced inhibitory effects of nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by nebicapone than the former.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 66%

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

Bonifácio¹,

Loureiro²,

Torrão³

et al. 2009

Biochemical Pharmacology

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“…COMT is found at high levels in a variety of human tissues, including ovarian, breast, liver, and kidney tissues (Mannisto et al, 1992). Recent studies have found that a functional polymorphism, a single G to A base-pair change in COMT, results in the substitution of valine with methionine (COMT Val158Met, rs4680) at codon 108 in the gene encoding soluble COMT and at codon 158 of the gene encoding membrane-bound COMT (Mao et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Lack of Association between the COMT rs4680 Polymorphism and Ovarian Cancer Risk: Evidence from a Meta-analysis of 3,940 Individuals

Dong²,

Wan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Catechol-O-methyltransferase (COMT) is involved in estrogen metabolism and is vital to estrogen-induced carcinogenesis, including that of ovarian cancer. Although many recent epidemiologic studies have investigated associations between the COMT rs4680 polymorphism and ovarian cancer risk, the results remain inconclusive. We therefore performed a meta-analysis to derive a more precise estimate of associations. Systematic searches of the PubMed, Embase, Web of Science, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and Chinese Biomedicine databases were undertaken to retrieve eligible studies. Odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were pooled to assess the strength of the association. In total, 8 case-control studies involving 1,293 cases and 2,647 controls were included in the meta-analysis. Overall, the results showed no evidence of significant association between the COMT rs4680 polymorphism and ovarian cancer risk in any of the assessed genetic models. Subgroup analyses by ethnicity also did not reveal any significant association in any genetic model (p>0.05). In conclusion, our findings suggest that the COMT rs4680 polymorphism may not contribute to the risk of ovarian cancer.

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“…This extension carries a hydrophobic signal-anchor domain in its N-terminus, which directs MB-COMT cotranslationally into the membrane . These structural features explain why the two enzymes have similar properties, and why they crossreact immunologically (Mannisto et al, 1992;Roth 1992). Interestingly, MB-COMT is probably oriented towards the cytoplasmic side of membranes .…”

mentioning

confidence: 99%

Expression of recombinant soluble and membrane‐bound catechol O‐methyltransferase in eukaryotic cells and identification of the respective enzymes in rat brain

Tilgmann

Melén

Lundström

et al. 1992

European Journal of Biochemistry

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The rat and human recombinant soluble and membrane-bound catechol 0-methyltransferase (Sand MB-COMT, respectively) were expressed using mammalian and baculovirus vectors. LOW levels of rat and human S-COMT polypeptides were detected by immunoprecipitation in K-562 cell lines transfected with the S-COMT vectors. From K-562 cells transfected with the rat MB-COMT construct, both s-and MB-COMT recombinant proteins were detected by a rat COMT-specific antiserum. Infection of lepidopteran Spodoptera frugiperda cells with recombinant s-or MB-COMT baculovirus constructs yielded high amounts of enzymically active and immunoreactive S-or MB-COMT proteins, respectively. Pulse/chase experiments with [' 5S]methionine-labelled insect cells infected with the MB-COMT baculovirus showed that the 30-kDa recombinant human MB-COMT polypeptide was not processed into the 25-kDa S-COMT form. Subcellular fractionations of insect cells, followed by immunoblotting with COMT antiserum, showed that recombinant S-COMT was found only in the soluble, cytoplasmic fraction, whereas MB-COMT resided both in soluble and membrane fractions. The recombinant MB-COMT sedimented in Percoll gradients at the density of 1.042 g/ml cosedimenting with the plasma-membrane marker. Fractionation and immunoblotting experiments on homogenized total rat brains indicated that the rat S-COMT (24 kDa) and some of the rat MB-COMT (28 kDa) was recovered in soluble fractions, whereas the microsomal material having COMT activity contained the MB-COMT polypeptide. The rat brain microsomal MB-COMT had a density of 1.042 g/ml in Percoll gradients, cosedimenting with the plasma-membrane and roughendoplasmic-reticulum marker enzymes. The metalpara methylation ratio of dihydroxybenzoic-acid substrate by different recombinant and rat brain COMT-containing subcellular fractions was analysed.Catechol 0-methyltransferase (COMT) inactivates catecholamine neurotransmitters (dopamine, epinephrine and norepinephrine) and catechol steroids (e. g.

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Characteristics of catechol O-methyltransferase (COMT) and properties of selective COMT inhibitors

Cited by 109 publications

References 167 publications

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

Lack of Association between the COMT rs4680 Polymorphism and Ovarian Cancer Risk: Evidence from a Meta-analysis of 3,940 Individuals

Expression of recombinant soluble and membrane‐bound catechol O‐methyltransferase in eukaryotic cells and identification of the respective enzymes in rat brain

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