hERG subunit composition determines differential drug sensitivity

• Published in: British journal of pharmacology Vol. 164; no. 2b; pp. 419 - 432
• Main Authors: Abi‐Gerges, N, Holkham, H, Jones, EMC, Pollard, CE, Valentin, J‐P, Robertson, GA
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011
• Subjects: Action Potentials - drug effects; arrhythmia; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - genetics; Cell Line, Transformed; Drug Evaluation, Preclinical - methods; drug sensitivity; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - genetics; Fluoxetine - pharmacology; HEK293 Cells; hERG; hERG 1a; hERG 1b; hERG blockers; Humans; Inhibitory Concentration 50; KCNH2; Kv11.1; Long QT Syndrome - chemically induced; Long QT Syndrome - genetics; Piperidines - pharmacology; Protein Subunits; Pyridines - pharmacology; Research Papers; safety assessment; Sensitivity and Specificity; torsades de pointes; Torsades de Pointes - chemically induced; Torsades de Pointes - genetics
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01378.x

BACKGROUND AND PURPOSE The majority of human ether‐a‐go‐go‐related gene (hERG) screens aiming to minimize the risk of drug‐induced long QT syndrome have been conducted using heterologous systems expressing the hERG 1a subunit, although both hERG 1a and 1b subunits contribute to the K+ channels producing the repolarizing current IKr. We tested a range of compounds selected for their diversity to determine whether hERG 1a and 1a/1b channels exhibit different sensitivities that may influence safety margins or contribute to a stratified risk analysis. EXPERIMENTAL APPROACH We used the IonWorks™ plate‐based electrophysiology device to compare sensitivity of hERG 1a and 1a/1b channels stably expressed in HEK293 cells to 50 compounds previously shown to target hERG channels. Potency was determined as IC50 values (µM) obtained from non‐cumulative, eight‐point concentration–effect curves of normalized data, fitted to the Hill equation. To minimize possible sources of variability, compound potency was assessed using test plates arranged in alternating columns of cells expressing hERG 1a and 1a/1b. KEY RESULTS Although the potency of most compounds was similar for the two targets, some surprising differences were observed. Fluoxetine (Prozac) was more potent at blocking hERG 1a/1b than 1a channels, yielding a corresponding reduction in the safety margin. In contrast, E‐4031 was a more potent blocker of hERG 1a compared with 1a/1b channels, as previously reported, as was dofetilide, another high‐affinity blocker. CONCLUSIONS AND IMPLICATIONS The current assays may underestimate the risk of some drugs to cause torsades de pointes arrhythmia, and overestimate the risk of others.