Cholesterol Protects the Liquid-Ordered Phase of Raft Model Membranes from the Destructive Effect of Ionic Liquids

Abstract

Ionic liquids (ILs), although being a class of promising green solvents, have received many reports on the toxicity to living organisms. In this work, aiming at elucidating the disruptive effect of ILs to cell membrane lipid rafts, we investigated the effect of three 1-octylimidazolium-based ILs on the properties of the liquid ordered phase (L o , a commonly used lipid raft model) of egg sphingomyelin (SM)-cholesterol model membrane. We found that, in the absence of cholesterol, a very low IL:SM molar ratio of 0.01:1 could disrupt the integrity of the bilayer structure. In sharp contrast, the presence of cholesterol in lipid bilayers helps the L o phase resist the damaging effect of the ILs. For the role of the IL headgroup, we found that the mono-and trisubstituted species show a stronger destructive effect on the structures of the model rafts than the commonly used disubstituted counterpart.

Cholesterol-Controlled Interaction of Ionic Liquids with Model Cellular Membranes

“…The surface pressure–area isotherm generated by a Langmuir trough is useful for studying interactions among amphiphilic molecules that form a single molecular layer at the air–water interface. ,,− Researchers have adopted this approach to understand the thermodynamics of the interaction of ILs with lipids. ,, It has been reported that the polar head group and hydrophobicity of lipids and the nature of anions and cations of ILs along with the pH of the environment play significant roles in this interaction. , Apart from electrostatics and van der Waals interactions, the thermodynamic state of a lipid in the membrane is important here . Further, as mentioned in the Introduction section, the interaction between a lipid and an IL may highly be influenced by the presence of other membranous component, such as cholesterol. , In the present study, the respective isotherms are generated by plotting the surface pressure against the area per molecule, which is calculated by considering the number of molecules of lipid (single component), lipid and IL (two components), and lipid, cholesterol, and IL (three components). The area/molecule signifies the average area occupied by a single molecule either in its pristine form (lipid) or in a mixed system (two or three components).…”

“…65 Further, as mentioned in the Introduction section, the interaction between a lipid and an IL may highly be influenced by the presence of other membranous component, such as cholesterol. 61,62 In the present study, the respective isotherms are generated by plotting the surface pressure against the area per molecule, which is calculated by considering the number of molecules of lipid (single component), lipid and IL (two components), and lipid, cholesterol, and IL (three components). The area/ molecule signifies the average area occupied by a single molecule either in its pristine form (lipid) or in a mixed system (two or three components).…”

“…Even though cholesterol is one of the important components of a mammalian membrane, there are only a few reports on the interaction of ILs on lipid membranes in the presence of cholesterol. − More systematic experimental, theoretical, and simulations works are required to elucidate the cholesterol-controlled interaction of ILs with the membrane. Previous studies suggested that the destructive nature of ILs on the membrane depends on the concentration of ILs. , In the presence of cholesterol, this effect is expected to be modified, which is reported by Hao et al by taking an egg sphingomyelin (SM) membrane in the presence of a high cholesterol concentration (40 mol %) . The presence of cholesterol has been found to reduce the permeability of bilayers made of 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC); a glycerol-based phospholipid like sphingomyelin also shows a high affinity to cholesterol …”

How 1,n-Bis(3-alkylimidazolium-1-yl) Alkane Interacts with the Phospholipid Membrane and Impacts the Toxicity of Dicationic Ionic Liquids

“…The MTT assay was performed to estimate the viability of HeLa cells on the addition of different ionic liquids, as described previously. 44 HeLa cells, seeded in a 96-well plate, were subjected to varying concentrations (0, 10,25,35,40,50,60,75,85,100,125,150, and 175 μM) of DILs in triplicates for a period of 24 h to evaluate their cytotoxicity. Stock solutions of all ionic liquids (10 mM) were prepared in the MEM with 10% FBS.…”

“…As a result, DILs are relatively less toxic as compared to their monocationic counterparts carrying alkyl chains of comparable length . The toxicity of MILs correlates with their ability to interact and perturb the cellular membrane. ,, Several computational and experimental studies have been employed to study the mechanism of the interaction of monocations with the model phospholipid membranes. ,− However, the structural details of dication–membrane interaction and its correlation with ionic liquid toxicity are not well understood.…”