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Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.
Nguyen L, Robson MJ, Healy JR, Scandinaro AL, Matsumoto RR
(2014) PLoS One 9: e89985
MeSH Terms: Adrenergic alpha-Antagonists, Animals, Antidepressive Agents, Behavior, Animal, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Dextromethorphan, Dose-Response Relationship, Drug, Ethylenediamines, Excitatory Amino Acid Antagonists, Ketamine, Kinetics, Male, Mice, Piperazines, Protein Binding, Quinidine, Receptors, N-Methyl-D-Aspartate, Receptors, sigma, Swimming
Show Abstract · Added August 26, 2015
Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [(3)H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.
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20 MeSH Terms
Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease.
Bajpai P, Sangar MC, Singh S, Tang W, Bansal S, Chowdhury G, Cheng Q, Fang JK, Martin MV, Guengerich FP, Avadhani NG
(2013) J Biol Chem 288: 4436-51
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Adrenergic alpha-Antagonists, Animals, Cell Line, Cytochrome P-450 CYP2D6, Dopamine Agents, Dopaminergic Neurons, Dynamins, Humans, Mice, Mitochondria, Mitochondrial Proteins, Parkinsonian Disorders, Quinidine, Reactive Oxygen Species, Ubiquitin-Protein Ligases
Show Abstract · Added March 26, 2014
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP(+)), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP(+), as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.
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16 MeSH Terms
An allosteric mechanism for drug block of the human cardiac potassium channel KCNQ1.
Yang T, Smith JA, Leake BF, Sanders CR, Meiler J, Roden DM
(2013) Mol Pharmacol 83: 481-9
MeSH Terms: Alanine, Allosteric Regulation, Animals, Binding Sites, CHO Cells, Cell Line, Cricetinae, Cysteine, Heart, Humans, KCNQ1 Potassium Channel, Models, Molecular, Mutagenesis, Site-Directed, Myocardium, Quinidine
Show Abstract · Added May 30, 2013
The intracellular aspect of the sixth transmembrane segment within the ion-permeating pore is a common binding site for many voltage-gated ion channel blockers. However, the exact site(s) at which drugs bind remain controversial. We used extensive site-directed mutagenesis coupled with molecular modeling to examine mechanisms in drug block of the human cardiac potassium channel KCNQ1. A total of 48 amino acid residues in the S6 segment, S4-S5 linker, and the proximal C-terminus of the KCNQ1 channel were mutated individually to alanine; alanines were mutated to cysteines. Residues modulating drug block were identified when mutant channels displayed <50% block on exposure to drug concentrations that inhibited wild-type current by ≥90%. Homology modeling of the KCNQ1 channel based on the Kv1.2 structure unexpectedly predicted that the key residue modulating drug block (F351) faces away from the permeating pore. In the open-state channel model, F351 lines a pocket that also includes residues L251 and V254 in S4-S5 linker. Docking calculations indicated that this pocket is large enough to accommodate quinidine. To test this hypothesis, L251A and V254A mutants were generated that display a reduced sensitivity to blockage with quinidine. Thus, our data support a model in which open state block of this channel occurs not via binding to a site directly in the pore but rather by a novel allosteric mechanism: drug access to a side pocket generated in the open-state channel configuration and lined by S6 and S4-S5 residues.
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15 MeSH Terms
Inhibition of human cytochrome P450 3A4 by cholesterol.
Shinkyo R, Guengerich FP
(2011) J Biol Chem 286: 18426-33
MeSH Terms: Anti-Arrhythmia Agents, Cells, Cultured, Cholesterol, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Enzyme Inhibitors, Hepatocytes, Humans, Microsomes, Liver, Models, Biological, Nifedipine, Oxidation-Reduction, Quinidine, Vasodilator Agents
Show Abstract · Added March 7, 2014
If cholesterol is a substrate of P450 3A4, then it follows that it should also be an inhibitor, particularly in light of the high concentrations found in liver. Heme perturbation spectra indicated a K(d) value of 8 μM for the P450 3A4-cholesterol complex. Cholesterol inhibited the P450 3A4-catalyzed oxidations of nifedipine and quinidine, two prototypic substrates, in liver microsomes and a reconstituted enzyme system with K(i) ∼ 10 μM in an apparently non-competitive manner. The concentration of cholesterol could be elevated 4-6-fold in cultured human hepatocytes by incubation with cholesterol; the level of P450 3A4 and cell viability were not altered under the conditions used. Nifedipine oxidation was inhibited when the cholesterol level was increased. We conclude that cholesterol is both a substrate and an inhibitor of P450 3A4, and a model is presented to explain the kinetic behavior. We propose that the endogenous cholesterol in hepatocytes should be considered in models of prediction of metabolism of drugs and steroids, even in the absence of changes in the concentrations of free cholesterol.
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14 MeSH Terms
The organic cation transporter, OCTN1, expressed in the human heart, potentiates antagonism of the HERG potassium channel.
McBride BF, Yang T, Liu K, Urban TJ, Giacomini KM, Kim RB, Roden DM
(2009) J Cardiovasc Pharmacol 54: 63-71
MeSH Terms: Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cation Transport Proteins, Electrophysiology, Ether-A-Go-Go Potassium Channels, Flecainide, Gene Expression, Heart, Humans, Immunohistochemistry, In Situ Hybridization, Inhibitory Concentration 50, Myocytes, Cardiac, Organic Cation Transport Proteins, Patch-Clamp Techniques, Potassium Channels, Quinidine, Sulfonamides
Show Abstract · Added June 26, 2014
BACKGROUND - Variable function and expression of drug transporters have been proposed as mechanisms contributing to variable response to drug therapy. Block of the HERG channel, encoding IKr, can lead to serious arrhythmias, and a key drug-blocking site in HERG has been identified on the intracellular face of the pore. We begin to advance the hypothesis that active drug uptake enhances IKr block.
METHODS AND RESULTS - Reverse transcriptase-polymerase chain reaction identified expression in the human atrium and ventricle of 14 of 31 candidate drug uptake and efflux transporters, including OCTN1 (SLC22A4), a known uptake transporter of the HERG channel blocker quinidine. In situ hybridization and immunostaining localized OCTN1 expression to cardiomyocytes. The IC50 for quinidine block of IKr in CHO cells transfected with HERG alone was significantly higher than cells transfected with HERG + OCTN1 (0.66 +/- 0.15 microM versus 0.14 +/- 0.06 microM [52% absolute increase in drug block; 95% confidence interval, 0.4-0.64 microM]), and this effect was further potentiated by a common genetic variant of OCTN1, L503F. In the absence of OCTN1, quinidine block could be 91% +/- 5% washed out, but with the transporter, washout was incomplete (57% +/- 6%). OCTN1 coexpression also facilitated HERG block by flecainide and ibutilide, but not erythromycin.
CONCLUSIONS - Coexpression of the organic cation transporter, OCTN1, expressed in human cardiac myocytes, intensifies quinidine-induced HERG block. These findings establish a critical hypothesis that variable drug transporter activity may be a potential risk factor for torsade de pointes.
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18 MeSH Terms
Probing the mechanisms underlying modulation of quinidine sensitivity to cardiac I(Ks) block by protein kinase A-mediated I(Ks) phosphorylation.
Yang T, Kanki H, Zhang W, Roden DM
(2009) Br J Pharmacol 157: 952-61
MeSH Terms: Amino Acid Sequence, Animals, CHO Cells, Cricetinae, Cricetulus, Cyclic AMP-Dependent Protein Kinases, Humans, KCNQ1 Potassium Channel, Molecular Sequence Data, Phosphorylation, Potassium Channel Blockers, Potassium Channels, Voltage-Gated, Quinidine
Show Abstract · Added June 26, 2014
BACKGROUND AND PURPOSE - Cardiac I(Ks) is enhanced by protein kinase A (PKA) stimulation. And PKA-stimulated I(Ks) is about threefold less sensitive to quinidine block than basal current. In this study, we further tested two competing hypotheses: I(Ks) phosphorylation either (i) modulates access of blocking drugs to a binding site; or (ii) destabilizes the drug-channel interaction.
EXPERIMENTAL APPROACH - To distinguish between these hypotheses, we studied quinidine block of I(Ks) channels in which three PKA site residues of the alpha-subunit KCNQ1 were mutated with a bulky negative charged aspartic acid (D). To study alleviation of I(Ks) block by quinidine, we compared activating current at +60 mV, either with or without 5 s hyperpolarizing prepulses to -120 mV.
KEY RESULTS - Without PKA stimulation, quinidine (100 microM) blocked wild-type current to a similar extent with and without the prepulse (93 +/- 2% of pre-drug current at +60 mV vs. 95 +/- 1%). With PKA-stimulated wild-type channels, however, there was less block with the hyperpolarization to -120 mV: at +60 mV, block was 71 +/- 2% (-prepulse) versus 58 +/- 3% (+prepulse). Individual D-mutations and the triple-D mutant were resistant to quinidine block similar to that seen with PKA-stimulated wild-type I(Ks).
CONCLUSIONS AND IMPLICATIONS - We conclude that phosphorylation-induced insertion of bulky negative charges alleviates quinidine block and that PKA-induced stimulation, by conferring negative charges to the channels, blunts I(Ks) block as the interaction between the channels and blockers becomes destabilized. These effects would be of clinical significance in providing protective mechanisms against pro-arrhythmias caused by drug-induced inhibition of I(Ks) and I(Kr).
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13 MeSH Terms
Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives.
Kannankeril PJ, Roden DM, Norris KJ, Whalen SP, George AL, Murray KT
(2005) Heart Rhythm 2: 134-40
MeSH Terms: Anti-Arrhythmia Agents, Electrocardiography, Female, Genetic Predisposition to Disease, Humans, Long QT Syndrome, Male, Middle Aged, Quinidine
Show Abstract · Added January 20, 2015
OBJECTIVES - The purpose of this study was to test for a genetic component to risk for acquired long QT syndrome (LQTS).
BACKGROUND - Many drugs prolong the QT interval, and some patients develop excessive QT prolongation and occasionally torsades de pointes-the acquired LQTS. Similarities between the acquired and congenital forms of the long QT syndrome suggest genetic factors modulate susceptibility.
METHODS - Intravenous quinidine was administered to 14 relatives of patients who safely tolerated chronic therapy with a QT-prolonging drug (control relatives) and 12 relatives of patients who developed acquired LQTS, and ECG intervals between groups were compared.
RESULTS - Baseline QT and heart-rate corrected QT (QTc) were similar (QT/QTc: 394 +/- 28/410 +/- 20 ms vs 395 +/- 24/418 +/- 20 ms; control vs acquired LQTS) and prolonged equally in the two groups. The interval from the peak to the end of the T wave, an index of transmural dispersion of repolarization, prolonged significantly with quinidine in acquired LQTS relatives (63 +/- 17 to 83 +/- 18 ms, P = .017) but not in control relatives (66 +/- 19 to 71 +/- 18 ms, P = 0.648). In addition, the baseline peak to end of the T wave as a fraction of the QT interval was similar in both groups but was longer in acquired LQTS relatives after quinidine (16.3 +/- 3.5% and 19.5 +/- 3.9% in control and acquired LQTS relatives, respectively, P = .042).
CONCLUSIONS - First-degree relatives of patients with acquired long QT syndrome have greater drug-induced prolongation of terminal repolarization compared to control relatives, supporting a genetic predisposition to acquired long QT syndrome.
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9 MeSH Terms
Role of glutamic acid 216 in cytochrome P450 2D6 substrate binding and catalysis.
Guengerich FP, Hanna IH, Martin MV, Gillam EM
(2003) Biochemistry 42: 1245-53
MeSH Terms: Amines, Amino Acid Substitution, Binding Sites, Catalysis, Cytochrome P-450 CYP2D6, Ethanolamines, Glutamic Acid, Glutamine, Humans, Hydroxylation, Methylation, Mutagenesis, Site-Directed, Oxidation-Reduction, Protein Binding, Quinidine, Recombinant Proteins, Spiro Compounds, Static Electricity, Substrate Specificity, Sulfonamides, Tyramine
Show Abstract · Added March 5, 2014
Human cytochrome P450 (P450) 2D6 is an important enzyme involved in the metabolism of drugs, many of which are amines or contain other basic nitrogen atoms. Asp301 has generally been considered to be involved in electrostatic docking with the basic substrates, on the basis of previous modeling studies and site-directed mutagenesis. Substitution of Glu216 with a residue other than Asp strongly attenuated the binding of quinidine, bufuralol, and several other P450 2D6 ligands. Catalytic activity with the substrates bufuralol and 4-methoxyphenethylamine was strongly inhibited by neutral or basic mutations at Glu216 (>95%), to the same extent as the substitution of Asn at Asp301. Unlike the Asp301 mutants, the Gln216 mutant (E216Q) retained 40% enzyme efficiency with the substrate spirosulfonamide, devoid of basic nitrogen, suggesting that the substitutions at Glu216 affect binding of amine substrates more than other catalytic steps. Attempts to induce catalytic specificity toward new substrates by substitutions at Asp301 and Glu216 were unsuccessful. Collectively, the results provide evidence for electrostatic interaction of amine substrates with Glu216, and we propose that both of these acidic residues plus at least another residue(s) is (are) involved in binding the repertoire of P450 2D6 ligands.
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21 MeSH Terms
Coumarin substrates for cytochrome P450 2D6 fluorescence assays.
Nakamura K, Hanna IH, Cai H, Nishimura Y, Williams KM, Guengerich FP
(2001) Anal Biochem 292: 280-6
MeSH Terms: Amino Acid Sequence, Catalysis, Coumarins, Cytochrome P-450 CYP2D6, Cytochrome P-450 CYP2D6 Inhibitors, Enzyme Inhibitors, Fluorescent Dyes, Humans, Kinetics, Microsomes, Liver, Molecular Sequence Data, Quinidine, Recombinant Proteins, Substrate Specificity
Show Abstract · Added March 5, 2014
A set of nine 4-aminomethyl-7-alkoxycoumarin derivatives was synthesized and characterized as substrates for O-dealkylation by recombinant cytochrome P450 2D6, a major human enzyme involved in drug metabolism. Enzymatic O-dealkylation yields 7-hydroxycoumarins, which have useful fluorescence properties. The substrates, which differed in substitution at the amino and 7-hydroxy positions, varied in terms of catalytic efficiency of O-dealkylation and in their selectivity as substrates for cytochrome P450 2D6 in human liver microsomes. Several of the compounds are useful as cytochrome P450 2D6 substrates in single-phase, rapid-throughput assays.
Copyright 2001 Academic Press.
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14 MeSH Terms
Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments].
Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM
(1999) Circulation 99: 552-7
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Biological Transport, Active, Caco-2 Cells, Cardiovascular Agents, Digoxin, Drug Interactions, Drug Resistance, Multiple, Humans, Mice, Quinidine, Tissue Distribution
Show Abstract · Added December 10, 2013
BACKGROUND - Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein-mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction.
METHODS AND RESULTS - First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 micromol/L quinidine inhibited P-glycoprotein-mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in mdr1a(-/-) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data showed that quinidine itself is a P-glycoprotein substrate, quinidine doses were reduced in mdr1a(-/-) mice to produce plasma concentrations similar to those in wild-type control animals. Quinidine increased plasma digoxin concentrations by 73.0% (P=0.05) in wild-type animals, compared with 19.5% (P=NS) in mdr1a(-/-) mice. Moreover, quinidine increased digoxin brain concentrations by 73.2% (P=0.05) in wild-type animals; by contrast, quinidine did not increase digoxin brain concentrations in mdr1a(-/-) mice but rather decreased them (-30.7%, P<0.01).
CONCLUSIONS - Quinidine and digoxin are both substrates for P-glycoprotein, and quinidine is a potent inhibitor of digoxin transport in vitro. The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein-mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.
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12 MeSH Terms