Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant

Abstract

The lipophilic polycyclic aromatic hydrocarbon (PAH) phenanthrene is relatively abundant in polluted air and water and can access and accumulate in human tissue. Phenanthrene has been reported to interact with cardiac ion channels in several fish species. This study was undertaken to investigate the ability of phenanthrene to interact with hERG (human Ether-à-go-go-Related Gene) encoded Kv11.1 K+ channels, which play a central role in human ventricular repolarization. Pharmacological inhibition of hERG can be proarrhythmic. Whole-cell patch clamp recordings of hERG current (IhERG) were made from HEK293 cells expressing wild-type (WT) and mutant hERG channels. WT IhERG1a was inhibited by phenanthrene with an IC50 of 17.6 ± 1.7 µM, whilst IhERG1a/1b exhibited an IC50 of 1.8 ± 0.3 µM. WT IhERG block showed marked voltage and time dependence, indicative of dependence of inhibition on channel gating. The inhibitory effect of phenanthrene was markedly impaired by the attenuated inactivation N588K mutation. Remarkably, mutations of S6 domain aromatic amino acids (Y652, F656) in the canonical drug binding site did not impair the inhibitory action of phenanthrene; the Y652A mutation augmented IhERG block. In contrast, the F557L (S5) and M651A (S6) mutations impaired the ability of phenanthrene to inhibit IhERG, as did the S624A mutation below the selectivity filter region. Computational docking using a cryo-EM derived hERG structure supported the mutagenesis data. Thus, phenanthrene acts as an inhibitor of the hERG K+ channel by directly interacting with the channel, binding to a distinct site in the channel pore domain.

Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk

“…For instance, substitutions of Y652 or F656 with alanine, which have been known to be crucial residues for the block, abolished the facilitation by nifekalant. Y652 is also crucial for the facilitation of phenanthrene [47]. These findings suggest that facilitation, similar to the block, occurs through interactions within residues that form the central cavity of the hERG pore.…”

“…Some drugs, known as blockers, reduce both the IV and GV relationships. Additionally, some hERG blockers not only reduce the IV and GV relationships but also shift them to the left, as shown in Figure 1 [36][37][38]43,[45][46][47]. This leftward shift in the GV relationship is referred to as the "facilitation" of voltage-dependent activation by the drug.…”

“…Numerous reports on hERG facilitators have been published [36][37][38]43,[45][46][47]. Among these hERG facilitators, our group focused on Class III antiarrhythmic agents such as amiodarone and nifekalant [36,37,44,51].…”

Lipid Profile Altered in Phenanthrene Exposed Zebrafish Embryos with Implications for Neurological Development and Early Life Nutritional Status

“…Studies have shown that crude oil, or phenanthrene alone, can rapidly impair the function of isolated fish cardiomyocytes by disrupting ion flux. , Follow-up in vitro mutagenesis experiments demonstrated that this is likely due to specific interactions with the cardiac Ether-a-go-go-Related Gene (ERG) encoded K + channels . However, early life-stage exposure to phenanthrene or crude oil impacts numerous organs in addition to the heart.…”

“…12,13 Follow-up in vitro mutagenesis experiments demonstrated that this is likely due to specific interactions with the cardiac Ether-a-go-go-Related Gene (ERG) encoded K + channels. 14 However, early life-stage exposure to phenanthrene or crude oil impacts numerous organs in addition to the heart. The enduring question is whether some or all of these outcomes are downstream of specific cardiac defects.…”