ArticleBritish journal of pharmacology2006
Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine.
Article in British journal of pharmacology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 192 citations in OpenAlex.
- Lenalidomide at therapeutic and supratherapeutic doses does not prolong QTc intervals in the thorough QTc study conducted in healthy men.Basic & clinical pharmacology & toxicology · 2013Trial
- Amiodarone irrecoverably impairs the function of human ether-a-go-go-related gene potassium channels.Molecular pharmacology · 2026Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Synergistic antidepressant-like effect of xylopic acid co-administered with selected antidepressants.IBRO neuroscience reports · 2024Article
- Precision Medicine in Antidepressants Treatment.Handbook of experimental pharmacology · 2023Review
- Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS.International journal of cardiology. Heart & vasculature · 2022Article
- Increasing the Efficacy of Seproxetine as an Antidepressant Using Charge-Transfer Complexes.Molecules (Basel, Switzerland) · 2022Article
- The ERG1 KFrontiers in molecular neuroscience · 2022Review
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
- Toward a broader view of mechanisms of drug cardiotoxicity.Cell reports. Medicine · 2021Review
- Cardiac hERG KHandbook of experimental pharmacology · 2021Article
- Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells.Scientific reports · 2019Article
- Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression.Scientific reports · 2019Article
- Cardiovascular safety of prokinetic agents: A focus on drug-induced arrhythmias.Neurogastroenterology and motility · 2018Review
- Review
- hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen.Scientific reports · 2017Article
- Acquired long QT syndrome and phosphoinositide 3-kinase.Trends in cardiovascular medicine · 2017Review
- Inhibition of cloned hERG potassium channels by risperidone and paliperidone.Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
- Computational Tool for FastFrontiers in chemistry · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
15 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
background and purposeFluoxetine (Prozac) is a widely prescribed drug in adults and children, and it has an active metabolite, norfluoxetine, with a prolonged elimination time. Although uncommon, Prozac causes QT interval prolongation and arrhythmias; a patient who took an overdose of Prozac exhibited a prolonged QT interval (QTc 625 msec). We looked for possible mechanisms underlying this clinical finding by analysing the effects of fluoxetine and norfluoxetine on ion channels in vitro. EXPERIMENTAL APPROACH: We studied the effects of fluoxetine and norfluoxetine on the electrophysiology and cellular trafficking of hERG K+ and SCN5A Na+ channels heterologously expressed in HEK293 cells. KEY
resultsVoltage clamp analyses employing square pulse or ventricular action potential waveform protocols showed that fluoxetine and norfluoxetine caused direct, concentration-dependent, block of hERG current (IhERG). Biochemical studies showed that both compounds also caused concentration-dependent reductions in the trafficking of hERG channel protein into the cell surface membrane. Fluoxetine had no effect on SCN5A channel or HEK293 cell endogenous current. Mutations in the hERG channel drug binding domain reduced fluoxetine block of IhERG but did not alter fluoxetine's effect on hERG channel protein trafficking. CONCLUSIONS AND IMPLICATIONS: Our findings show that both fluoxetine and norfluoxetine at similar concentrations selectively reduce IhERG by two mechanisms, (1) direct channel block, and (2) indirectly by disrupting channel protein trafficking. These two effects are not mediated by a single drug binding site. Our findings add complexity to understanding the mechanisms that cause drug-induced long QT syndrome.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.