Catechol O-methyltransferase. 7. Affinity labeling with the oxidation products of 6-aminodopamine

Borchardt, Ronald T.; Smissman, Edward E.; Nerland, Donald E.; Reid, Jack R.

doi:10.1021/jm00223a007

Cited by 25 publications

(10 citation statements)

References 7 publications

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“…ldentification of dopaminochrome from the PHSmediated cooxidation of dopamine is another aspect that has biological significance. Dopaminochrome has been suggested as the active alkylating agent that disrupts catecholamine metabolism by irreversibly deactivating catechol-O-methyltransferase ( Borchardt et al ., 1976) . This metabolite probably arises from oxidation of 6-hydroxydopamine (Tse et al ., 1975 ;Swan, 1976) formed in the PHS/AA oxidation of dopamine .…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin H Synthetase‐Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Mattammal

Strong

Lakshmi³

et al. 1995

Journal of Neurochemistry

145

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Differences in prostaglandin H synthetase (PHS) activity in the substantia nigra of age‐ and post‐mortem interval‐matched parkinsonian, Alzheimer's, and normal control brain tissue were assessed. Prostaglandin E2 (PGE2, an index of PHS activity) was higher in substantia nigra of parkinsonian brain tissue than Alzheimer's or control tissue. Incubation of substantia nigra slices with arachidonic acid (AA) increased PGE2 synthesis. Dopamine stimulated PHS synthesis of PGE2. [3H]Dopamine was activated by PHS to electrophilic intermediate(s) that covalently bound to DNA, microtubulin protein, bovine serum albumin, and sulfhydryl reagents. When AA was replaced by hydrogen peroxide, PHS/H2O2‐supported binding proceeded at rates similar to those observed with PHS/AA. Indomethacin and aspirin inhibited AA‐mediated cooxidation of dopamine but not H2O2‐mediated metabolism. PHS‐mediated metabolism of dopamine was not affected by monoamine oxidase inhibitors. Substrate requirements and effects of specific inhibitors suggest cooxidation of dopamine is mediated by the hydroperoxidase activity of PHS. 32P‐postlabeling was used to detect dopamine‐DNA adducts. PHS/AA activation of dopamine in the presence of DNA resulted in the formation of five dopamine‐DNA adducts, i.e., 23, 43, 114, 70, and 270 amol/µg DNA. DNA adduct formation was PHS, AA, and dopamine dependent. PHS catalyzed cooxidation of dopamine in dopaminergic neuronal degeneration is discussed.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin H Synthetase‐Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Mattammal

Strong

Lakshmi³

et al. 1995

Journal of Neurochemistry

145

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“…186 The catecholamine quinones are also potent irreversible inhibitors of COMT which could contribute to the neurotoxicity mechanism (Table 3). 187,188 4.2.5. NQO1 Inhibition (Figure 5).…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

Bolton

Dunlap

2016

Chem. Res. Toxicol.

328

247

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Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through the induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity. Quinones are formed through a variety of mechanisms from simple oxidation of catechols/hydroquinones catalyzed by a variety of oxidative enzymes and metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation. Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can redox cycle with their semiquinone radical anions leading to the formation of reactive oxygen species (ROS) including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Production of ROS can alter redox balance within cells through the formation of oxidized cellular macromolecules including lipids, proteins, and DNA. This perspective explores the varied biological targets of quinones including GSH, NADPH, protein sulfhydryls [heat shock proteins, P450s, cyclooxygenase-2 (COX-2), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1, (NQO1), kelch-like ECH-associated protein 1 (Keap1), IκB kinase (IKK), and arylhydrocarbon receptor (AhR)], and DNA. The evidence strongly suggests that the numerous mechanisms of quinone modulations (i.e., alkylation versus oxidative stress) can be correlated with the known pathology/cytoprotection of the parent compound(s) that is best described by an inverse U-shaped dose–response curve.

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“…A reduced oxygen species or a covalent mechanism may mediate inactivation as had been proposed earlier. [16][17][18][19][20] The rate of inactivation of the rat brain synaptosomal enzyme was found to be slower than that of the partially purified bovine enzyme. This was consistent with the requirement for the inhibitors to penetrate the synaptosomes before they could reach the enzyme.…”

Section: Sessionmentioning

confidence: 99%

Inhibition and inactivation of presynaptic cholinergic markers using redox-reactive choline analogs

Patel¹,

Messer²,

Hudson³

1993

J. Med. Chem.

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Inhibition and inactivation of two presynaptic cholinergic "markers", choline acetyltransferase and high affinity choline transporter, has been investigated using inhibitors designed with a redox-reactive catechol tethered to a quaternary ammonium group. Two quaternary ammonium alkyl-substituted catechols, 3[(trimethylammonio)methyl]catechol (TMC, 1) and N,N-dimethylepinephrine (catecholine, 2) were shown to bind weakly and noncompetitively to bovine choline acetyltransferase yet inactivated the enzyme in a time course consistent with the involvement of early intermediates in the spontaneous oxidation of these catechols. Both agents also inhibited high-affinity choline uptake. The time course of TMC and catecholine spontaneous oxidation-dependent inactivation of high affinity choline uptake sites was slower than, if it occurred at all, the spontaneous degradation of measurable choline transport in synaptosomes. When compared with inhibition of uptake of other neurotransmitters, it was shown that catecholine demonstrated more selectivity than TMC toward inhibition of choline transport. Km (microM) and Vmax (pmol/min per mg of protein) were measured for high affinity transport of choline, dopamine, and serotonin and were observed to be Km = 2.04 +/- 0.31, Vmax = 22 +/- 1; Km = 1.4, Vmax = 53; and Km = 0.15, Vmax = 23, respectively, in good agreement with published literature values. Ki's (mM) for catecholine and TMC, calculated from experimentally determined IC50's, were for catecholine 0.13 +/- 0.06, 0.53 +/- 0.09, and 0.39 +/- 0.10, and for TMC 0.06 +/- 0.03, 0.09 +/- 0.03, and 0.09 +/- 0.08, for choline, dopamine, and serotonin transport, respectively. In vivo studies using catecholine suggest that this compound impairs learning ability associated with long-term memory. Thus, catecholine represents a lead compound in a potential series of redox-reactive choline analogs, which may become useful irreversible antagonists of the critical cholinergic macromolecular targets underlying cholinergic hypofunction in disorders such as Alzheimer's disease.

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Catechol O-methyltransferase. 7. Affinity labeling with the oxidation products of 6-aminodopamine

Cited by 25 publications

References 7 publications

Prostaglandin H Synthetase‐Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Prostaglandin H Synthetase‐Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

Inhibition and inactivation of presynaptic cholinergic markers using redox-reactive choline analogs

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