Imidacloprid and its major metabolites blocks the alpha subunit of the human hERG (KV11.1) channel: Evidence from in-silico and fluorescence polarization studies.

Abstract

Neonicotinoids are high affinity agonists of insect Nicotinic Acetyl Choline Receptors (nAChRs) resulting in insect paralysis and death. Although they are assumed to have relatively low affinity towards mammalian and other non-insect nAChRs, studies have shown that they can cause neuro-endocrine toxicity, immunotoxicity and endocrine toxicity. Moreover, as a result of bioaccumulation the levels of neonicotinoids can be even traced in non-farming population at an significant level. KCHN2 gene encodes ERG1 or hERG or KV11.1 which is responsible for Ikr current. Multiple chemical molecules can block this KV11.1-alpha sub unit and can result in prolongation of QT interval causing Drug induced Long QT Syndrome (DI-LQTS). This could potentially trigger Torsades de Pointes (TdP), a unique form of the premature ventricular complex which are spontaneous in origin and often result in Sudden Cardiac Death (SCD). Imidacloprid (IMI) is highly bioavailable and undergoes biotransformation by cytochrome p450 monooxygenases (CYP) and aldehyde oxidases (AOX) forming Desnitro-Imidacloprid (DNI) and Imidacloprid-Olefin (IOL). Interestingly, acute poisoning with IMI can result in cardiac features such as ventricular tachyarrhythmias with severe hypotension. Nonetheless, despite of the evidence regarding the toxic bioaccumulation of neonicotinoids, a little is known about their cardiovascular toxicity. Henceforth, the current study aims to understand the effect of imidacloprid and its major metabolites on hERG (KV11.1) channel blockade using molecular docking studies. Findings of the study highlighted that IMI, DNI and IOL can potentially bind to residues like Tyr652 and Phe656 in the pore forming domain and can cause hERG (KV 11.1) blockade.