Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function.

Liam Curry,Jala Alahmed,Richard Roberts,Hani Almukhtar,Paul A Smith

doi:10.1093/toxsci/kfz068

Abstract

Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognized "off targets" for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study, we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells because mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca2+ influx via opening of voltage-gated Ca2+ channels (VGCCs). We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption, and ATP-sensitive-K+-channel activity were monitored as markers of mETC activity, respiration, and cellular ATP/ADP ratio respectively; Ca2+ channel activity and Ca2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 approximately 3 µM) and mETC (1 < IC50 < 10 µM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 µM reversed activation of VGCCs by glucose but had no significant effect in the sugar's absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an "off target".

Highlights

Mitochondrial electron transport complexes (Nadanaciva et al, 2007; Hargreaves et al, 2016; Wallace, 2008) and plasma membrane ion channels are well recognised “off targets” for drugs (Lynch et al, 2017; Real et al, 2018)
These results suggest that the IC50 for the lipophilic statin effect on mitochondrial function lies between 1 to 10 μM; a range that encompasses the IC50 of 3 μM for oxygen consumption rate (OCR); a potency similar to that seen in skeletal muscle: IC50 ~2 μM (Sirvent, Mercier, et al, 2005)
The IC50 value we report is extracellular in origin this is probably representative of the value experienced by the mitochondrial electron transport complexes (mETC) since our MIN6 cell line do not possess p-glycoprotein that would affect cellular levels of lipophilic drugs (Daunt et al, 2006), simvastatin has been reported to block p-glycoprotein (Wang et al, 2001)

Summary

Introduction

Mitochondrial electron transport (mETC) complexes (Nadanaciva et al, 2007; Hargreaves et al, 2016; Wallace, 2008) and plasma membrane ion channels are well recognised “off targets” for drugs (Lynch et al, 2017; Real et al, 2018) For some drugs, both moieties may be “off targets”; a situation which confounds the interpretation of adverse drug effects both in the clinic and laboratory. Both moieties may be “off targets”; a situation which confounds the interpretation of adverse drug effects both in the clinic and laboratory An example of this occurs in insulin secreting beta cells with the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, a lipophilic drug used to treat hypercholesteremia. The aims of the present study were to investigate these ideas and determine if simvastatin can adversely affect the activity of L-type Ca2+ channels in pancreatic β-cell indirectly via mitochondrial effects and in doing so reveal a novel outcome for the action of drugs for which mETC is an “off target”

Objectives

Methods

Results

Conclusion