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Abstract
We studied the interactions of the hypotensive drug, 2-hydroxyoleic acid (2OHOA), with model membranes using the techniques of DSC, 31P NMR and X-ray diffraction. We demonstrate that 2OHOA alters the thermotropic behaviour of 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE), thereby promoting the formation of hexagonal phases (HII), despite stabilizing the lamellar phase (Lα). The lattice parameters of lamellar and non-lamellar structures were not altered by the presence of 2OHOA. The molecular bases underlying the alterations in membrane structure provoked by 2OHOA were analysed by comparing the effects produced by 2OHOA with the closely related fatty acids (FAs), oleic acid (OA) and elaidic acid (EA). The capacity of C-18 FAs to induce HII-phase formation followed the order OA>2OHOA>EA. Furthermore, while 2OHOA stabilized the Lα phase, OA destabilized it. The net negative charge of 2OHOA at physiological pH (∼7.4) influenced its effect on membrane structure. By analysing the molecular architecture of 2OHOA in DEPE monolayers, interactions between the carboxylate groups of 2OHOA and the amine groups of DEPE were observed, as well as between the 2-hydroxyl group of the FA and the carbonyl oxygen of the phospholipid acyl chain. These structural characteristics provoked an increase in the P-to-N and P-to-P distances of neighbouring phospholipid headgroups in the presence of 2OHOA, with respect to those observed with OA and EA. The higher headgroup area at the lipid–water interface in presence of 2OHOA could account for the differential effect of this drug on the phase behaviour of DEPE membranes.
PL, phospholipid; PC, phosphatidylcholine; PE, phosphoethanolamine; DEPE, 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine; DOPC, 1,2-dioleyl-sn-glycero-3-phosphatidylcholine; 2OHOA, 2-hydroxyoleic acid; OA, oleic acid; SA, stearic acid; EA, elaidic acid; FA, fatty acid; sFA, synthetic fatty acid; Lβ, gel lamellar phase, Lα, liquid lamellar phase; HII, inverted hexagonal phase; Tm, gel-to-liquid lamellar phase transition temperature; TH, lamellar-to-hexagonal phase transition temperatures; PKC, protein kinase C
PL, phospholipid; PC, phosphatidylcholine; PE, phosphoethanolamine; DEPE, 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine; DOPC, 1,2-dioleyl-sn-glycero-3-phosphatidylcholine; 2OHOA, 2-hydroxyoleic acid; OA, oleic acid; SA, stearic acid; EA, elaidic acid; FA, fatty acid; sFA, synthetic fatty acid; Lβ, gel lamellar phase, Lα, liquid lamellar phase; HII, inverted hexagonal phase; Tm, gel-to-liquid lamellar phase transition temperature; TH, lamellar-to-hexagonal phase transition temperatures; PKC, protein kinase C
