Abstract
The effects of selected statins on the structure and properties of lipid membranes composed of zwitterionic (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, DMPE) or anionic (1,2-dimyristoyl-sn-glycero-3-phospho-l-serine, DMPS) lipids were studied for the first time by Langmuir technique combined with polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) and Brewster angle microscopy (BAM). The interactions of statins of different hydrophobicity: pravastatin, fluvastatin, and cerivastatin with the polar region of the lipids forming the membrane were monitored by PM-IRRAS and the changes of the overall monolayer structure and organization were described on the basis of surface pressure vs. area per molecule measurements and Brewster angle microscopy. Large differences in the action of each of the statins on the lipid monolayers were observed and explained by their different hydrophobicity combined with the different degree of hydration of the lipid polar headgroups in the monolayer. Monolayer fluidizing effect was connected with the interaction of statins in the headgroup region of the membrane affecting the original hydrogen bonding in the lipid layers. The most hydrophilic pravastatin interacted only with the polar head groups of the monolayer and affected the organization of the polar part of the lipid membrane by increasing the headgroups hydration. In the case of DMPS, the contribution of electrostatic interactions between the negatively charged headgroups and the drug was observed, and for this lipid especially strong dehydration effect of cerivastatin was revealed. It facilitated the incorporation of the hydrophobic part of the drug into the nonpolar region of the DMPS layer and in this case there was almost no fluidization of the layer. Strong dehydration effects may be dangerous for the lipid membranes and may also be one of the reasons to avoid cerivastatin in the therapies, despite its known efficacy especially in view of the large doses and prolonged application that are usually needed.
Highlights
Statins are the most common hypolipidemic drugs which act as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase (HMG-CoA reductase), the enzyme which catalyzes the rate-limiting step: the deacylation of HMG-CoA to CoA and mevalonate in the cholesterol biosynthetic pathway [1,2,3,4]
In this report we focus on showing how the contact with a solution containing statins affects the organization of simple one-component lipid layers (DMPC, DMPE or DMPS) treated as one leaflet of a lipid membrane, which is free from any rigid support (Fig. 1)
The surface pressure-area per molecule isotherms for the DMPC monolayer were recorded for the pure phosphate-buffer saline (PBS) buffer subphase or water and following the addition of statins: pravastatin, fluvastatin and cerivastatin (Figs. 2A and S1)
Summary
Statins are the most common hypolipidemic drugs which act as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase (HMG-CoA reductase), the enzyme which catalyzes the rate-limiting step: the deacylation of HMG-CoA to CoA and mevalonate in the cholesterol biosynthetic pathway [1,2,3,4]. One of the mechanisms for controlling HMG-CoA reductase activity is the socalled negative feedback [5]. Reductase activity decreases as the concentration of mevalonate and cholesterol increases. Cholesterol is an important lipid in membranes of higher eukaryotes and accounts for ~30–50% of the total plasma lipid content. Cholesterol is mainly produced in hepatocytes and from there it is transported throughout the body systems using lipoproteins, LDL and HDL [7]. Too high levels of LDL-cholesterol result in cardiovascular diseases and are nowadays the primary cause of disability and premature death [8,9]. Several approaches to treat hypercholesterolemia have been used worldwide since it represents a major risk for coronary heart disease
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