Rationale for Selective COMT Inhibitors as Adjuncts in the Drug Treatment of Parkinson's Disease

Männistö, Pekka T.; Kaakkola, Seppo

doi:10.1111/j.1600-0773.1990.tb00756.x

Cited by 162 publications

(106 citation statements)

References 40 publications

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“…The two isoforms share identical amino acid sequences, except the MB-COMT contains an NH 2 -terminal extension of 50 amino acids to serve as a hydrophobic anchor to the membrane (28). COMT is widely distributed among various organs in the body, including lung, where high COMT activity was found (29). Except in brain, S-COMT is the predominant form in most tissues (30 -32).…”

mentioning

confidence: 99%

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Zhang

Jin

Chen

et al. 2011

Journal of Biological Chemistry

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Polycyclic aromatic hydrocarbons (PAH)2 are ubiquitous environmental pollutants that are products of fossil fuel combustion and found in tobacco smoke and are suspect lung carcinogens (1, 2). PAH are considered to be procarcinogens and require metabolic activation to elicit their deleterious effects. Benzo[a]pyrene (B[a]P) is a representative PAH and widely used to study the metabolic activation of PAH (3, 4).There are three major pathways for the activation of B[a]P. In the first pathway, P450 peroxidases catalyze the generation of radical cations (5) PAH o-quinones, produced by AKRs are electrophilic and highly reactive to endogenous nucleophiles. PAH o-quinones can readily form conjugates with cellular thiols to yield and GSH conjugates, leading to their elimination (12,13). PAH o-quinones can also react with DNA to form both stable and depurinating adducts, which may result in mutagenesis (14 -16). PAH o-quinones are also able to undergo nonenzymatic/enzymatic reduction to reform catechols at the expense of NADPH and establish futile redox cycles that amplify the generation of reactive oxygen species (ROS). ROS can cause DNA damage resulting in the formation of 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8-oxo-dGuo) lesions and can contribute to G to T transversions in ras and p53 (17,18). PAH o-quinones were found to be more mutagenic than diol-epoxides in an in vitro p53 mutagenesis assay provided they redox-cycled and a linear correlation was observed

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confidence: 99%

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Zhang

Jin

Chen

et al. 2011

Journal of Biological Chemistry

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“…This observation has prompted interest in the development of potent COMT inhibitors, to be used as adjuncts in L-DOPA therapy of Parkinson's disease 1990).…”

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confidence: 99%

Molecular Modeling and Metabolic Studies of The Interaction of Catechol-O-Methyltransferase and a New Nitrocatechol Inhibitor

Palma¹,

Bonifácio²,

Loureiro³

et al. 2003

Drug Metab Dispos

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“…Under these circumstances, the 3-O-methylation of L-DOPA becomes a predominant elimination route, having a significant impact in the availability of L-DOPA to the brain, indicating that inhibition of this metabolic route should prove beneficial for Parkinsonian patients [5].…”

Section: Introductionmentioning

confidence: 99%

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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Rationale for Selective COMT Inhibitors as Adjuncts in the Drug Treatment of Parkinson's Disease

Cited by 162 publications

References 40 publications

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Molecular Modeling and Metabolic Studies of The Interaction of Catechol-O-Methyltransferase and a New Nitrocatechol Inhibitor

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

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