title: Statins (HMG-coenzyme A reductase inhibitors)-biomimetic membrane binding mechanism investigated by molecular chromatography.
abstract: Many studies have demonstrated that the statin beneficial effects on cardiovascular diseases like coronary are linked to their hypocholesterolemic properties. These lipid-lowering drugs are the first-line pharmacologic therapy for hypercholesterolemia. In this paper, the interaction of a series of statin molecules STCOOH (pravastatin (prava), mevastatin (meva), simvastatin (simva) and fluvastatin (fluva)) with a phosphatidylcholine monolayer immobilized on to porous silica particles has been studied using a biochromatographic approach (molecular chromatography). The immobilized artificial membrane (IAM) provided a biophysical model system to study the binding of the statin molecules to a lipid membrane. For all the test statin molecules, linear retention plots were observed at all temperatures. An analysis of the thermodynamics (i.e., enthalpy (DeltaH(0)), entropy (DeltaS(0)*)) of the interaction of the statin molecules with the immobilized monolayer was also carried out. The DeltaH(0) and DeltaS(0)* values were negative due to van der Waals interactions and hydrogen bonding between the statin molecules with the polar head groups of the phospholipid monolayer (polar retention effect). The statin elution order was: Prava<<<Meva<Atorva<<Simva<Fluva. This result associated with IC50 data of each statin molecule confirmed that pravastatin, which exhibited the lowest association with the lipid monolayer, was taken up by a membrane transporter. In addition, the logarithm of the statin retention factor with the lipid membrane extrapolated to a total aqueous bulk solvent at pH 7.0 (log k'(w-IAM)) was measured and compared to the octanol-water partition coefficient (logP). The observed significant correlation showed an affinity enhanced with the increase in the molecule lipophilicity and confirmed that the hydrophobic forces played an important role in the statin molecule-biomembrane association mechanism. As well, the affinity of STCOOH to IAM is high and changes slightly with the bulk solvent pH, because the number of protons linked to binding is low. This confirmed the importance to take into account the electrostatic interaction in this association mechanism. At pHs lower than approximately 7.0, the binding process is accompanied by protons release and at higher pHs protons are taken up. A change in the phospholipid monolayer phosphate group pK(a) has been proposed to contribute to the positive number of protons exchanged at pHs higher than approximately 7.0. This demonstrated that this phosphate residue could function as a general base/proton shuttle by facilitating the deprotonation of STCOOH, i.e., this hyper-reactive residue in the IAM surface could play a catalytic function.
authors.affiliation: Equipe des Sciences Séparatives et Biopharmaceutiques (2SB/EA-3924), Laboratoire de Chimie Analytique, Faculté de Médecine Pharmacie, Université de Franche-Comté, Place Saint Jacques, Besançon Cedex, France.
authors.forename: Fatimata Seydou
authors.initials: FS
authors.lastname: Sarr
authors.forename: Claire
authors.initials: C
authors.lastname: André
authors.forename: Yves Claude
authors.initials: YC
authors.lastname: Guillaume
mesh_terms: D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D008567:Membranes, Artificial; D018716:Molecular Mimicry; D013816:Thermodynamics
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008567:Membranes, Artificial