Mechanisms underlying probucol-induced hERG-channel deficiency

Abstract

The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Reduction of IhERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on IhERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.

In silico prediction of hERG blockers using machine learning and deep learning approaches

“…The sixth is 3‐chloro‐N‐ethylaniline, represented by the compound Trazodone, a serotonin uptake inhibitor for the treatment of moderate depression, which has been shown to inhibit hERG channels and cause prolongation of the QT interval in vitro (Tarantino et al, 2005). The seventh is 3,5‐diethyltoluene, whose representative compound is Probucol, a cholesterol‐lowering drug that reduces hERG channel currents and thus causes LQTS (Shi et al, 2015).…”

Evaluation of chronic drug-induced electrophysiological and cytotoxic effects using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)

“…However, in our study we did not observe a significant prolongation of FPD or FPDc, even at the highest concentration (i.e., 10 μM, 25-times the fC max ). Although probucol is reported to reduce hERG expression in the plasma membrane without directly blocking hERG channel ( Shi et al, 2015 ) and to prolong QT and cause TdPs in patients and in animal studies ( Nogawa et al, 2013 ), the prolongation of the QT interval is not as evident as after treatment with other drugs, such as from arsenic trioxide and/or pentamidine. In men, Hayashi et al (2004) reported the occurrence of TdP and excessive QT prolongation during a 3-month treatment with probucol in a long-QT syndrome patient carrying a missense hERG mutation.…”